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>>WE WOULD LIKE TO WELCOME

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YOU AND THANK YOU FOR JOINING US

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TO THE YET TO BE CHARTED

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WORKSHOP WITH THE EMPHASIS ON

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LYMPHATIC SYSTEM IN HEALTH AND

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DISEASE.

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LAST YEAR'S SUCCESSFUL WORKSHOP

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IS AVAILABLE ON DEMAND IN NIH

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VIDEO WEBSITE.

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WE WOULD LIKE TO WELCOME

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SPEAKERS, MODERATORS AND OVER

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700 REGISTRANTS WITH A GREAT

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COVERAGE OF ALL STAKEHOLDERS

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INCLUDING ACADEMIA, GOVERNMENT

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AND INDUSTRY RESEARCHERS,

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CLINICIANS, AND PATIENT AND

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PATIENT CAREGIVERS WHO REPRESENT

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10% OF OUR REGISTRANTS.

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WE ARE OVERWHELMED BY THE GREAT

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RESPONSE WE RECEIVED AND HOPE TO

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LIVE UP TO THE EXPECTATIONS OF

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THE LYMPHATIC COMMUNITY AND HAVE

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A SUCCESSFUL TWO-DAY WORKSHOP.

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I'LL START BY BRIEF HOUSEKEEPING

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ANNOUNCEMENTS.

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THIS WORKSHOP IS RECORDED AND

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WILL BE AVAILABLE FOR EVERYONE

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IN PERPETUITY IN NIH VIDEOCAST

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COLLECTION.

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THE LINKS FOR THE VIDEOCAST

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RECORDING ALONG WITH THE

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DETAILED INFORMATION OF ALL

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SPEAKERS CAN BE FOUND ON THE

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REGISTRATION PAGE.

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DURING THE WORKSHOP, THE

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SPEAKERS WILL PRESENT THEIR

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TALKS AND THEY WILL ANSWER THE

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QUESTIONS AS A PANEL AT THE END

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OF EVERY SESSION THAT WILL BE

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LED BY THE SESSION MODERATOR.

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PLEASE SUBMIT YOUR QUESTIONS

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BOTH ZOOM AND VIDEOCAST

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ATTENDEES, PUT YOUR QUESTIONS IN

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THE Q & A AND THE MODERATOR
WILL

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READ AND DIRECT YOUR QUESTIONS

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TO THE PANELISTS.

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AND WE REQUEST THAT OUR SPEAKERS

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SHOULD RAISE THEIR HANDS AND

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WHEN YOU ARE CALLED, UNMUTE AND

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ASK YOUR QUESTION LIVE.

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NEXT I WOULD LIKE TO INTRODUCE

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AND THANK TO ALL OUR ORGANIZING

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COMMITTEE WHO WORKED TIRELESSLY

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TO PUT TOGETHER THIS EXCITING

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AGENDA OF THE WORKSHOP.

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DR. RANDOLPH FROM WASHINGTON

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UNIVERSITY, NIDDK, NATIONAL

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HEART, LUNG AND BLOOD INSTITUTE

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AND OUR WONDERFUL CHAIRS.

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WITHOUT FURTHER ADO, I WOULD

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LIKE TO PASS THE MIC TO OUR

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CHAIRS.

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>> THANK YOU.

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GOOD MORNING AND WELCOME,

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EVERYONE.

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MY NAME IS BABAK MEHRARA, I'M A

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SURGEON SCIENTIST AT MEMORIAL

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SLOAN KETTERING SCIENCE CENTER.

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>> GOOD MORNING AND
WELCOME.

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I'M ANDREA RADTKE.

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MY RESEARCH FOCUSES AT THE

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DEVELOPMENT AND APPLICATION OF

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TECHNOLOGIES THAT ENABLE

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DETAILED SPATIAL MAPPING OF

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CELLS AND STRUCTURES WITHIN

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HUMAN LYMPHOID ORGANS.

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>> WE ARE HONORED THAT YOU
CAN

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JOIN US FOR THE YET TO BE

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CHARTED LYMPHATIC SYSTEM IN

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HEALTH AND DISEASE SEMINAR.

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THE PRIMARY OBJECTIVE OF THIS

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MEETING IS TO ADVANCE OUR

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UNDERSTANDING OF HOW THE

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LYMPHATIC SYSTEM DEVELOPS,

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FUNCTIONS IN HEALTH AND DISEASE

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AND MOST IMPORTANTLY HOW THE

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DISSEMINATION OF THIS KNOWLEDGE

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MAY IMPROVE HOW WE TREAT

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LYMPHATIC DISORDERS.

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A SPECIAL FOCUS HAS BEEN PLACED

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ON LYMPHEDEMA AND THE ROLE OF

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LIX IN    

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LYMPHATICS IN OBESITY.

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>> WE ARE HAVE A POSTURE
OF

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GRATITUDE, WE ARE SO GRATEFUL

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FOR THE DEDICATION IN CREATIVITY

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AND PLANNING FOR THIS WORKSHOP.

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WE WANT TO THANK NHLBI AND

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NIDDK.

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WE WANT TO NOTE THAT GWEN IS

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UNABLE TO ATTEND DUE TO A

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SCHEDULING CONFLICT BUT WE ARE

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GRATEFUL FOR HER EXCELLENT

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CONTRIBUTIONS.

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WE'D ALSO LIKE TO THANK THE

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TRANS-NIH LYMPHATIC COORDINATING

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COMMITTEE AND, OF COURSE,

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DR. ZORINA GALIS.

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ZORINA IS ONE OF THE VISIONARIES

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BEHIND MANY TRANS-NIH

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INITIATIVES AND INVOLVED IN

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ADVANCING OUR UNDERSTANDING OF

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THE HUMAN BODY.

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>> WE WANT TO THANK THE
SPEAKERS

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FOR THEIR COMMITMENT TO THE

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FIELD AND PRESENTING THEIR WORK.

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WE KNOW THIS IS A LOT OF WORK

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AND PUTTING TOGETHER ANOTHER

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TALK IS JUST ONE MORE THING BUT

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WE WANT TO THANK THEM FOR DOING

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SO.

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ALSO THE LYMPHATIC EDUCATION AND

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RESEARCH NETWORK AND ALL THE

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ADVOCACY GROUPS INVOLVED FOR

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THEIR TIEFERLESS       TIRELESS.

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LASTLY THANKS TO CAMERON,

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CASSIE, CYNTHIA AND TAYLOR WHO

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WILL SHARE THEIR PERSONAL

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STORIES WITH ALL OF YOU

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TOMORROW.

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THANK YOU ALL FOR YOUR

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COMMITMENT AND COMPASSION FOR

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LYMPHATIC RESEARCH.

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WE'RE HUMBLED TO WELCOME OVER

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700 REGISTRANTS

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>> THE SELECTION OF TOPICS
AS A

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MULTIDISCIPLINARY EFFORT IS

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REQUIRED TO ADVANCE THE FIELD.

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FURTHERMORE, IT IS IMPERATIVE

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THAT WE HEAR FROM PATIENTS,

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CLINICIANS, PROGRAM DIRECTORS,

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JUNIOR AND SENIOR INVESTIGATORS,

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AND ALL 700 OF YOU.

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THE NAME OF THE SYMPOSIUM, YET

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TO BE CHARTED, IS DELIBERATE AS

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THE LYMPHATIC SYSTEM REPRESENTS

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ONE OF THE LAST FRONTIERS OF

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ANATOMICAL MEDICINE.

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FURTHERMORE, A MAJOR THEME OF

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THIS MEETING IS CREATING A

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USABLE MAP FOR RESEARCHERS AND

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CLINICIANS, A MAP, IT IS SAID,

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ORGANIZES WONDER, AND THE

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LYMPHATIC SYSTEM IS TRULY

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WONDER-FILLED.

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FIRST FUNCTIONS AND MOST ORGANS

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AND TISSUES OF THE HUMAN BODY,

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TRANSPORTS A THOUSAND-PLUS

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PROTEINS IN LYMPH FLUID ALONE

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AND MOST IMPORTANTLY, NEGATIVELY

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IMPACTS THE LIVES OF HUNDREDS OF

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MILLIONS OF PEOPLE SUFFERING

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FROM LYMPHATIC DISEASES AROUND

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THE WORLD.

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TODAY WE WILL HEAR FROM JUST

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FOUR OF THESE PATIENTS.

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>> WE CLOSE BY WELCOMING
YOU TO

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THIS EXCITING MEETING AND THANK

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YOU FOR YOUR TIME.

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PLEASE JOIN US IN WELCOMING BACK

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DR. PATRICIA GREENWEL FROM THE

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DIVISION OF DIGESTIVE DISEASE

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AND NUTRITION, THE NIDDK.

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THANK YOU SO MUCH FOR HAVING US.

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>> HELLO, GOOD MORNING.

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I WOULD LIKE TO INTRODUCE

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DR. STEVE JAMES, DIRECTOR OF THE

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DIVISION OF DIGESTIVE DISEASES

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AND NUTRITION, NIDDK.

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STEVE?

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>> CAN YOU HEAR ME?

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I JUST LOGGED IN.

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THANK YOU.

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WELCOME, ALL OF YOU, WHEREVER

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YOU MAY BE TO THIS VERY EXCITING

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MEETING.

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THE NIDDK AND NHLBI HAVE

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CO-SPONSORED THIS WORKSHOP, AND

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IT'S REALLY OUR PLEASURE TO

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WELCOME YOU.

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THE LYMPHATIC SYSTEM IS A

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COMPLEX AND INTRICATE NETWORK OF

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CAPILLARES      

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KAIB LARRYS AND VESSELS THAT

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PERMEATE NEARLY EVERY ORGAN OF

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THE BODY.

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THEY'RE DYNAMIC AND PLAY

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CRITICAL AND ACTIVE ROLES IN

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MAINTENANCE OF FLUID

200
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HOMEOSTASIS, TRAFFICKING AND

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MATURATION OF THE IMMUNE CELLS,

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ABSORPTION OF KEY NUTRIENTS,

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SELECTIVE TRANSPORT OF SOME

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HORMONES, AND MODULATION OF

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INFLAMMATORY RESPONSES.

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ALTERATIONS IN THE LYMPHATIC

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SYSTEM INCLUDING ENHANCED

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PROLIFERATION AND IN SOME

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INSTANCES MORPHOLOGICAL CHANGES

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HAVE BEEN OBSERVED IN MANY

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DISEASE STATES.

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SOME OF THESE CHANGES ARE

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CONGENITAL AND OTHERS DEVELOP AS

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A RESULT OF DISEASE OR INJURY.

215
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IN THE UNITED STATES, SEVERAL

216
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MILLION AMERICANS SUFFER FROM

217
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LYMPHEDEMA AND OTHER DISEASES.

218
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THERE'S AN ENORMOUS RENEWAL OF

219
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INTEREST IN   AND THE IMPORTANCF

220
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LYMPHATICS -- TO NOW INCLUDE

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ACUTE AND CHRONIC INFLAMMATION.

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MORE GENERALLY.

223
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THE DIGESTIVE SYSTEM CRITICALLY

224
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DEPENDS ON ADEQUATE LYMPHATIC

225
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FUNCTION.

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ABOUT 70% OF THE TOTAL LYMPH

227
00:08:14,200 --> 00:08:15,120
FORMED IN THE BODY ORIGINATES IN

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THE SMALL INTESTINE AND LIVER.

229
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DEFECTS IN GASTROINTESTINAL

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LYMPHATIC DEVELOPMENT AND

231
00:08:23,160 --> 00:08:26,240
STRUCTURE, LYMPH PUMP FUNCTION

232
00:08:26,240 --> 00:08:27,320
OR REMODELING PRODUCE SEVERAL

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FORMS OF GI PATHOLOGY, AND

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EXACERBATE G.I. INJURY.

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MALFUNCTIONS IN THE LYMPHATIC

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SYSTEM HAVE BEEN IMPLICATED IN

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SEVERAL DISEASE STATES, SUCH AS

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OBESITY, METABOLIC SYNDROME,

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INFLAMMATORY BOWEL DISEASES,

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LIVER FIBROSIS AND CIRRHOSIS.

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A BETTER UNDERSTANDING OF THE

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LYMPHATIC SYSTEM IN HEALTH AND

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DISEASE STATES COULD LEAD TO THE

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DEVELOPMENT OF NOVEL THERAPIES

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FOR MANY OF THESE CONDITIONS.

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LYMPHATICS RESEARCH HAS BEEN A

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PRIORITY AREA FOR NIDDK FOR

248
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SEVERAL YEARS.

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NIDDK HAS PARTICIPATED IN

250
00:09:01,240 --> 00:09:02,520
SEVERAL NIH-WIDE ACTIVITIES TO

251
00:09:02,520 --> 00:09:05,520
ENCOURAGE THE STUDY OF

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LYMPHATICS IN HEALTH AND DISEASE

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INCLUDE WORKSHOPS AND SEVERAL

254
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FUNDING OPPORTUNITY

255
00:09:09,120 --> 00:09:10,280
ANNOUNCEMENTS.

256
00:09:10,280 --> 00:09:12,360
OVERALL, THESE INITIATIVES HAVE

257
00:09:12,360 --> 00:09:13,680
BEEN QUITE SUCCESSFUL AND OUR

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00:09:13,680 --> 00:09:14,920
GRANT PORTFOLIO IN THIS AREA HAS

259
00:09:14,920 --> 00:09:16,000
MORE THAN DOUBLED IN THE LAST

260
00:09:16,000 --> 00:09:17,640
FIVE YEARS.

261
00:09:17,640 --> 00:09:19,600
OUR INITIATIVES HAVE RESULTED IN

262
00:09:19,600 --> 00:09:23,320
NEW INTERESTS FROM THE PART OF

263
00:09:23,320 --> 00:09:25,280
INVESTIGATORS AT NIDDK-RELATED

264
00:09:25,280 --> 00:09:28,880
TOPICS AND HAVE BEEN SPARCED NEW

265
00:09:28,880 --> 00:09:32,200
COLLABORATIONS AND GRANT

266
00:09:32,200 --> 00:09:33,840
APPLICATIONS IN AREAS SUCH AS

267
00:09:33,840 --> 00:09:35,480
LYMPHATICS DEVELOPMENT,

268
00:09:35,480 --> 00:09:36,320
REMODELING AND FUNCTION IN

269
00:09:36,320 --> 00:09:37,520
HEALTH AND DISEASE OF THE

270
00:09:37,520 --> 00:09:39,000
DIGESTIVE SYSTEM, THE ROLE OF

271
00:09:39,000 --> 00:09:40,960
LYMPHATICS IN OBESITY AND

272
00:09:40,960 --> 00:09:43,120
METABOLIC SYNDROME, AND THE ROLE

273
00:09:43,120 --> 00:09:44,960
OF LYMPHATICS IN FAT AND OTHER

274
00:09:44,960 --> 00:09:46,760
NUTRIENT ABSORPTION.

275
00:09:46,760 --> 00:09:48,600
THE PURPOSE OF THIS TWO-DAY

276
00:09:48,600 --> 00:09:50,200
WORKSHOP IS TO BRING TOGETHER

277
00:09:50,200 --> 00:09:53,360
BASIC TRANSLATIONAL AND CLINICAL

278
00:09:53,360 --> 00:09:54,880
LYMPHATICS EXPERTS TO PRESENT

279
00:09:54,880 --> 00:09:56,480
THE LATEST ADVANCES IN THE

280
00:09:56,480 --> 00:09:58,080
FIELD, ENGAGE INTERDISCIPLINARY

281
00:09:58,080 --> 00:09:59,640
DISCUSSIONS, AND TO IDENTIFY

282
00:09:59,640 --> 00:10:02,480
KNOWLEDGE GAPS AND OPPORTUNITIES

283
00:10:02,480 --> 00:10:02,920
IN THE FIELD.

284
00:10:02,920 --> 00:10:06,880
WE HOPE THIS EEFNTD     EVENT WD

285
00:10:06,880 --> 00:10:11,120
COLLABORATIVE PARTNERSHIPS AMONG

286
00:10:11,120 --> 00:10:11,680
MANY.

287
00:10:11,680 --> 00:10:13,400
I PARTICULARLY WANT TO THANK THE

288
00:10:13,400 --> 00:10:23,920
COORGANIZERS OF THE WORKSHOP,

289
00:10:24,200 --> 00:10:29,720
AND THE PROGRAM STAFF FROM

290
00:10:29,720 --> 00:10:33,080
NHLBI, AND PATRICIA GREENWEL FRP

291
00:10:33,080 --> 00:10:33,280
NIDDK.

292
00:10:33,280 --> 00:10:35,280
I ALSO WANT TO THANK THE MANY

293
00:10:35,280 --> 00:10:36,320
SPEAKERS WHO WILL INFORM US

294
00:10:36,320 --> 00:10:38,480
ABOUT THE LATEST ADVANCES AND

295
00:10:38,480 --> 00:10:39,120
IMPORTANTLY REPRESENTATIVES WHO

296
00:10:39,120 --> 00:10:41,200
WILL TELL US ABOUT THE

297
00:10:41,200 --> 00:10:42,040
PERSPECTIVE OF PATIENTS AND

298
00:10:42,040 --> 00:10:43,160
THEIR FAMILIES.

299
00:10:43,160 --> 00:10:50,000
I'LL NOW TURN THE MEETING BACK

300
00:10:50,000 --> 00:10:51,240
TO DR. ROVIRA.

301
00:10:51,240 --> 00:10:51,560
THANK YOU.

302
00:10:51,560 --> 00:10:54,120
>> TODAY I HAVE THE
PLEASURE TO

303
00:10:54,120 --> 00:10:56,520
INTRODUCE DR. ZORINA GALIS,

304
00:10:56,520 --> 00:10:59,680
CHIEF OF VASCULAR BIOLOGY AND

305
00:10:59,680 --> 00:11:01,000
HYPERTENSION BRANCH AT NHLBI.

306
00:11:01,000 --> 00:11:02,200
DR. GA LIST HAS EXTENSIVE

307
00:11:02,200 --> 00:11:05,560
EXPERIENCE IN ACADEMIA INDUSTRY

308
00:11:05,560 --> 00:11:07,880
AND GOVERNMENT, AND HER CAREER

309
00:11:07,880 --> 00:11:08,520
CONTRIBUTIONS REFLECT HER SPIRIT

310
00:11:08,520 --> 00:11:09,960
OF INNOVATION AND DEVOTION TO

311
00:11:09,960 --> 00:11:10,200
SERVICE.

312
00:11:10,200 --> 00:11:11,880
IT IS MY HONOR TO INTRODUCE

313
00:11:11,880 --> 00:11:12,440
DR. ZORINA GALIS.

314
00:11:12,440 --> 00:11:13,000
THANK YOU.

315
00:11:13,000 --> 00:11:15,160
>> THANK YOU SO MUCH,
ILSA, AND

316
00:11:15,160 --> 00:11:16,040
THANK YOU AGAIN, EVERYONE.

317
00:11:16,040 --> 00:11:17,800
I DON'T WANT TO REPEAT ALL THE

318
00:11:17,800 --> 00:11:19,000
THANKS, I THINK IT'S VERY

319
00:11:19,000 --> 00:11:23,240
OBVIOUS THAT IT TAKES A HUGE

320
00:11:23,240 --> 00:11:26,480
TEAM AND HUGE EFFORT TO ORGANIZE

321
00:11:26,480 --> 00:11:29,800
SUCH MEETINGS AND I AM SO

322
00:11:29,800 --> 00:11:32,000
GRATEFUL THAT WE WERE ABLE TO BE

323
00:11:32,000 --> 00:11:33,560
INTERESTING TO SO MANY PEOPLE

324
00:11:33,560 --> 00:11:38,240
WHO ARE GOING TO HELP US FORWARD

325
00:11:38,240 --> 00:11:38,800
RESEARCHING THIS FIELD.

326
00:11:38,800 --> 00:11:40,960
I WOULD LIKE TO SHOW YOU SOME

327
00:11:40,960 --> 00:11:42,160
SLIDES, SO HOPEFULLY I AM ABLE

328
00:11:42,160 --> 00:11:52,520
TO SHARE MY SCREEN.

329
00:11:58,120 --> 00:12:02,400
SO I WANTED TO JUST BRIEFLY

330
00:12:02,400 --> 00:12:04,040
RE-INTRODUCE THE IDEA THAT NIH

331
00:12:04,040 --> 00:12:06,600
IS REALLY DEDICATED TO

332
00:12:06,600 --> 00:12:08,160
SUPPORTING THE LYMPHATIC

333
00:12:08,160 --> 00:12:10,000
RESEARCH, AS WELL AS MANY OTHER

334
00:12:10,000 --> 00:12:12,240
TOPICS, BUT WE ARE HERE TO

335
00:12:12,240 --> 00:12:14,080
CELEBRATE AND TO FIND OUT WHAT

336
00:12:14,080 --> 00:12:17,400
ELSE WE CAN DO IN ADVANCING THE

337
00:12:17,400 --> 00:12:19,600
CURRENT KNOWLEDGE ABOUT THE

338
00:12:19,600 --> 00:12:23,640
LYMPHATIC SYSTEM.

339
00:12:23,640 --> 00:12:25,600
SO MANY OF YOU ALREADY KNOW THAT

340
00:12:25,600 --> 00:12:30,160
NIH IS HART OF     PART OF HHS .

341
00:12:30,160 --> 00:12:31,840
GOVERNMENT AND THEREFORE WE ARE

342
00:12:31,840 --> 00:12:33,160
RESPONSIBLE TO THE TAXPAYERS FOR

343
00:12:33,160 --> 00:12:38,200
WHAT WE DO WITH THE INVESTMENTS.

344
00:12:38,200 --> 00:12:39,480
THIS SLIDE REPRESENTS THE

345
00:12:39,480 --> 00:12:43,480
BUDGETS THAT ARE ALLOCATED TO

346
00:12:43,480 --> 00:12:45,960
NIH, AND IT'S THE 2021 BUDGET

347
00:12:45,960 --> 00:12:48,880
BECAUSE THAT'S ALREADY CLOSED

348
00:12:48,880 --> 00:12:52,520
THE BOOKS.

349
00:12:52,520 --> 00:12:53,080
THE HEART, LUNG AND BLOOD

350
00:12:53,080 --> 00:12:55,320
INSTITUTE IN TERMS OF FUNDING IS

351
00:12:55,320 --> 00:13:00,720
RANKING CURRENTLY AS THE FOURTH

352
00:13:00,720 --> 00:13:02,000
OF THE 27 DIFFERENT INSTITUTES

353
00:13:02,000 --> 00:13:02,760
AND CENTERS.

354
00:13:02,760 --> 00:13:04,320
WE RECEIVE A LOT OF QUESTIONS

355
00:13:04,320 --> 00:13:07,720
AND FEEDBACK FROM POTENTIAL

356
00:13:07,720 --> 00:13:08,920
APPLICANTS, GRANTEES AND SO

357
00:13:08,920 --> 00:13:11,000
FORTH, SO I THOUGHT I WILL TRY

358
00:13:11,000 --> 00:13:12,320
TO BRIEFLY RESPOND TO SOME OF

359
00:13:12,320 --> 00:13:14,200
THESE QUESTIONS DURING MY TALK

360
00:13:14,200 --> 00:13:15,600
AND SOME OF YOU ARE VERY

361
00:13:15,600 --> 00:13:17,800
FAMILIAR WITH THE ANSWERS, FOR

362
00:13:17,800 --> 00:13:19,640
SOME OF YOU, THIS MAY BE AN EYE

363
00:13:19,640 --> 00:13:22,720
OPENER AND IT WILL HELP

364
00:13:22,720 --> 00:13:24,320
HOPEFULLY PROVIDE MORE

365
00:13:24,320 --> 00:13:25,320
INFORMATION ABOUT WHAT YOU NEED

366
00:13:25,320 --> 00:13:27,160
TO KNOW.

367
00:13:27,160 --> 00:13:29,600
THE MOST COMMON QUESTIONS WITH

368
00:13:29,600 --> 00:13:33,320
OUR INSTITUTE OR NIDDK OR MAYBE

369
00:13:33,320 --> 00:13:35,520
NIAID OR WHICH INSTITUTE IS

370
00:13:35,520 --> 00:13:38,000
INTERESTED IN THE PROPOSAL

371
00:13:38,000 --> 00:13:39,440
SOMEBODY IS THINKING ABOUT

372
00:13:39,440 --> 00:13:40,920
APPLYING, WHAT PEER REVIEW

373
00:13:40,920 --> 00:13:43,720
SECTION MIGHT REVIEW IT, WHO

374
00:13:43,720 --> 00:13:46,640
COULD THEY TALK TO AT NIH IF

375
00:13:46,640 --> 00:13:51,040
ANYBODY TO FIND OUT HOW TO MOVE

376
00:13:51,040 --> 00:13:52,120
FORWARD WITH THEIR APPLICATIONS.

377
00:13:52,120 --> 00:13:53,320
AND OF COURSE A LOT OF PEOPLE

378
00:13:53,320 --> 00:13:55,400
ARE VERY INTERESTED IN HOW MUCH

379
00:13:55,400 --> 00:13:58,240
MONEY IS NIH OR ANY SPECIFIC

380
00:13:58,240 --> 00:13:59,880
INSTITUTE INVESTING IN LYMPHATIC

381
00:13:59,880 --> 00:14:01,120
RESEARCH AND WHETHER WE HAVE

382
00:14:01,120 --> 00:14:04,160
SPECIFIC INITIATIVES TO HELP

383
00:14:04,160 --> 00:14:05,040
WITH THAT.

384
00:14:05,040 --> 00:14:06,760
THAT IS A TOOL THAT IN THIS DAY

385
00:14:06,760 --> 00:14:08,760
AND AGE, I'M SURE EVERYBODY WILL

386
00:14:08,760 --> 00:14:12,480
BE VERY HAPPY TO KNOW IS AT

387
00:14:12,480 --> 00:14:13,240
THEIR FINGERTIPS.

388
00:14:13,240 --> 00:14:15,880
IT'S CALLED THE NIH MATCH MAKER,

389
00:14:15,880 --> 00:14:19,920
AND YOU CAN JUST PUT IN YOUR

390
00:14:19,920 --> 00:14:22,320
PROPOSAL, YOUR SPECIFIC AIMS, OR

391
00:14:22,320 --> 00:14:23,600
SUMMARY, A POSTER, ANY TYPE OF

392
00:14:23,600 --> 00:14:27,640
TEXT THAT DEVIBES WHAT YOU     S

393
00:14:27,640 --> 00:14:29,200
WHAT YOU INTEND TO DO AND BY

394
00:14:29,200 --> 00:14:30,400
PRESSING THE BUTTON YOU CAN

395
00:14:30,400 --> 00:14:31,840
IMMEDIATELY SEE WHICH INSTITUTE

396
00:14:31,840 --> 00:14:33,480
MIGHT BE MOST IMMEDIATELY

397
00:14:33,480 --> 00:14:35,200
INTERESTED IN YOUR RESEARCH,

398
00:14:35,200 --> 00:14:36,720
WHAT MECHANISM YOU MIGHT WANT TO

399
00:14:36,720 --> 00:14:37,400
USE, BUT AT THE SAME TIME, YOU

400
00:14:37,400 --> 00:14:38,840
CAN ALSO FIND OUT WHAT IS THE

401
00:14:38,840 --> 00:14:41,560
SIMILAR RESEARCH AND WHO IS

402
00:14:41,560 --> 00:14:43,760
PERFORMING IT AT VARIOUS

403
00:14:43,760 --> 00:14:46,040
INSTITUTES ACROSS THE U.S. OF A

404
00:14:46,040 --> 00:14:47,600
THAT CAN HELP YOU FIND

405
00:14:47,600 --> 00:14:49,400
COLLABORATORS YOU MAY NEED IN

406
00:14:49,400 --> 00:14:50,520
ORDER TO PUT IN YOUR OWN

407
00:14:50,520 --> 00:14:53,160
APPLICATION.

408
00:14:53,160 --> 00:14:54,040
ANOTHER IMPORTANT QUESTION IS,

409
00:14:54,040 --> 00:14:57,000
WHO IS GOING TO REVIEW, WHICH

410
00:14:57,000 --> 00:14:59,160
STUDY SECTION IS GOING TO REVIEW

411
00:14:59,160 --> 00:15:00,840
YOUR APPLICATION AND YOU'LL FIND

412
00:15:00,840 --> 00:15:05,480
OUT THAT THERE IS A REVIEW ART

413
00:15:05,480 --> 00:15:07,400
WHICH IS ASSISTIVE REFERRAL TOOL

414
00:15:07,400 --> 00:15:09,120
THAT YOU CAN USE AND YOU CAN BE

415
00:15:09,120 --> 00:15:10,840
MATCHED WITH VARIOUS SCIENTIFIC

416
00:15:10,840 --> 00:15:11,880
APPLICATIONS AND YOU CAN ALSO

417
00:15:11,880 --> 00:15:16,000
FIND OUT WHO IS RUNNING THAT

418
00:15:16,000 --> 00:15:16,880
PEER REVIEW SECTION AND CALL

419
00:15:16,880 --> 00:15:18,960
THEM FOR HELP.

420
00:15:18,960 --> 00:15:20,400
MANY OF YOU MAY KNOW THIS

421
00:15:20,400 --> 00:15:22,360
ALREADY, BUT I'VE BEEN A GRANTEE

422
00:15:22,360 --> 00:15:23,800
MYSELF AND SOMETIMES THE NIH

423
00:15:23,800 --> 00:15:25,640
LOOKS LIKE A BLACK BOX.

424
00:15:25,640 --> 00:15:26,840
YOU SEND IN YOUR APPLICATION,

425
00:15:26,840 --> 00:15:28,720
YOU HAVE NO IDEA WHAT'S

426
00:15:28,720 --> 00:15:31,320
HAPPENING TO IT, WHERE IS IT, AT

427
00:15:31,320 --> 00:15:31,720
WHICH POINT.

428
00:15:31,720 --> 00:15:33,400
SO ONCE YOU SUBMIT YOUR

429
00:15:33,400 --> 00:15:36,480
APPLICATION, IT GOES TO A CENTER

430
00:15:36,480 --> 00:15:38,680
FOR SCIENTIFIC REVIEW, WHICH IS

431
00:15:38,680 --> 00:15:41,600
SEPARATE FROM ALL THE OTHER

432
00:15:41,600 --> 00:15:42,880
INSTITUTES, AND THAT WILL ASSIGN

433
00:15:42,880 --> 00:15:46,640
TO THE REVIEW SECTION AS WELL TO

434
00:15:46,640 --> 00:15:49,600
INSTITUTE THAT SEEMS MOST LIKELY

435
00:15:49,600 --> 00:15:50,920
TO MATCH THE INTENT OF THE

436
00:15:50,920 --> 00:15:58,000
APPLICATION.

437
00:15:58,000 --> 00:16:00,760
SO YOU AS AN APPLICANT GOING TO

438
00:16:00,760 --> 00:16:02,400
FIND OUT WHAT THE SCORE IS, THE

439
00:16:02,400 --> 00:16:06,240
SCORE IS GOING TO BE REVIEWED BY

440
00:16:06,240 --> 00:16:08,280
THE SCIENTIFIC COUNCIL OR THE

441
00:16:08,280 --> 00:16:10,680
SPECIFIC INSTITUTE I EXEMPLIFY

442
00:16:10,680 --> 00:16:11,880
HERE IN NHLBI.

443
00:16:11,880 --> 00:16:13,880
AND YOU'LL FIND OUT AND LUCKILY

444
00:16:13,880 --> 00:16:15,400
YOU TURNED INTO POTENTIALLY A

445
00:16:15,400 --> 00:16:18,040
P.I. WHO HAS BEEN FUNDED, AND SO

446
00:16:18,040 --> 00:16:22,080
AT THIS POINT IN TIME, YOU FIND

447
00:16:22,080 --> 00:16:24,920
OUT ALSO HOW MUCH MONEY WAS

448
00:16:24,920 --> 00:16:27,640
APPROVED FOR YOUR RESEARCH.

449
00:16:27,640 --> 00:16:29,520
DURING THIS PROCESS, YOU

450
00:16:29,520 --> 00:16:31,800
COMMUNICATE HOPEFULLY WITH THE

451
00:16:31,800 --> 00:16:35,240
PERSON WHO LEADS THE REVIEW,

452
00:16:35,240 --> 00:16:37,840
WHICH IS THE SCIENTIFIC REVIEW

453
00:16:37,840 --> 00:16:39,680
OFFICER, WITH THE ASSIGNED

454
00:16:39,680 --> 00:16:41,680
PROGRAM OFFICER AND WITH THE

455
00:16:41,680 --> 00:16:47,680
GRANTS MANAGER AND ACTUALLY THEY

456
00:16:47,680 --> 00:16:49,960
HAVE EXPERTISE TO ADVISE YOU ON

457
00:16:49,960 --> 00:16:51,720
WHAT'S NEEDED TO BE APPROVED AND

458
00:16:51,720 --> 00:16:54,000
INITIATE YOUR WORK, ANY MONEY OR

459
00:16:54,000 --> 00:16:56,760
TIMELINE OR APPROVAL QUESTIONS,

460
00:16:56,760 --> 00:16:58,680
THEY ARE THE BEST TO ANSWER.

461
00:16:58,680 --> 00:17:00,240
SO THIS PROCESS IS ACTUALLY A

462
00:17:00,240 --> 00:17:01,680
PRETTY LONG PROCESS.

463
00:17:01,680 --> 00:17:04,200
IT TAKES IN THE BEST CASE

464
00:17:04,200 --> 00:17:04,600
SCENARIO 10 MONTHS.

465
00:17:04,600 --> 00:17:06,040
IN THE BEGINNING, YOU ARE IN

466
00:17:06,040 --> 00:17:08,240
WHAT THEY CALL REVIEWLAND AND

467
00:17:08,240 --> 00:17:09,640
YOU ARE IN PROGRAMLAND.

468
00:17:09,640 --> 00:17:11,200
AT ANY TIME, THOUGH, THERE IS

469
00:17:11,200 --> 00:17:12,720
STILL THE HUMAN TOUCH AND THERE

470
00:17:12,720 --> 00:17:14,920
IS THIS MYSTERIOUS RED PHONE WE

471
00:17:14,920 --> 00:17:17,000
HAVE AT NIH, WE NEVER KNEW

472
00:17:17,000 --> 00:17:18,520
EXACTLY WHAT'S THE SIGNIFICANCE

473
00:17:18,520 --> 00:17:22,800
OF THE RED COLOR, BUT IT'S A

474
00:17:22,800 --> 00:17:23,320
TOUCH PHONE.

475
00:17:23,320 --> 00:17:25,720
SO YOU CAN, ANY TIME, CALL THESE

476
00:17:25,720 --> 00:17:27,480
PEOPLE, YOU CAN ALSO SEND AN

477
00:17:27,480 --> 00:17:32,960
EMAIL AND MY FAVORITE EXAMPLE IS

478
00:17:32,960 --> 00:17:35,760
THIS EMAIL THAT I RECEIVED BASED

479
00:17:35,760 --> 00:17:39,720
ON SOMEBODY MATCHING THEIR IDEA

480
00:17:39,720 --> 00:17:41,480
WITH ME, I APPEARED AS THE FIRST

481
00:17:41,480 --> 00:17:43,560
MATCH, ALTHOUGH APPARENTLY NCI

482
00:17:43,560 --> 00:17:45,080
WOULD HAVE BEEN THE BEST

483
00:17:45,080 --> 00:17:46,520
INSTITUTE, BUT AS A PERSON

484
00:17:46,520 --> 00:17:48,600
HAVING SO MANY LYMPHATIC

485
00:17:48,600 --> 00:17:52,520
RESEARCH PROPOSALS, I GOT AN

486
00:17:52,520 --> 00:17:52,760
EMAIL.

487
00:17:52,760 --> 00:17:54,080
AS YOU CAN SEE, YOU CAN

488
00:17:54,080 --> 00:17:55,600
IMMEDIATELY GET MY EMAIL OR

489
00:17:55,600 --> 00:17:59,200
ANYBODY ELSE'S WHO MATCHES WITH

490
00:17:59,200 --> 00:18:04,000
YOU FROM DR. DHRUV SINGHAL

491
00:18:04,000 --> 00:18:08,840
APPLYING FOR HIS FIRST RSM R01 D

492
00:18:08,840 --> 00:18:11,080
WE HAD A VERY NICE EXCHANGE OF

493
00:18:11,080 --> 00:18:12,440
QUESTIONS AND ANSWERS AND HE

494
00:18:12,440 --> 00:18:13,640
APPLIED AND HE IS NOW OUR

495
00:18:13,640 --> 00:18:14,040
GRANTEE.

496
00:18:14,040 --> 00:18:15,560
WE DO HAVE A COMMITTEE THAT

497
00:18:15,560 --> 00:18:17,240
UNDERSTANDS THE FACT THAT SINCE

498
00:18:17,240 --> 00:18:21,080
LYMPHATIC RESEARCH TOUCHES SO

499
00:18:21,080 --> 00:18:23,360
MANY BODY ORGANS AND FUNCTIONS,

500
00:18:23,360 --> 00:18:26,680
AS WELL AS DISEASE, MAY BE

501
00:18:26,680 --> 00:18:28,200
SOMETIMES HARD TO PLACE THEM

502
00:18:28,200 --> 00:18:31,800
WITHIN THE NIH, SO OUR TRANS-NIH

503
00:18:31,800 --> 00:18:33,200
LYMPHATIC COORDINATING COMMITTEE

504
00:18:33,200 --> 00:18:36,080
HAS A LOT OF MEMBERS,

505
00:18:36,080 --> 00:18:37,360
INSTITUTES, AS WELL AS VERY

506
00:18:37,360 --> 00:18:40,320
IMPORTANTLY RECEIVES FEEDBACK

507
00:18:40,320 --> 00:18:42,600
FROM OUR GUEST SOCIETIES AND YOU

508
00:18:42,600 --> 00:18:46,440
CAN SEE HERE THE CURRENT MEMBERS

509
00:18:46,440 --> 00:18:51,240
AND GUESTS.

510
00:18:51,240 --> 00:18:55,080
YOU CAN IMAGINE THAT WE'RE

511
00:18:55,080 --> 00:18:56,040
MAINLY AN INFORMATION EXCHANGE,

512
00:18:56,040 --> 00:18:56,880
WE TRY TO MAKE SURE THAT

513
00:18:56,880 --> 00:18:58,480
EVERYBODY IS AWARE OF ALL THE

514
00:18:58,480 --> 00:19:00,040
OPPORTUNITIES AND THE LATEST

515
00:19:00,040 --> 00:19:02,720
INFORMATION IN TERMS OF SCIENCE,

516
00:19:02,720 --> 00:19:04,160
OF DATABASES AND OTHER THINGS,

517
00:19:04,160 --> 00:19:06,800
BUT WE ALSO WORK TOGETHER ON

518
00:19:06,800 --> 00:19:08,960
SPECIFIC INITIATIVES SUCH AS A

519
00:19:08,960 --> 00:19:12,000
COUPLE THAT I'M GOING TO

520
00:19:12,000 --> 00:19:13,160
EXEMPLIFY NOW.

521
00:19:13,160 --> 00:19:14,800
IN ORDER TO ANSWER THIS

522
00:19:14,800 --> 00:19:16,200
QUESTION, IT'S A VERY COMPLEX

523
00:19:16,200 --> 00:19:18,720
QUESTION ACTUALLY, HOW MUCH DOES

524
00:19:18,720 --> 00:19:22,440
NIH OR IN OUR CASE NHLBI INVEST

525
00:19:22,440 --> 00:19:24,440
IN LYMPHATIC RESEARCH, WE HAVE

526
00:19:24,440 --> 00:19:27,040
TO DRAW FROM A LOT OF

527
00:19:27,040 --> 00:19:27,800
INFORMATION.

528
00:19:27,800 --> 00:19:29,000
THIS INFORMATION AGAIN IS AT

529
00:19:29,000 --> 00:19:31,640
YOUR FINGERTIPS THROUGH THE NIH

530
00:19:31,640 --> 00:19:33,840
REPORT, OPEN ACCESS DATA AND

531
00:19:33,840 --> 00:19:35,800
TOOLS, AND THERE IS A SPECIFIC

532
00:19:35,800 --> 00:19:37,960
SECTION THAT IS CALLED RESEARCH

533
00:19:37,960 --> 00:19:41,360
CONDITION AND DISEASE

534
00:19:41,360 --> 00:19:42,760
CATEGORIZATION OR RCDC.

535
00:19:42,760 --> 00:19:43,560
IT'S IMPORTANT TO KNOW THAT

536
00:19:43,560 --> 00:19:46,600
THESE ARE NOT REPRESENTING

537
00:19:46,600 --> 00:19:47,400
STATIC NUMBERS.

538
00:19:47,400 --> 00:19:49,240
THEY REALLY EVOLVE WITH SCIENCE,

539
00:19:49,240 --> 00:19:52,200
BUDGET AND SO FORTH, AND THEY'RE

540
00:19:52,200 --> 00:19:53,840
ALSO NOT MUTUALLY EXCLUSIVE, AS

541
00:19:53,840 --> 00:19:56,360
IT'S VERY DIFFICULT TO PUT ANY

542
00:19:56,360 --> 00:19:58,400
RESEARCH PROPOSAL, ESPECIALLY

543
00:19:58,400 --> 00:20:00,920
ABOUT TOPICS SUCH AS LYMPHATIC

544
00:20:00,920 --> 00:20:02,880
RESEARCH, IN JUST ONE CATEGORY.

545
00:20:02,880 --> 00:20:05,320
SO WHAT I'M GOING TO SHOW YOU

546
00:20:05,320 --> 00:20:08,400
REPRESENTS OUR BEST EFFORT TO DO

547
00:20:08,400 --> 00:20:10,200
THIS THAT IS ASSIST BID MACHINE

548
00:20:10,200 --> 00:20:14,960
LEARNING      ASSISTED BY

549
00:20:14,960 --> 00:20:16,240
TECHNOLOGY AND OTHER

550
00:20:16,240 --> 00:20:17,360
TECHNOLOGIES NOW AVAILABLE.

551
00:20:17,360 --> 00:20:20,360
AS OF 2022, WE LAUNCHED TWO NEW

552
00:20:20,360 --> 00:20:30,040
RCD CCTT GRIS,       D CCTT    .

553
00:20:30,040 --> 00:20:31,800
THE CATEGORY ALREADY HAD ABOUT

554
00:20:31,800 --> 00:20:33,640
LYMPHOMA, SO AT ANY TIME

555
00:20:33,640 --> 00:20:36,280
LYMPHATIC RESEARCH SHOULD BE

556
00:20:36,280 --> 00:20:38,240
CONTAINING ONE OF THESE

557
00:20:38,240 --> 00:20:39,080
CATEGORIES, THIS IS JUST SHOWING

558
00:20:39,080 --> 00:20:42,880
SOME NUMBERS THAT ARE RELATED

559
00:20:42,880 --> 00:20:45,560
ONLY TO THE TYPE OF R01s, TYPE

560
00:20:45,560 --> 00:20:48,560
1 AND 2, THAT MEANS FIRST IN THE

561
00:20:48,560 --> 00:20:50,320
RENEWAL, AND THEY WILL COVER

562
00:20:50,320 --> 00:20:54,800
LYMPHATIC RESEARCH, INCLUDING

563
00:20:54,800 --> 00:20:56,400
LYMPHOMA OR NOT INCLUDING

564
00:20:56,400 --> 00:20:58,040
LYMPHOMA, AS WELL AS WE HAVE A

565
00:20:58,040 --> 00:21:03,720
SPECIAL CATEGORY ON LYMPHEDEMA

566
00:21:03,720 --> 00:21:04,240
NOW.

567
00:21:04,240 --> 00:21:05,400
I'M GOING TO SHOW YOU YOU CAN

568
00:21:05,400 --> 00:21:06,440
FIND MUCH MORE ABOUT THESE

569
00:21:06,440 --> 00:21:09,880
THINGS, NOT ONLY THE TOTAL

570
00:21:09,880 --> 00:21:10,720
AMOUNT, BUT WHAT TYPE OF

571
00:21:10,720 --> 00:21:12,360
MECHANISM IS USED, WHAT'S THE

572
00:21:12,360 --> 00:21:13,480
TITLE, WHO ARE THE

573
00:21:13,480 --> 00:21:14,280
INVESTIGATORS, WHAT'S THE AMOUNT

574
00:21:14,280 --> 00:21:15,640
OF FUNDING AND SO FORTH.

575
00:21:15,640 --> 00:21:17,400
SO I INVITE YOU TO PLEASE LOOK

576
00:21:17,400 --> 00:21:18,880
AT THESE.

577
00:21:18,880 --> 00:21:20,920
YOU CAN ALSO BREAK DOWN THE

578
00:21:20,920 --> 00:21:23,760
NUMBERS BY INSTITUTES, AND IF WE

579
00:21:23,760 --> 00:21:26,560
LOOK AT RESEARCH THAT INCLUDES

580
00:21:26,560 --> 00:21:28,160
LYMPHOMA, NCI IS ACTUALLY THE

581
00:21:28,160 --> 00:21:31,760
NUMBER ONE FUNDER OF LYMPHATIC

582
00:21:31,760 --> 00:21:32,000
RESEARCH.

583
00:21:32,000 --> 00:21:35,440
IF LYMPHOMA IS EXCLUDED, NHLBI,

584
00:21:35,440 --> 00:21:36,320
THE HEART, LUNG AND BLOOD

585
00:21:36,320 --> 00:21:37,480
INSTITUTE, IS THE NUMBER ONE

586
00:21:37,480 --> 00:21:39,480
FUNDER.

587
00:21:39,480 --> 00:21:43,880
BARS HERE REPRESENT -- THE DARK

588
00:21:43,880 --> 00:21:45,960
BAR REPRESENTS LYMPHATIC

589
00:21:45,960 --> 00:21:47,080
RESEARCH NOT INCLUDING LYMPHOMA

590
00:21:47,080 --> 00:21:49,240
AND THE ONE ABOVE INCLUDING

591
00:21:49,240 --> 00:21:49,520
LYMPHOMA.

592
00:21:49,520 --> 00:21:50,680
AS YOU CAN SEE OVERALL, THE

593
00:21:50,680 --> 00:21:51,440
TRENDS ARE UP.

594
00:21:51,440 --> 00:21:53,520
THE OTHER IMPORTANT QUESTION ON

595
00:21:53,520 --> 00:21:56,520
EVERYBODY'S MIND, AM I GOING TO

596
00:21:56,520 --> 00:21:58,120
BE SUCCESSFUL?

597
00:21:58,120 --> 00:22:01,280
AND WHAT'S SHOWN HERE IS THE

598
00:22:01,280 --> 00:22:03,800
SUCCESS OF LYMPHATIC RESEARCH --

599
00:22:03,800 --> 00:22:05,880
I'M SORRY, MY COMPUTER IS TOO

600
00:22:05,880 --> 00:22:06,240
JUMPY.

601
00:22:06,240 --> 00:22:08,160
ON THE LEFT SIDE, YOU CAN SEE

602
00:22:08,160 --> 00:22:11,000
THAT IT'S BEEN VARIABLE, BUT ON

603
00:22:11,000 --> 00:22:12,960
AVERAGE, IS ABOUT 30%, WHICH

604
00:22:12,960 --> 00:22:16,880
MEANS FOR THE FIRST APPLICATION

605
00:22:16,880 --> 00:22:19,040
AND RENEWAL, WHILE THE OVERALL

606
00:22:19,040 --> 00:22:22,840
SUCCESS OF R01s AT NIH HOVERS

607
00:22:22,840 --> 00:22:25,320
AROUND 20%.

608
00:22:25,320 --> 00:22:27,080
SO THE LYMPHATIC RESEARCH IS

609
00:22:27,080 --> 00:22:30,600
PRETTY WELL RECEIVED, AND

610
00:22:30,600 --> 00:22:31,920
FUNDED, BUT OF COURSE IT DEPENDS

611
00:22:31,920 --> 00:22:33,000
ON HOW MANY APPLICATIONS ARE

612
00:22:33,000 --> 00:22:34,400
RECEIVED.

613
00:22:34,400 --> 00:22:38,000
ONE BRIGHT SPOT I THINK WE WANT

614
00:22:38,000 --> 00:22:38,720
TO HIGHLIGHT IS THE FACT THAT

615
00:22:38,720 --> 00:22:40,320
THERE ARE A LOT OF YOUNG

616
00:22:40,320 --> 00:22:41,640
INVESTIGATORS WHO ARE INTERESTED

617
00:22:41,640 --> 00:22:42,520
IN LYMPHATIC RESEARCH.

618
00:22:42,520 --> 00:22:44,440
IF YOU LOOK HERE ON THE LEFT

619
00:22:44,440 --> 00:22:45,880
SIDE, I'LL TRY NOT TO ADVANCE

620
00:22:45,880 --> 00:22:50,040
SLIDE BY TOUCHING THE SCREEN,

621
00:22:50,040 --> 00:22:52,800
THE ESI REPRESENT ABOUT A THIRD

622
00:22:52,800 --> 00:22:54,520
OF ALL THE APPLICANTS AND THEIR

623
00:22:54,520 --> 00:22:55,520
RATE OF SUCCESS IS EVEN BETTER

624
00:22:55,520 --> 00:22:57,160
THAN THE NORMAL RATE OF SUCCESS,

625
00:22:57,160 --> 00:23:02,760
SO I'M INVITING ALL YOU NEW

626
00:23:02,760 --> 00:23:06,560
INVESTIGATORS TO APPLY.

627
00:23:06,560 --> 00:23:08,120
NHLBI HAS A SPECIAL PROGRAM BY

628
00:23:08,120 --> 00:23:10,240
WHICH YOU GET A 10-POINT BONUS

629
00:23:10,240 --> 00:23:13,120
IF YOU APPLY.

630
00:23:13,120 --> 00:23:17,960
ONE OF THESE APPLICANTS WAS

631
00:23:17,960 --> 00:23:18,640
DR. SINGHAL.

632
00:23:18,640 --> 00:23:20,040
HE DIDN'T NEED IT BUT IT'S OUT

633
00:23:20,040 --> 00:23:21,680
THERE TO INVITE ALL OF YOU AND

634
00:23:21,680 --> 00:23:22,880
ENHANCE THE NEW GENERATION OF

635
00:23:22,880 --> 00:23:23,560
RESEARCHERS.

636
00:23:23,560 --> 00:23:26,600
WE ALSO ARE VERY PROUD OF THE

637
00:23:26,600 --> 00:23:26,960
OUTPUTS.

638
00:23:26,960 --> 00:23:29,200
WE HAVE SUPPORTED A NUMBER OF

639
00:23:29,200 --> 00:23:30,440
CLINICAL TRIALS, PATENTS,

640
00:23:30,440 --> 00:23:32,520
DATASETS AND SO FORTH IN A LARGE

641
00:23:32,520 --> 00:23:34,080
NUMBER OF HIGHLY CITED

642
00:23:34,080 --> 00:23:37,440
PUBLICATIONS.

643
00:23:37,440 --> 00:23:41,280
THE OTHER QUESTION THAT'S VERY

644
00:23:41,280 --> 00:23:42,600
FREQUENTLY ON PEOPLE'S MIND IS

645
00:23:42,600 --> 00:23:43,800
WHETHER WE SUPPORT SPECIFIC

646
00:23:43,800 --> 00:23:45,600
INITIATIVES THAT ARE FOCUSED ON

647
00:23:45,600 --> 00:23:47,520
THE LYMPHATIC SYSTEM.

648
00:23:47,520 --> 00:23:50,240
ONE OF THESE INITIATIVES WHICH

649
00:23:50,240 --> 00:23:52,120
IS FOCUSED ACTUALLY ON MAPPING

650
00:23:52,120 --> 00:23:54,520
THE ENTIRE HUMAN BODY BUT NOW

651
00:23:54,520 --> 00:23:57,120
CONTAINS A LOT OF THE

652
00:23:57,120 --> 00:24:00,720
INFORMATION AND FUNDING TO MAP

653
00:24:00,720 --> 00:24:02,560
THE LYMPHATIC SYSTEM IS THE

654
00:24:02,560 --> 00:24:03,720
HUMAN BIOMOLECULAR ATLAS PROGRAM

655
00:24:03,720 --> 00:24:05,560
THAT IS DEVELOPING A FRAMEWORK

656
00:24:05,560 --> 00:24:11,160
ALLOWING US TO MAN THE     MAP N

657
00:24:11,160 --> 00:24:12,200
BODY FROM THE CLINICAL LEVEL ALL

658
00:24:12,200 --> 00:24:15,600
THE WAY TO THE SINGLE CELL

659
00:24:15,600 --> 00:24:17,480
RESOLUTION AND ADVANCE SCIENCE

660
00:24:17,480 --> 00:24:19,120
ACROSS THE HUMAN BODY.

661
00:24:19,120 --> 00:24:20,840
WE'RE DEVELOPING TECHNOLOGIES

662
00:24:20,840 --> 00:24:22,520
AND MOST IMPORTANTLY WE'RE

663
00:24:22,520 --> 00:24:24,480
DEVELOPING ALSO COLLABORATION

664
00:24:24,480 --> 00:24:28,880
ACROSS EXPERTISE DOMAIN AND

665
00:24:28,880 --> 00:24:31,280
ORGANS AND SO FORTH.

666
00:24:31,280 --> 00:24:36,800
SO THIS PROGRAM IS ONE OF THE

667
00:24:36,800 --> 00:24:37,600
INITIATIVES I'M VERY FAMILIAR

668
00:24:37,600 --> 00:24:39,680
WITH, I'VE BEEN INVOLVED IN

669
00:24:39,680 --> 00:24:41,120
LAUNCHING IT, AND I'M JUST GOING

670
00:24:41,120 --> 00:24:42,640
TO SHOW VERY QUICKLY THAT IT

671
00:24:42,640 --> 00:24:43,960
TAKES MANY, MANY YEARS TO

672
00:24:43,960 --> 00:24:46,360
DEVELOP SUCH INITIATIVES.

673
00:24:46,360 --> 00:24:49,200
WE INTENTIONALLY STARTED IN 2014

674
00:24:49,200 --> 00:24:51,480
WITH THE REQUEST TO MAP THE

675
00:24:51,480 --> 00:24:53,160
ENTIRE HUMAN VASCULATURE,

676
00:24:53,160 --> 00:24:55,440
INCLUDING THE LYMPHATICS, AND WE

677
00:24:55,440 --> 00:24:58,200
WENT THROUGH MANY DIFFERENT

678
00:24:58,200 --> 00:25:01,000
ITERATIONS AND FINALLY WE WERE

679
00:25:01,000 --> 00:25:05,400
APPROVED AS A PROGRAM THAT

680
00:25:05,400 --> 00:25:07,080
ACTUALLY DEVELOPS A MAP OF THE

681
00:25:07,080 --> 00:25:10,720
ENTIRE HUMAN BODY, AND THE FIRST

682
00:25:10,720 --> 00:25:11,640
CALL FOR APPLICATION WAS

683
00:25:11,640 --> 00:25:13,240
LAUNCHED IN 2018, SO IT TOOK

684
00:25:13,240 --> 00:25:16,360
FOUR YEARS TO GET THERE.

685
00:25:16,360 --> 00:25:17,200
INTERESTINGLY ENOUGH, WE JUST

686
00:25:17,200 --> 00:25:24,520
HAD THE LAST ROUND OF CALL TO

687
00:25:24,520 --> 00:25:25,720
APPLICATIONS AND WE RECEIVED

688
00:25:25,720 --> 00:25:26,480
AWARDS THAT WERE MADE IN

689
00:25:26,480 --> 00:25:30,240
SEPTEMBER OF THIS YEAR, SO VERY

690
00:25:30,240 --> 00:25:30,800
RECENTLY.

691
00:25:30,800 --> 00:25:31,960
WE BRING TOGETHER AS I SAID

692
00:25:31,960 --> 00:25:33,240
PEOPLE FROM ACROSS THE UNITED

693
00:25:33,240 --> 00:25:34,920
STATES AND SOMETIMES ACROSS THE

694
00:25:34,920 --> 00:25:38,520
WORLD IF SUCH CAPABILITIES ARE

695
00:25:38,520 --> 00:25:39,400
WARRANTED.

696
00:25:39,400 --> 00:25:44,760
WE MAP A LOT OF ORGANS.

697
00:25:44,760 --> 00:25:46,080
WE SPECIFICALLY -- I

698
00:25:46,080 --> 00:25:49,040
SPECIFICALLY BROUGHT HERE A

699
00:25:49,040 --> 00:25:51,200
COUPLE OF EXAMPLES THROUGH MANY

700
00:25:51,200 --> 00:25:52,400
TECHNOLOGIES AND I SPECIFICALLY

701
00:25:52,400 --> 00:25:53,120
BROUGHT A COUPLE OF EXAMPLES

702
00:25:53,120 --> 00:25:55,800
THAT COME FROM OUR DISTINGUISHED

703
00:25:55,800 --> 00:25:59,960
CHAIR, DR. ANGELA RADTKE WHO IS

704
00:25:59,960 --> 00:26:01,200
ACTUALLY INSIDE THE CLINICAL

705
00:26:01,200 --> 00:26:02,920
CENTER AT THE NIH BUT SHE IS

706
00:26:02,920 --> 00:26:04,240
DOING FANTASTIC WORK IN

707
00:26:04,240 --> 00:26:07,480
ADVANCING THE MAPPING OF THE

708
00:26:07,480 --> 00:26:09,080
LYMPHATIC ORGANS.

709
00:26:09,080 --> 00:26:11,880
AND WE ARE HERE, THIS LINE SHOWS

710
00:26:11,880 --> 00:26:14,720
WE MADE NEW AWARDS THAT ARE

711
00:26:14,720 --> 00:26:18,000
LOOKING AT MAPPING DIFFERENT

712
00:26:18,000 --> 00:26:20,960
TISSUES AND ORGANS, AND WE MADE

713
00:26:20,960 --> 00:26:25,880
ALSO AWARDS TO MAP -- TO DEVELOP

714
00:26:25,880 --> 00:26:27,320
DEMONSTRATION PROJECT THAT

715
00:26:27,320 --> 00:26:28,840
SHOWED THE BIOLOGICAL AND

716
00:26:28,840 --> 00:26:31,240
MEDICAL UTILITY OF WHAT WE ARE

717
00:26:31,240 --> 00:26:32,080
DOING.

718
00:26:32,080 --> 00:26:37,040
I DO WANT TO SAY THAT WE

719
00:26:37,040 --> 00:26:39,120
SPECIFICALLY NAMED LYMPHATIC

720
00:26:39,120 --> 00:26:40,640
RESEARCH WHEN WE WROTE THE CALL

721
00:26:40,640 --> 00:26:45,280
FOR APPLICATIONS, AND I WAS

722
00:26:45,280 --> 00:26:47,200
INVOLVED IN MANY EFFORTS TO

723
00:26:47,200 --> 00:26:50,600
ENGAGE THE LYMPHATIC RESEARCH

724
00:26:50,600 --> 00:26:51,280
COMMUNITY.

725
00:26:51,280 --> 00:26:53,480
WE GAVE AND ORGANIZED MANY

726
00:26:53,480 --> 00:26:54,880
SEMINARS, INCLUDING WITH THE

727
00:26:54,880 --> 00:26:58,760
HELP OF THE BOSTON LYMPHATIC,

728
00:26:58,760 --> 00:27:03,600
WHERE WE BROADCASTED THIS

729
00:27:03,600 --> 00:27:04,600
RESEARCH FUNDING OPPORTUNITY.

730
00:27:04,600 --> 00:27:05,920
EVEN MORE IMPORTANTLY, WE ARE

731
00:27:05,920 --> 00:27:08,240
VERY HAPPY TO ANNOUNCE THAT WE

732
00:27:08,240 --> 00:27:10,200
HAVE THE NEWEST ADDITION TO THIS

733
00:27:10,200 --> 00:27:11,840
PROGRAM IS THE MULTI-SCALE

734
00:27:11,840 --> 00:27:14,120
MAPPING OF THE HUMAN LYMPHATIC

735
00:27:14,120 --> 00:27:17,200
VESSELS, WHICH IS LED BY AN

736
00:27:17,200 --> 00:27:20,240
OUTSTANDING GROUP OF RESEARCHERS

737
00:27:20,240 --> 00:27:22,760
AND PHYSICIANS FROM ACROSS THE

738
00:27:22,760 --> 00:27:27,680
U.S. OF A, DR. SINGHAL,

739
00:27:27,680 --> 00:27:29,200
DR. VLACHOS AND DR. HONG.

740
00:27:29,200 --> 00:27:34,480
AND WHAT THE BASIS OF THIS

741
00:27:34,480 --> 00:27:37,960
PROPOSAL IS, IS DR. SINGHAL IS

742
00:27:37,960 --> 00:27:39,200
INDICATING THAT HAVING A MAP OF

743
00:27:39,200 --> 00:27:44,080
THE LYMPHATIC VESSEL IS ACTUALLY

744
00:27:44,080 --> 00:27:45,720
THE FOUNDATION FOR THE CLINICAL

745
00:27:45,720 --> 00:27:48,040
APPROACH ESPECIALLY IN

746
00:27:48,040 --> 00:27:48,880
LYMPHEDEMA, KNOWING WHICH

747
00:27:48,880 --> 00:27:51,200
PATIENTS WILL HAVE POTENTIAL

748
00:27:51,200 --> 00:27:54,280
VARIATIONS OF THE LYMPHATIC

749
00:27:54,280 --> 00:27:57,520
VESSELS AND HOW TO USE SUCH

750
00:27:57,520 --> 00:28:00,920
KNOWLEDGE TO ACTUALLY TRY TO

751
00:28:00,920 --> 00:28:04,120
PREVENT LYMPHEDEMA.

752
00:28:04,120 --> 00:28:06,400
SO ONE OF THE MAJOR THINGS

753
00:28:06,400 --> 00:28:07,400
THEY'RE GOING TO DO, THEY'RE

754
00:28:07,400 --> 00:28:10,360
GOING TO ACTUALLY BRING BACK TO

755
00:28:10,360 --> 00:28:12,200
THIS TIME A BOOK FROM 1938,

756
00:28:12,200 --> 00:28:14,600
WHICH I UNDERSTAND IS THE MAIN

757
00:28:14,600 --> 00:28:21,720
SOURCE OF INFORMATION STILL,

758
00:28:21,720 --> 00:28:23,360
ROUVIERE, MAPPING THE LYMPHATIC

759
00:28:23,360 --> 00:28:24,800
VESSELS TO SOMETHING MUCH MORE

760
00:28:24,800 --> 00:28:25,120
MODERN.

761
00:28:25,120 --> 00:28:26,880
THERE'S AN OPEN SOURCE PLATFORM

762
00:28:26,880 --> 00:28:27,840
BEING DEVELOPED THAT'S GOING TO

763
00:28:27,840 --> 00:28:30,720
BE AVAILABLE TO INVESTIGATE ALL

764
00:28:30,720 --> 00:28:32,960
THE DETAILS OF THE LYMPHATIC

765
00:28:32,960 --> 00:28:33,440
VASCULATURE.

766
00:28:33,440 --> 00:28:35,520
I KNOW YOU CANNOT SEE REALLY

767
00:28:35,520 --> 00:28:38,000
HERE IN THE SMALL IMAGES, BUT

768
00:28:38,000 --> 00:28:39,560
THIS IS A QUITE SOPHISTICATED

769
00:28:39,560 --> 00:28:41,360
APPROACH IN DEVELOPING KNOWLEDGE

770
00:28:41,360 --> 00:28:43,400
OF THE MAP THAT'S GOING TO BE

771
00:28:43,400 --> 00:28:45,560
USED BY PHYSICIAN RESEARCHERS

772
00:28:45,560 --> 00:28:50,680
AND CAN BE TRAVELED JUST LIKE IN

773
00:28:50,680 --> 00:28:53,640
THAT MOVIE THAT WE ALL REMEMBER,

774
00:28:53,640 --> 00:28:55,280
TRAVELING THE VASCULATURE.

775
00:28:55,280 --> 00:28:58,880
THE REASON IS THEY ARE ALSO

776
00:28:58,880 --> 00:29:00,680
GOING TO APPLY VERY INTERESTING

777
00:29:00,680 --> 00:29:04,720
NEW TECHNOLOGIES THAT GO FROM

778
00:29:04,720 --> 00:29:07,000
THE 3D MAPPING TO SINGLE CELL

779
00:29:07,000 --> 00:29:08,400
ANALYSIS, SO WE'RE GOING TO KNOW

780
00:29:08,400 --> 00:29:10,840
HOW THE LYMPHATIC SYSTEM IS

781
00:29:10,840 --> 00:29:14,600
ORGANIZED AND SPECIFICALLY THE

782
00:29:14,600 --> 00:29:16,320
VASCULATURE IN THIS APPLICATION

783
00:29:16,320 --> 00:29:17,600
FROM THE LEVEL -- THE CLINICAL

784
00:29:17,600 --> 00:29:18,920
LEVEL WHERE THE PHYSICIANS AND

785
00:29:18,920 --> 00:29:22,840
MOST OF THE PATIENTS OPERATE ALL

786
00:29:22,840 --> 00:29:25,400
THE WAY DOWN TO THE SINGLE CELL

787
00:29:25,400 --> 00:29:29,000
OF GENE EXPRESSION AND

788
00:29:29,000 --> 00:29:29,720
FUNCTIONAL ANALYSIS, WHERE MOST

789
00:29:29,720 --> 00:29:31,720
OF THE RESEARCHERS OPERATE, BUT

790
00:29:31,720 --> 00:29:34,120
THAT'S NEEDED IN ORDER TO CREATE

791
00:29:34,120 --> 00:29:35,880
THE MEDICAL KNOWLEDGE TO ADVANCE

792
00:29:35,880 --> 00:29:37,200
THE FIELD.

793
00:29:37,200 --> 00:29:40,800
SO THIS IS ALL I HAD TO SAY, BUT

794
00:29:40,800 --> 00:29:42,640
I DO WANT TO LEAVE YOU WITH THE

795
00:29:42,640 --> 00:29:44,160
MESSAGE THAT THIS IS A TEAM

796
00:29:44,160 --> 00:29:46,240
SPORT, RESEARCH IS A TEAM SPORT.

797
00:29:46,240 --> 00:29:47,560
WE ARE ON YOUR TEAM.

798
00:29:47,560 --> 00:29:51,320
I WANT TO TELL YOU THAT A LOT OF

799
00:29:51,320 --> 00:29:52,960
THIS INFORMATION IS AT YOUR

800
00:29:52,960 --> 00:29:54,240
FINGERTIPS.

801
00:29:54,240 --> 00:29:55,800
MY FAVORITE SEARCH ENGINE,

802
00:29:55,800 --> 00:29:58,080
GOOGLE, WILL FIND THE QUESTIONS

803
00:29:58,080 --> 00:30:00,720
AND PEOPLE WHO CAN HELP YOU WITH

804
00:30:00,720 --> 00:30:02,800
THE QUESTIONS YOU HAVE ABOUT

805
00:30:02,800 --> 00:30:03,080
NIH.

806
00:30:03,080 --> 00:30:05,080
WE ARE HAPPY TO BE HERE.

807
00:30:05,080 --> 00:30:07,080
WE CAME HERE AND I CAN VOUCH FOR

808
00:30:07,080 --> 00:30:09,120
EVERYBODY I WORK WITH, THEY CAME

809
00:30:09,120 --> 00:30:10,440
TO THE NIH NOT BECAUSE THEY

810
00:30:10,440 --> 00:30:12,120
DIDN'T HAVE ANYTHING ELSE BETTER

811
00:30:12,120 --> 00:30:14,080
TO DO, BUT BECAUSE WE ARE

812
00:30:14,080 --> 00:30:17,200
DEDICATED TO SERVICE AND TO

813
00:30:17,200 --> 00:30:18,960
SCIENCE AND HELPING YOU ADVANCE

814
00:30:18,960 --> 00:30:19,600
SCIENCE.

815
00:30:19,600 --> 00:30:22,440
I WANT TO GIVE SPECIAL THANKS IN

816
00:30:22,440 --> 00:30:30,760
CONNECTION TO THIS TALK TO OUR

817
00:30:30,760 --> 00:30:32,000
PORTFOLIO ANALYTICS BRANCH WHO

818
00:30:32,000 --> 00:30:33,440
HELP WITH THE PORTFOLIO

819
00:30:33,440 --> 00:30:36,680
ANALYSIS, AND MY FRIENDS AND

820
00:30:36,680 --> 00:30:42,360
COLLEAGUES, ILSA ROVIRA AND

821
00:30:42,360 --> 00:30:43,560
SELEN CATANIA FOR ALL THE

822
00:30:43,560 --> 00:30:44,480
ENORMOUS WORK THEY DID TO PUT

823
00:30:44,480 --> 00:30:45,760
TOGETHER THE WORKSHOP BUT ALSO

824
00:30:45,760 --> 00:30:46,640
SPECIFICALLY FOR BEING SO KIND

825
00:30:46,640 --> 00:30:49,720
AND HELPING WITH THIS TALK.

826
00:30:49,720 --> 00:30:52,360
I BELIEVE THAT THERE IS TIME TO

827
00:30:52,360 --> 00:30:53,640
ASK QUESTIONS AT THE END OF THE

828
00:30:53,640 --> 00:30:56,480
SESSION OR SOMEBODY CAN TELL ME,

829
00:30:56,480 --> 00:30:59,640
BUT I'M LOOKING FORWARD TO YOUR

830
00:30:59,640 --> 00:31:01,760
QUESTIONS, BOTH DURING THIS

831
00:31:01,760 --> 00:31:02,520
WORKSHOP AS WELL AS AFTER.

832
00:31:02,520 --> 00:31:04,040
NOW YOU KNOW HOW TO FIND US.

833
00:31:04,040 --> 00:31:05,480
THANK YOU, EVERYONE.

834
00:31:05,480 --> 00:31:07,040
>> THANK YOU, ZORINA.

835
00:31:07,040 --> 00:31:10,640
NEXT IS GOING TO BE DR. MICHAEL

836
00:31:10,640 --> 00:31:11,600
DAVIS.

837
00:31:11,600 --> 00:31:13,480
ANDREA, WILL YOU BE --

838
00:31:13,480 --> 00:31:16,880
>> YES, HAPPY TO INTRODUCE
HIM.

839
00:31:16,880 --> 00:31:18,520
IT'S MY PLEASURE TO INTRODUCE

840
00:31:18,520 --> 00:31:19,960
OUR FIRST KEYNOTE SPEAKER,

841
00:31:19,960 --> 00:31:21,160
DR. MICHAEL DAVIS, A

842
00:31:21,160 --> 00:31:22,520
DISTINGUISHED PROFESSOR AT THE

843
00:31:22,520 --> 00:31:24,040
UNIVERSITY OF MISSOURI COLUMBIA

844
00:31:24,040 --> 00:31:25,120
SCHOOL OF MEDICINE, AND LEADER

845
00:31:25,120 --> 00:31:27,280
IN THE DEVELOPMENT OF TOOLS,

846
00:31:27,280 --> 00:31:29,040
TECHNOLOGIES AND ANIMAL MODELS

847
00:31:29,040 --> 00:31:29,800
TO STUDY LYMPHATIC FUNCTION.

848
00:31:29,800 --> 00:31:32,320
THE TITLE OF HIS TALK IS

849
00:31:32,320 --> 00:31:33,760
MECHANISMS OF LYMPHATIC

850
00:31:33,760 --> 00:31:34,960
CONTRACTILE AND VALVE

851
00:31:34,960 --> 00:31:35,920
DYSFUNCTION IN METABOLIC

852
00:31:35,920 --> 00:31:37,120
SYNDROME.

853
00:31:37,120 --> 00:31:38,560
WELCOME, DR. DAVIS.

854
00:31:38,560 --> 00:31:40,360
>> THANK YOU.

855
00:31:40,360 --> 00:31:43,720
I WILL START BY INTRODUCING THE

856
00:31:43,720 --> 00:31:46,040
LYMPHATIC SYSTEM TO A GENERAL

857
00:31:46,040 --> 00:31:47,120
AUDIENCE.

858
00:31:47,120 --> 00:31:49,080
IT'S A ONE-WAY VASCULAR NETWORK

859
00:31:49,080 --> 00:31:53,040
THAT RUNS IN PARALLEL TO THE

860
00:31:53,040 --> 00:31:54,040
BLOOD VASCULAR SYSTEM.

861
00:31:54,040 --> 00:31:55,120
IN ALMOST EVERY TISSUE, THERE

862
00:31:55,120 --> 00:31:57,960
ARE NETWORKS OF LYMPHATIC

863
00:31:57,960 --> 00:32:01,560
CAPILLARIES THAT ABSORB LYMPH,

864
00:32:01,560 --> 00:32:03,880
COALESCE INTO COLLECTING

865
00:32:03,880 --> 00:32:05,400
LYMPHATIC VESSELS WHICH HAVE AT

866
00:32:05,400 --> 00:32:08,360
LEAST ONE CELL LAYER OF MUSCLE,

867
00:32:08,360 --> 00:32:10,400
SMOOTH MUSCLE, AND A SERIES OF

868
00:32:10,400 --> 00:32:11,080
ONE-WAY VALVES.

869
00:32:11,080 --> 00:32:13,640
THESE SPONTANEOUSLY CONTRACT AND

870
00:32:13,640 --> 00:32:20,400
PROPEL LYMPH CENTRALLY BUT MOST

871
00:32:20,400 --> 00:32:21,680
OF THE LYMPH IS DRAINED INTO THE

872
00:32:21,680 --> 00:32:23,280
CONFLUENCE OF THE GREAT VEINS IN

873
00:32:23,280 --> 00:32:23,680
THE NECK.

874
00:32:23,680 --> 00:32:26,960
HERE YOU SEE THESE LYMPHOVENOUS

875
00:32:26,960 --> 00:32:28,600
VALVES AT THIS CONFLUENCE IN

876
00:32:28,600 --> 00:32:29,360
PURPLE HERE.

877
00:32:29,360 --> 00:32:31,120
THE GREEN STRUCTURES ARE VENOUS

878
00:32:31,120 --> 00:32:33,080
VALVES.

879
00:32:33,080 --> 00:32:36,000
THERE ARE THREE CLASSIC ROLES

880
00:32:36,000 --> 00:32:39,760
FOR THE LYMPHATIC SYSTEM IN

881
00:32:39,760 --> 00:32:43,000
HOMEOSTASIS, INTERSTITIAL FLUID

882
00:32:43,000 --> 00:32:45,120
AND PROTEIN BALANCE, FAT

883
00:32:45,120 --> 00:32:46,960
ABSORPTION FROM THE INS TESSAL

884
00:32:46,960 --> 00:32:48,040
TRACT, IMMUNE CELL TRAFFICKING.

885
00:32:48,040 --> 00:32:49,240
OVER THE PAST 10 YEARS, THERE

886
00:32:49,240 --> 00:32:51,080
ARE AT LEAST 10 NEWLY

887
00:32:51,080 --> 00:32:52,840
APPRECIATED ROLES, AND I'VE JUST

888
00:32:52,840 --> 00:32:53,520
LISTED A FEW OF THEM.

889
00:32:53,520 --> 00:32:55,400
I WON'T GO INTO DETAILS BECAUSE

890
00:32:55,400 --> 00:32:56,880
THEY WILL BE COVERED BY SPEAKERS

891
00:32:56,880 --> 00:33:00,120
IN THIS SYMPOSIUM.

892
00:33:00,120 --> 00:33:02,400
I WILL JUST MENTION THAT

893
00:33:02,400 --> 00:33:04,520
LYMPHEDEMA IS A SIGNIFICANT

894
00:33:04,520 --> 00:33:06,280
HUMAN HEALTH PROBLEM.

895
00:33:06,280 --> 00:33:07,440
PRIMARY LYMPHEDEMA, ALTHOUGH

896
00:33:07,440 --> 00:33:09,400
RELATIVELY RARE, INVOLVES

897
00:33:09,400 --> 00:33:12,360
GENETIC MUTATIONS OF LYMPHATIC

898
00:33:12,360 --> 00:33:15,000
VESSEL DEVELOPMENT AND VALVE

899
00:33:15,000 --> 00:33:16,640
DEVELOPMENT THAT PRODUCE PRETTY

900
00:33:16,640 --> 00:33:19,040
CATASTROPHIC RESULTS IN TERMS OF

901
00:33:19,040 --> 00:33:22,000
FAILURE TO ABSORB INTERSTITIAL

902
00:33:22,000 --> 00:33:23,880
FLUID.

903
00:33:23,880 --> 00:33:24,720
SECONDARY LYMPHEDEMA IS MUCH

904
00:33:24,720 --> 00:33:25,240
MORE COMMON.

905
00:33:25,240 --> 00:33:27,560
THERE ARE ABOUT 10 MILLION CASES

906
00:33:27,560 --> 00:33:31,320
PER YEAR IN THE U.S.

907
00:33:31,320 --> 00:33:32,920
MOSTLY A CONSEQUENCE OF

908
00:33:32,920 --> 00:33:34,240
CONGESTIVE HEART FAILURE,

909
00:33:34,240 --> 00:33:35,440
CHRONIC VENOUS DISEASE, AND

910
00:33:35,440 --> 00:33:37,640
CANCER SURGERY AND RADIOTHERAPY.

911
00:33:37,640 --> 00:33:39,720
BUT AROUND THE WORLD, THERE ARE

912
00:33:39,720 --> 00:33:45,120
MANY MORE CASES, OVER

913
00:33:45,120 --> 00:33:47,160
130 MILLION PREDICTED OR

914
00:33:47,160 --> 00:33:48,800
FILARIA, PARASITES THAT PLUG UP

915
00:33:48,800 --> 00:33:50,320
THE LYMPHATIC SYSTEM.

916
00:33:50,320 --> 00:33:51,600
THE CONSEQUENCES OF UNTREATED

917
00:33:51,600 --> 00:33:53,480
LYMPHEDEMA ARE PAIN, IMMOBILITY,

918
00:33:53,480 --> 00:33:55,920
INCREASED RISK OF INFECTION,

919
00:33:55,920 --> 00:34:03,040
FIBROSIS AND TISSUE DAMAGE.

920
00:34:03,040 --> 00:34:04,000
COLLECTING LYMPHATICS ARE

921
00:34:04,000 --> 00:34:05,640
CRITICAL FOR ACTIVE LYMPH

922
00:34:05,640 --> 00:34:05,880
TRANSPORT.

923
00:34:05,880 --> 00:34:08,120
IF YOU LOOK, A LOT OF TEXTBOOKS

924
00:34:08,120 --> 00:34:09,920
STILL GIVE ONE THE IMPRESSION

925
00:34:09,920 --> 00:34:13,840
THAT LYMPH PROPULSION IS PURELY

926
00:34:13,840 --> 00:34:16,360
PASSIVE, FROM CONTRACTIONS OF

927
00:34:16,360 --> 00:34:19,760
SKELETAL MUSCLES THAT COMPRESS

928
00:34:19,760 --> 00:34:20,840
LYMPH VESSELS BUT THERE'S

929
00:34:20,840 --> 00:34:21,800
ACTUALLY VERY GOOD STUDIES THAT

930
00:34:21,800 --> 00:34:23,280
SHOW THAT TWO THIRDS OF PUMPING

931
00:34:23,280 --> 00:34:24,800
IN DEPENDENT EXTREMITIES UNDER

932
00:34:24,800 --> 00:34:27,960
QUIET STANDING ARE DUE TO ACTIVE

933
00:34:27,960 --> 00:34:28,320
CONTRACTIONS.

934
00:34:28,320 --> 00:34:33,000
SO THIS IS A RAT MESENTERIC

935
00:34:33,000 --> 00:34:33,680
LYMPHATIC VESSEL.

936
00:34:33,680 --> 00:34:37,920
WE'VE ISOLATED AND CANNULATED IN

937
00:34:37,920 --> 00:34:38,680
MICRO PIPETTES.

938
00:34:38,680 --> 00:34:40,880
I PUT IN RED CELLS AS FLOW

939
00:34:40,880 --> 00:34:41,120
MARKERS.

940
00:34:41,120 --> 00:34:44,720
YOU CAN SEE THAT WHEN THE VESSEL

941
00:34:44,720 --> 00:34:46,760
EXPANDS IN DIASTOLE, IT DRAWS IN

942
00:34:46,760 --> 00:34:48,120
FLUID AND CELLS FROM THE INFLOW

943
00:34:48,120 --> 00:34:50,600
PIPETTE, AND WHEN IT CONTRACTS,

944
00:34:50,600 --> 00:34:51,920
IT EXPELS A SMALL AMOUNT OF

945
00:34:51,920 --> 00:34:54,440
FLUID AND THE OUTFLOW VALVE

946
00:34:54,440 --> 00:34:57,840
SNAPS BACK TO PREVENT BACKFLOW.

947
00:34:57,840 --> 00:34:59,480
THESE LYMPHATIC CONTRACTIONS ARE

948
00:34:59,480 --> 00:35:01,480
INITIATED BY ACTION POTENTIALS

949
00:35:01,480 --> 00:35:04,080
IN LYMPHATIC MUSCLE.

950
00:35:04,080 --> 00:35:05,880
ACTION POTENTIALS LOOK SOMETHING

951
00:35:05,880 --> 00:35:06,280
LIKE THIS.

952
00:35:06,280 --> 00:35:09,040
THESE ARE GENERATED BY A CYCLE

953
00:35:09,040 --> 00:35:12,080
OF IONIC INTERACTIONS THAT

954
00:35:12,080 --> 00:35:13,840
PRODUCE DIASTOLIC

955
00:35:13,840 --> 00:35:14,800
DEPOLARIZATION, EVENTUALLY

956
00:35:14,800 --> 00:35:16,480
RESULT IN OPENING OF L-TYPE

957
00:35:16,480 --> 00:35:18,880
CALCIUM CHANNELS WHICH ALLOW

958
00:35:18,880 --> 00:35:20,520
CALCIUM INFLUX TO DRIVE THESE

959
00:35:20,520 --> 00:35:21,160
TWITCH CONTRACTIONS.

960
00:35:21,160 --> 00:35:22,560
SO EACH ACTION POTENTIAL WILL

961
00:35:22,560 --> 00:35:25,960
DRIVE A SINGLE TWITCH

962
00:35:25,960 --> 00:35:27,400
CONTRACTION, AND THE ONE-WAY

963
00:35:27,400 --> 00:35:30,000
VALVES BASICALLY TRANSFORM THE

964
00:35:30,000 --> 00:35:33,000
PULSATILE MOVEMENT INTO A

965
00:35:33,000 --> 00:35:33,840
STEP-WISE INCREASE IN LYMPH

966
00:35:33,840 --> 00:35:36,400
FLOW.

967
00:35:36,400 --> 00:35:40,200
MY LAB HAS DEVELOPED MULTIPLE

968
00:35:40,200 --> 00:35:42,200
METHODS FOR STUDYING

969
00:35:42,200 --> 00:35:43,280
PARTICULARLY MOUSE LYMPHATIC

970
00:35:43,280 --> 00:35:44,680
VESSELS, BUT WE ALSO STUDY

971
00:35:44,680 --> 00:35:48,720
VESSELS FROM RATS AND HUMANS.

972
00:35:48,720 --> 00:35:50,840
FROM 1 TO 4 SEGMENTS OF VALVES,

973
00:35:50,840 --> 00:35:54,560
2-VALVE SEGMENTS FOR PUMP TESTS,

974
00:35:54,560 --> 00:35:57,080
1-VALVE SEGMENTS FOR

975
00:35:57,080 --> 00:35:57,760
QUANTITATIVE ANALYSIS OF

976
00:35:57,760 --> 00:36:00,320
LYMPHATIC VALVE FUNCTION.

977
00:36:00,320 --> 00:36:01,920
WE'VE DEVELOPED METHODS FOR

978
00:36:01,920 --> 00:36:04,880
CALCIUM IMAGING,

979
00:36:04,880 --> 00:36:05,400
ELECTROPHYSIOLOGY, AND WE

980
00:36:05,400 --> 00:36:07,160
ACTUALLY DO SOME IN VIVO

981
00:36:07,160 --> 00:36:08,400
STUDIES, WHICH A LOT OF PEOPLE

982
00:36:08,400 --> 00:36:12,640
DON'T APPRECIATE THAT WE DO.

983
00:36:12,640 --> 00:36:14,920
AND THIS SLIDE JUST SHOWS THE

984
00:36:14,920 --> 00:36:15,360
TYPICAL ANALYSIS.

985
00:36:15,360 --> 00:36:19,040
SO THIS IS A POPLITEAL LYMPHATIC

986
00:36:19,040 --> 00:36:20,320
FROM THE LOWER LEG OF THE MOUSE

987
00:36:20,320 --> 00:36:22,280
TAKEN OUT, CANNULATED ON MICRO

988
00:36:22,280 --> 00:36:25,000
PIPETTES, CLEANED OF MOST FAT

989
00:36:25,000 --> 00:36:26,200
AND CONNECTIVE TISSUE.

990
00:36:26,200 --> 00:36:28,400
SO WE TYPICALLY USE THIS TYPE OF

991
00:36:28,400 --> 00:36:30,160
ANALYSIS BECAUSE IT HAS DEFINED

992
00:36:30,160 --> 00:36:31,480
PRESSURES AND FLOWS.

993
00:36:31,480 --> 00:36:33,880
WE CAN CHANGE THE SOLUTIONS

994
00:36:33,880 --> 00:36:35,400
INSIDE AND OUTSIDE THE VESSEL,

995
00:36:35,400 --> 00:36:37,280
AND WE CAN USE DEFINED

996
00:36:37,280 --> 00:36:39,000
CONCENTRATIONS OF AGONISTS AND

997
00:36:39,000 --> 00:36:41,960
ANTAGONISTS.

998
00:36:41,960 --> 00:36:43,320
THIS TRACE HERE, PRESSURE AND

999
00:36:43,320 --> 00:36:45,920
DIAMETER OVER TIME, SHOW THE

1000
00:36:45,920 --> 00:36:48,520
EXQUISITE SENSITIVITY OF

1001
00:36:48,520 --> 00:36:50,600
LYMPHATIC CONTRACTIONS TO

1002
00:36:50,600 --> 00:36:51,040
PRESSURE.

1003
00:36:51,040 --> 00:36:53,120
SO EACH ONE OF THESE DOWNWARD

1004
00:36:53,120 --> 00:36:56,520
DEFLECTIONS IN DIAMETER IS A

1005
00:36:56,520 --> 00:36:59,120
3 TO 52ND CONTRACTION, AS WAS

1006
00:36:59,120 --> 00:37:00,360
SHOWN IN THE VIDEO.

1007
00:37:00,360 --> 00:37:02,640
YOU CAN SEE THAT THE PRESSURE

1008
00:37:02,640 --> 00:37:03,600
CHANGES FIVE FOLD BETWEEN

1009
00:37:03,600 --> 00:37:05,360
PRESSURE OF 3 CENTIMETERS WATER

1010
00:37:05,360 --> 00:37:09,960
AND A HALF COUNCILMEMBER OF 16-D

1011
00:37:09,960 --> 00:37:14,040
IT INCREASES WHEN YOU GO TO

1012
00:37:14,040 --> 00:37:14,800
THE -- PRESSURES.

1013
00:37:14,800 --> 00:37:16,760
WE PUT IT IN CALCIUM-FREE

1014
00:37:16,760 --> 00:37:20,680
SOLUTION, GET PASSIVE -- WE CAN

1015
00:37:20,680 --> 00:37:22,560
CALCULATE TONE, AMPLITUDE,

1016
00:37:22,560 --> 00:37:23,760
FREQUENCY, EJECTION FRACTION AND

1017
00:37:23,760 --> 00:37:26,600
INDEX OF FLOW WHICH WE CALL

1018
00:37:26,600 --> 00:37:27,800
FRACTIONAL PUMP FLOW BECAUSE THE

1019
00:37:27,800 --> 00:37:29,280
ABSOLUTE FLOWS IN MOUSE ARE IN

1020
00:37:29,280 --> 00:37:31,520
RANGE OF NANOLITERS PER MINUTE,

1021
00:37:31,520 --> 00:37:33,600
WHICH ARE TOO SMALL TO DIRECTLY

1022
00:37:33,600 --> 00:37:40,360
MEASURE WITH FLOW PROBES MPLE

1023
00:37:40,360 --> 00:37:41,080
THE FREQUENCY PRESSURE

1024
00:37:41,080 --> 00:37:42,080
RELATIONSHIP IN THE MOUSE

1025
00:37:42,080 --> 00:37:43,400
INCREASES FIVE FOLD ON AVERAGE

1026
00:37:43,400 --> 00:37:45,040
FOR VESSELS OVER THIS PRESSURE

1027
00:37:45,040 --> 00:37:48,520
RANGE.

1028
00:37:48,520 --> 00:37:50,200
THE AMPLITUDE OF CONTRACTIONS IS

1029
00:37:50,200 --> 00:37:54,480
OPTIMAL, SOMEWHERE AROUND 1 TO E

1030
00:37:54,480 --> 00:37:56,240
FRACTIONAL PUMP FLOW IS OPTIMAL

1031
00:37:56,240 --> 00:37:57,760
BETWEEN 3 AND 5 CENTIMETERS OF

1032
00:37:57,760 --> 00:38:00,520
WATER AND IT HAS SORT OF A BROAD

1033
00:38:00,520 --> 00:38:02,360
PEAK THAT LOOKS KIND OF LIKE A

1034
00:38:02,360 --> 00:38:02,920
CARDIAC FUNCTION CURVE.

1035
00:38:02,920 --> 00:38:05,120
A LOT OF PEOPLE USE THESE TYPE

1036
00:38:05,120 --> 00:38:06,520
OF ANALYSIS, BUT WE ALL MAKE

1037
00:38:06,520 --> 00:38:11,560
SOME ASSUMPTIONS  WHEN WE USE

1038
00:38:11,560 --> 00:38:13,240
FRACTIONAL PUMP FLOW AS AN INDEX

1039
00:38:13,240 --> 00:38:14,000
OF PUMP OUTPUT.

1040
00:38:14,000 --> 00:38:16,960
THAT S WE ASSUME THAT THE VALVES

1041
00:38:16,960 --> 00:38:20,240
ARE 100% COMPETENT WITH NO

1042
00:38:20,240 --> 00:38:21,800
BACKLEAK, THAT THE CONTRACTION

1043
00:38:21,800 --> 00:38:25,400
WAVES ARE WELL ENTRAINED, SO

1044
00:38:25,400 --> 00:38:27,080
THAT THE CONTRACTION IS

1045
00:38:27,080 --> 00:38:29,760
EFFECTIVE, AND THAT THE VESSEL

1046
00:38:29,760 --> 00:38:31,840
WALL HAS LOW OR MINIMAL

1047
00:38:31,840 --> 00:38:35,480
PERMEABILITY.

1048
00:38:35,480 --> 00:38:38,000
MY LAB HAS NOTICED STUDYING

1049
00:38:38,000 --> 00:38:39,640
VARIOUS GENETIC MOUSE MODELS

1050
00:38:39,640 --> 00:38:42,600
OVER THE PAST 10 YEARS THAT A

1051
00:38:42,600 --> 00:38:43,440
LYMPHATIC DYSFUNCTION IN ALMOST

1052
00:38:43,440 --> 00:38:45,640
ALL OF THESE VARIABLES OCCURS.

1053
00:38:45,640 --> 00:38:48,080
SO THIS IS ONE EXAMPLE.

1054
00:38:48,080 --> 00:38:53,280
THESE ARE POPLITEAL VESSELS FROM

1055
00:38:53,280 --> 00:38:54,560
APOE KNOCKOUT MICE FED A HIGH

1056
00:38:54,560 --> 00:38:55,000
FAT DIET.

1057
00:38:55,000 --> 00:39:00,480
YOU CAN SEE -- THIS IS IN

1058
00:39:00,480 --> 00:39:02,360
COLLABORATION WITH ANGELI IN

1059
00:39:02,360 --> 00:39:02,680
SINGAPORE.

1060
00:39:02,680 --> 00:39:04,080
THE FREQUENCY VERSUS PRESSURE IS

1061
00:39:04,080 --> 00:39:07,800
NOT ALTERED BY THE APOE KNOCKOUT

1062
00:39:07,800 --> 00:39:11,080
BUT CONTRACTILE FUNCTION,

1063
00:39:11,080 --> 00:39:12,920
AMPLITUDE IS DEPRESSED BY 50% AT

1064
00:39:12,920 --> 00:39:15,160
ALL PRESSURES THAT WE STUDIED.

1065
00:39:15,160 --> 00:39:16,680
IF WE TAKE OUT SEGMENTS WITH

1066
00:39:16,680 --> 00:39:18,400
SINGLE VALVES AND DO

1067
00:39:18,400 --> 00:39:21,320
QUANTITATIVE MEASUREMENTS OF

1068
00:39:21,320 --> 00:39:23,240
VALVE BACKLEAK IN CLOSED VALVES,

1069
00:39:23,240 --> 00:39:26,320
I'M NOT GOING TO EXPLAIN THE

1070
00:39:26,320 --> 00:39:28,040
DETAILS BECAUSE JORGE WILL IN A

1071
00:39:28,040 --> 00:39:28,840
TALK LATER.

1072
00:39:28,840 --> 00:39:31,800
BUT THERE'S A SLIGHT BACKLEAK IN

1073
00:39:31,800 --> 00:39:33,760
VALVES FROM THE CONTROL GROUP,

1074
00:39:33,760 --> 00:39:36,440
BUT IT'S INCREASED FOUR FOLD IN

1075
00:39:36,440 --> 00:39:41,240
APOE KNOCKOUT VALVES.

1076
00:39:41,240 --> 00:39:42,960
THE NEXT TWO GRAPHS OVER HERE

1077
00:39:42,960 --> 00:39:44,080
SHOW THE BACK PRESSURE REQUIRED

1078
00:39:44,080 --> 00:39:46,520
TO CLOSE THE VALVE GIVES YOU AN

1079
00:39:46,520 --> 00:39:47,560
INDICATION OF THE STIFFNESS OF

1080
00:39:47,560 --> 00:39:49,440
THE VALVES.

1081
00:39:49,440 --> 00:39:51,960
NORMAL VALVES SHOW THIS KIND OF

1082
00:39:51,960 --> 00:39:54,400
CURVILINEAR RELATIONSHIP WITH

1083
00:39:54,400 --> 00:39:55,240
ADVERSE PRESSURE REQUIRED TO

1084
00:39:55,240 --> 00:39:57,440
CLOSE IT, AND THE DIAMETER.

1085
00:39:57,440 --> 00:40:00,440
SO AS THE VESSEL APPROACHES ITS

1086
00:40:00,440 --> 00:40:04,680
MAXIMAL DIAMETER, NORMALIZED TO

1087
00:40:04,680 --> 00:40:07,080
1 HERE, IT REQUIRES EVEN JUST A

1088
00:40:07,080 --> 00:40:08,120
FEW CENTIMETERS OF WATER TO

1089
00:40:08,120 --> 00:40:10,680
CLOSE THE VALVE, BUT ABOUT 30%

1090
00:40:10,680 --> 00:40:13,360
OF THE APOE KNOCKOUT VALVES

1091
00:40:13,360 --> 00:40:15,520
NEVER CLOSE UNDER ANYWHERE CLOSE

1092
00:40:15,520 --> 00:40:18,400
TO NORMAL PHYSIOLOGICAL

1093
00:40:18,400 --> 00:40:21,000
PRESSURES.

1094
00:40:21,000 --> 00:40:22,560
WHEN JOSH SCALLAN WAS IN MY LAB,

1095
00:40:22,560 --> 00:40:24,120
HE TOOK VESSELS OUT OF THESE

1096
00:40:24,120 --> 00:40:25,760
MICE AND DID QUANTITATIVE

1097
00:40:25,760 --> 00:40:28,240
MEASUREMENTS OF PERMEABILITY, OF

1098
00:40:28,240 --> 00:40:30,440
COLLECTING VESSEL PERMEABILITY.

1099
00:40:30,440 --> 00:40:32,560
THE NORMAL MICE ARE SOMEWHERE

1100
00:40:32,560 --> 00:40:38,360
CLOSE TO VENEAL LEVELS.

1101
00:40:38,360 --> 00:40:41,720
SO MY POSTDOC JINNY KIM HAS DONE

1102
00:40:41,720 --> 00:40:44,880
RECENT STUDIES IN DB/DB MICE.

1103
00:40:44,880 --> 00:40:46,880
SO THIS IS ONE MODEL, METABOLIC

1104
00:40:46,880 --> 00:40:47,840
SYNDROME.

1105
00:40:47,840 --> 00:40:52,520
MICE ARE EXTREMELY OWE   OBESE,E

1106
00:40:52,520 --> 00:40:56,960
VERY HIGH GLUCOSE LEVELS.

1107
00:40:56,960 --> 00:40:58,400
THIS IS DB/DB MOUSE TRACE.

1108
00:40:58,400 --> 00:41:02,600
YOU CAN SEE THEY'RE VERY BLUNTED

1109
00:41:02,600 --> 00:41:03,880
CONTRACTIONS, THEY'RE IRREGULAR

1110
00:41:03,880 --> 00:41:05,320
IN FREQUENCY, THERE ARE NO

1111
00:41:05,320 --> 00:41:06,080
CONTRACTIONS AT THE LOWER

1112
00:41:06,080 --> 00:41:10,200
PRESSURES AND INTERESTINGLY, WE

1113
00:41:10,200 --> 00:41:15,520
FIND THAT GLABECTOMIDE RESCUES

1114
00:41:15,520 --> 00:41:16,960
THE FREQUENCY HERE.

1115
00:41:16,960 --> 00:41:18,400
SO YOU CAN SEE THE FREQUENCY

1116
00:41:18,400 --> 00:41:22,320
PATTERN LOOKS MORE LIKE THE WILD

1117
00:41:22,320 --> 00:41:22,920
TYPE.

1118
00:41:22,920 --> 00:41:24,960
IT DOESN'T RESCUE THE AMPLITUDE

1119
00:41:24,960 --> 00:41:27,560
UNLESS YOU ALSO ADD AN ACTIVATOR

1120
00:41:27,560 --> 00:41:30,240
OF L-TYPE CALCIUM CHANNELS.

1121
00:41:30,240 --> 00:41:31,560
THIS SHOWS THE AVERAGE DATA

1122
00:41:31,560 --> 00:41:37,440
HERE, SHOWING DEPRESSION BY --

1123
00:41:37,440 --> 00:41:42,640
IN THE DB/DB MICE.

1124
00:41:42,640 --> 00:41:44,040
JOSH SCALLAN HAD DONE

1125
00:41:44,040 --> 00:41:45,080
PERMEABILITY MEASUREMENTS ON

1126
00:41:45,080 --> 00:41:48,120
THESE VESSELS AND IN DB/DB MICE

1127
00:41:48,120 --> 00:41:49,640
FROM BOTH MALES AND FEMALES, THE

1128
00:41:49,640 --> 00:41:51,160
TWO DIFFERENT COLORS HERE, THERE

1129
00:41:51,160 --> 00:41:56,200
IS A 50 FOLD INCREASE IN

1130
00:41:56,200 --> 00:41:57,240
PERMEABILITY, THE LOG SCALE ON

1131
00:41:57,240 --> 00:42:00,600
THE Y AXIS.

1132
00:42:00,600 --> 00:42:05,520
SO JINNY JUST LOOKED AT THE

1133
00:42:05,520 --> 00:42:08,000
EFFECTS OF GLEUS GLUCOSE, PER

1134
00:42:08,000 --> 00:42:12,000
SE, USED OFTEN IN DIABETIC

1135
00:42:12,000 --> 00:42:16,400
STUDIES IN VITRO, AND SO YOU CAE

1136
00:42:16,400 --> 00:42:19,480
AFTER A FEW MINUTES, THE

1137
00:42:19,480 --> 00:42:21,560
FREQUENCY HAS DECREASED IN THIS

1138
00:42:21,560 --> 00:42:23,080
VESSEL AT THE CONTROL PRESSURE,

1139
00:42:23,080 --> 00:42:26,800
AND THEN WHEN WE LOWER TO

1140
00:42:26,800 --> 00:42:27,840
0.5 CENTIMETERS OF WATER,

1141
00:42:27,840 --> 00:42:30,040
THERE'S NO CONTRACTIONS OF THAT

1142
00:42:30,040 --> 00:42:33,120
PRESSURE, AND THIS IS PRETTY

1143
00:42:33,120 --> 00:42:34,960
MUCH RESCUED HERE.

1144
00:42:34,960 --> 00:42:36,600
THIS IS THE CONCENTRATION

1145
00:42:36,600 --> 00:42:40,800
RESPONSE CURVE TO GLUCOSE, AND

1146
00:42:40,800 --> 00:42:42,400
THE CONTROL IS FOR OSMOTIC

1147
00:42:42,400 --> 00:42:44,160
EFFECTS.

1148
00:42:44,160 --> 00:42:45,720
SO THIS IS SUMMARY DATA SHOWING

1149
00:42:45,720 --> 00:42:47,800
DEPRESSION OF FREQUENCY AT EVERY

1150
00:42:47,800 --> 00:42:49,560
PRESSURE IN THE PRESENCE OF HIGH

1151
00:42:49,560 --> 00:42:56,280
GLUCOSE RESCUED BY GLABEKLOMIDE.

1152
00:42:56,280 --> 00:42:57,240
INTERESTINGLY WHEN WE LOOK THE A

1153
00:42:57,240 --> 00:43:01,120
VESSELS FROM AN ANIMAL MODEL OF

1154
00:43:01,120 --> 00:43:07,320
KETP CHANNEL MODEL KNOCKOUT,

1155
00:43:07,320 --> 00:43:09,560
KIR6.1 -- AND THOSE MICE ARE --

1156
00:43:09,560 --> 00:43:11,520
THE VESSELS ARE RESISTANT TO THE

1157
00:43:11,520 --> 00:43:15,360
EFFECTS OF HIGH GLUCOSE.

1158
00:43:15,360 --> 00:43:17,000
SUGGESTING IT IS WORKING THROUGH

1159
00:43:17,000 --> 00:43:24,360
KATP CHANNELS.

1160
00:43:24,360 --> 00:43:25,640
IF YOU COMPARE THE PRESSURE

1161
00:43:25,640 --> 00:43:27,200
DIAMETER RELATIONSHIPS OVER TIME

1162
00:43:27,200 --> 00:43:29,200
IN WILD TYPE AND IN KNOCKOUT

1163
00:43:29,200 --> 00:43:32,480
MICE, THEY LOOK VERY SIMILAR.

1164
00:43:32,480 --> 00:43:34,440
VESSELS STILL SHOW FREQUENCY

1165
00:43:34,440 --> 00:43:36,400
MODULATION, THEY SHOW GOOD

1166
00:43:36,400 --> 00:43:37,640
ALMOST PLI TEUD AT ALL

1167
00:43:37,640 --> 00:43:38,840
PRESSURES.

1168
00:43:38,840 --> 00:43:41,800
NOW, IF WE TRY TO INDUCE

1169
00:43:41,800 --> 00:43:44,080
METABOLIC STRESS BY INHIBITING

1170
00:43:44,080 --> 00:43:48,040
SPECIFIC PARTS OF THE

1171
00:43:48,040 --> 00:43:49,600
MITOCHONDRIAL ELECTRON TRANSPORT

1172
00:43:49,600 --> 00:43:52,840
SYSTEM, IN THIS CASE INHIBITING

1173
00:43:52,840 --> 00:43:56,240
COMPLEX 3, IF YOU USE 30

1174
00:43:56,240 --> 00:44:06,800
NANOMOLAR ANTIMYCIN A -- IF YOU

1175
00:44:07,600 --> 00:44:12,480
ADD BACK GLIBENCLAMIDE, THIS CAN

1176
00:44:12,480 --> 00:44:14,360
BE REVERSED.

1177
00:44:14,360 --> 00:44:15,880
THE KNOCKOUT MICE ARE COMPLETELY

1178
00:44:15,880 --> 00:44:20,040
RESISTANT TO THE EFFECTS OF

1179
00:44:20,040 --> 00:44:22,800
ANTIMYCIN A.

1180
00:44:22,800 --> 00:44:27,040
SO WE THINK THAT THE KATP

1181
00:44:27,040 --> 00:44:28,920
SENSITIVE POTASSIUM CHANNELS ARE

1182
00:44:28,920 --> 00:44:32,080
NORMALLY NOT ACTIVATED AT HIGH

1183
00:44:32,080 --> 00:44:33,640
LEVELS IN LYMPHATIC MUSCLE, BUT

1184
00:44:33,640 --> 00:44:35,520
ONCE THEY'RE ACTIVATED, SAY BY

1185
00:44:35,520 --> 00:44:37,480
METABOLIC STRESS, THEY APPLY A

1186
00:44:37,480 --> 00:44:40,360
VERY STRONG BREAK TO THE

1187
00:44:40,360 --> 00:44:41,440
PACEMAKING MECHANISM, SLOWING

1188
00:44:41,440 --> 00:44:44,120
DOWN THE FREQUENCY AND COMPARING

1189
00:44:44,120 --> 00:44:44,760
CONTRACTILE ACTIVITY.

1190
00:44:44,760 --> 00:44:46,520
THIS ISN'T THE ONLY WAY THAT

1191
00:44:46,520 --> 00:44:54,080
THESE CHANNELS ARE REGULATED.

1192
00:44:54,080 --> 00:44:56,720
IT'S SHOWN THAT EXCESS CIV PRO

1193
00:44:56,720 --> 00:44:59,600
DUCKS OF NITRIC OXIDE THROUGH

1194
00:44:59,600 --> 00:45:04,840
INOS LEADS TO -- GMP LEVELS AND

1195
00:45:04,840 --> 00:45:06,920
THAT CAN CROSS ACTIVATE PKA AND

1196
00:45:06,920 --> 00:45:08,680
BOTH OF THESE ENZYMES ARE KNOWN

1197
00:45:08,680 --> 00:45:09,880
TO PHOSPHORYLATE THE CHANNEL TO

1198
00:45:09,880 --> 00:45:12,760
INCREASE ITS ACTIVITY.

1199
00:45:12,760 --> 00:45:15,400
AND THEN THERE IS A GENETIC

1200
00:45:15,400 --> 00:45:19,680
CONDITION CALLED CANTU SYNDROME

1201
00:45:19,680 --> 00:45:20,880
IN WHICH PATIENTS HAVE

1202
00:45:20,880 --> 00:45:21,880
MUTATIONS, GAIN OF FUNCTION

1203
00:45:21,880 --> 00:45:24,520
MUTATIONS IN EITHER OF THE TWO

1204
00:45:24,520 --> 00:45:26,920
KATP CHANNEL SUBUNITS, AND 50%

1205
00:45:26,920 --> 00:45:28,560
OF THESE PATIENTS HAVE

1206
00:45:28,560 --> 00:45:31,000
LYMPHEDEMA.

1207
00:45:31,000 --> 00:45:33,280
SO WE THINK THAT THESE

1208
00:45:33,280 --> 00:45:35,440
OBSERVATIONS ARE BASICALLY

1209
00:45:35,440 --> 00:45:36,440
CONSISTENT WITH A LOT OF THE

1210
00:45:36,440 --> 00:45:39,520
LITERATURE SHOWING IN METABOLIC

1211
00:45:39,520 --> 00:45:42,200
DISORDERS     

1212
00:45:42,200 --> 00:45:43,480
DISORDERS, VARIOUS TYPES,

1213
00:45:43,480 --> 00:45:46,680
THERE'S LYMPHATIC CONTRACTILE

1214
00:45:46,680 --> 00:45:48,480
DYSFUNCTION, SECONDARY VALVE

1215
00:45:48,480 --> 00:45:50,400
DYSFUNCTION AND COLLECTING

1216
00:45:50,400 --> 00:45:51,360
VESTIBLE HYPERPERMEABILITY.

1217
00:45:51,360 --> 00:45:52,520
NOW I WANT TO TALK ABOUT THE

1218
00:45:52,520 --> 00:45:55,680
LAST TOPIC, WHICH IS ENTRAINMENT

1219
00:45:55,680 --> 00:45:57,440
OF CONTRACTION WAVES.

1220
00:45:57,440 --> 00:45:59,840
SO THIS MOVIE ON THE LEFT SHOWS

1221
00:45:59,840 --> 00:46:03,160
A LYMPHATIC VESSEL, A POPLITEAL

1222
00:46:03,160 --> 00:46:03,920
VESSEL ISOLATED FROM THE MOUSE

1223
00:46:03,920 --> 00:46:05,800
AND IT'S SHOWING SPONTANEOUS

1224
00:46:05,800 --> 00:46:06,600
CONTRACTIONS.

1225
00:46:06,600 --> 00:46:09,280
YOU NOTICE THAT IT'S ALMOST A

1226
00:46:09,280 --> 00:46:10,080
SYNCHRONOUS CONTRACTION OVER THE

1227
00:46:10,080 --> 00:46:12,360
WHOLE LENGTH OF THIS VESSEL.

1228
00:46:12,360 --> 00:46:14,320
SO THE WAY THAT WE QUANTIFY THIS

1229
00:46:14,320 --> 00:46:16,960
IS TO MEASURE DIAMETER AT EACH

1230
00:46:16,960 --> 00:46:18,880
POINT INSTEAD OF A SINGLE POINT,

1231
00:46:18,880 --> 00:46:20,080
EACH POINT ALONG THE VESSEL, AND

1232
00:46:20,080 --> 00:46:22,280
MAP IT AS A FUNCTION OF TIME.

1233
00:46:22,280 --> 00:46:31,480
SO EACH VERTICAL LINE ON THIS

1234
00:46:31,480 --> 00:46:32,160
SPATIO-TEMPORAL MAP IS A VIDEO

1235
00:46:32,160 --> 00:46:32,680
FRAME.

1236
00:46:32,680 --> 00:46:35,480
WHEN YOU COMPILE 10,000 VIDEO

1237
00:46:35,480 --> 00:46:36,800
FRAMES HERE, YOU GET THESE DARK

1238
00:46:36,800 --> 00:46:38,200
BANDS THAT REPRESENT SINGLE

1239
00:46:38,200 --> 00:46:39,320
CONTRACTIONS, SO FOUR SINGLE

1240
00:46:39,320 --> 00:46:41,520
CONTRACTIONS IN THAT MOVIE.

1241
00:46:41,520 --> 00:46:44,240
AND THE INTENSITY OF THE BAND IS

1242
00:46:44,240 --> 00:46:45,640
PROPORTIONAL TO THE DIAMETER

1243
00:46:45,640 --> 00:46:46,120
CHANGE.

1244
00:46:46,120 --> 00:46:47,800
SO THE STRONGER CONSTRICTION,

1245
00:46:47,800 --> 00:46:50,720
THE DARKER THE BAND.

1246
00:46:50,720 --> 00:46:55,400
THE LEFT EDGE REPRESENTS THE

1247
00:46:55,400 --> 00:46:56,520
SPEED OF CONDUCTION.

1248
00:46:56,520 --> 00:47:00,840
YOU CAN GET THE SLOPE THERE.

1249
00:47:00,840 --> 00:47:06,720
AND IF YOU LOOK AT COMPARISON TO

1250
00:47:06,720 --> 00:47:10,480
A VESSEL THAT COMES FROM A KATP

1251
00:47:10,480 --> 00:47:12,560
GAIN OF FUNCTION MOUSE, YOU CAN

1252
00:47:12,560 --> 00:47:15,080
SEE THAT THE CONTRACTION WAVES

1253
00:47:15,080 --> 00:47:17,280
ARE SLOWER CONDUCTING, THE

1254
00:47:17,280 --> 00:47:19,040
CONTRACTIONS ARE WEAKER, THERE

1255
00:47:19,040 --> 00:47:20,800
ARE MULTIPLE PACEMAKER SITES,

1256
00:47:20,800 --> 00:47:23,000
THE ST MAP LOOKS SOMETHING LIKE

1257
00:47:23,000 --> 00:47:24,320
THIS, YOU CAN SEE THE WAVES

1258
00:47:24,320 --> 00:47:27,680
CHANGING DIRECTIONS.

1259
00:47:27,680 --> 00:47:30,640
SO WHEN THE EXCITABILITY OF

1260
00:47:30,640 --> 00:47:31,440
LYMPHATICS MUSCLE IS REDUCED

1261
00:47:31,440 --> 00:47:33,720
THERE ARE CONTINUOUS CONTRACTION

1262
00:47:33,720 --> 00:47:35,920
WAVES, MULTIPLE PACEMAKER SITES,

1263
00:47:35,920 --> 00:47:36,560
CHANGES IN DIRECTION OF THE

1264
00:47:36,560 --> 00:47:38,160
WAVES AND REDUCED CONDUCTION

1265
00:47:38,160 --> 00:47:38,680
SPEED.

1266
00:47:38,680 --> 00:47:40,640
AND SO THIS LAST TEST IS THE

1267
00:47:40,640 --> 00:47:45,280
TEST THAT WE DEVELOPED THAT KIND

1268
00:47:45,280 --> 00:47:46,600
OF UNMASKS WHAT WE'VE BEEN

1269
00:47:46,600 --> 00:47:48,040
MISSING IN STANDARD CONTRACTION

1270
00:47:48,040 --> 00:47:48,360
ASSAYS.

1271
00:47:48,360 --> 00:47:51,360
SO THIS IS A TWO-VALVE SEGMENT,

1272
00:47:51,360 --> 00:47:53,760
INFLOW AND OUTFLOW VALVES, AND

1273
00:47:53,760 --> 00:47:56,720
WE'VE MAPPED OUT ALL THE

1274
00:47:56,720 --> 00:47:58,440
CONTRACTIONS TO SHOW IN THE WILD

1275
00:47:58,440 --> 00:48:00,040
TYPE VESSEL THEY'RE ALL

1276
00:48:00,040 --> 00:48:01,040
ENTRAINED, THEY GET WEAKER AS

1277
00:48:01,040 --> 00:48:02,480
YOU GO TO ELEVATED PRESSURES.

1278
00:48:02,480 --> 00:48:03,800
WE'VE GONE THROUGH THE VIDEOS

1279
00:48:03,800 --> 00:48:06,120
AND MEASURED THE POSITIONS OF

1280
00:48:06,120 --> 00:48:07,560
BOTH VALVES AT EACH POINT IN

1281
00:48:07,560 --> 00:48:13,360
TIME.

1282
00:48:13,360 --> 00:48:19,360
SO WHAT WE DO, WE HOILD THE

1283
00:48:19,360 --> 00:48:21,760
INFLOW PRESSURE CONSTANT AND --

1284
00:48:21,760 --> 00:48:24,360
TO MAKE THE VESSEL PUMP AGAINST

1285
00:48:24,360 --> 00:48:25,560
AN INCREASING OUTPUT LOAD.

1286
00:48:25,560 --> 00:48:28,080
SO AS OUTFLOW PLEASURE

1287
00:48:28,080 --> 00:48:29,520
INCREASES, THE VALVE GOES FROM

1288
00:48:29,520 --> 00:48:32,600
NORMALLY OPEN TO NORMALLY

1289
00:48:32,600 --> 00:48:35,800
CLOSED, AND IT ONLY OPENS

1290
00:48:35,800 --> 00:48:37,240
TRANSIENTLY DURING EACH

1291
00:48:37,240 --> 00:48:38,720
CONTRACTION AS IT EJECTS A SMALL

1292
00:48:38,720 --> 00:48:40,160
AMOUNT OF LYMPH.

1293
00:48:40,160 --> 00:48:41,640
WHEN THE PUMP REACHES A CERTAIN

1294
00:48:41,640 --> 00:48:42,960
POINT, IN THIS CASE ABOUT

1295
00:48:42,960 --> 00:48:44,240
9 CENTIMETERS OF WATER, IT NO

1296
00:48:44,240 --> 00:48:46,160
LONGER OPENS THE OUTPUT VALVE.

1297
00:48:46,160 --> 00:48:47,880
THAT'S AN INDICATOR THAT WE'VE

1298
00:48:47,880 --> 00:48:50,760
REACHED THE PUM LIMIT.

1299
00:48:50,760 --> 00:48:53,880
IF WE DO THIS SAME EXPERIMENT IN

1300
00:48:53,880 --> 00:48:55,920
A KATP GAIN OF FUNCTION MOUSE,

1301
00:48:55,920 --> 00:48:57,880
WE CAN SEE THAT THE PUMP LIMIT

1302
00:48:57,880 --> 00:48:59,080
HERE IS LESS THAN 1.

1303
00:48:59,080 --> 00:49:03,080
SO IT'S A REALLY PATHETIC PUMPER

1304
00:49:03,080 --> 00:49:04,480
EVEN THOUGH THE M PLI TEUD AND

1305
00:49:04,480 --> 00:49:06,680
FREQUENCY IS HIGHER, THE

1306
00:49:06,680 --> 00:49:07,720
AMPLITUDE IS NOT THAT MUCH

1307
00:49:07,720 --> 00:49:09,120
DIFFERENT THAN THE CONTROL.

1308
00:49:09,120 --> 00:49:11,880
SO IF WE COMPARE THE ANALYSIS OF

1309
00:49:11,880 --> 00:49:15,280
CONTRACTILE ACTIVITY WITH A

1310
00:49:15,280 --> 00:49:16,360
CONVENTIONAL ANALYSIS WITH THE

1311
00:49:16,360 --> 00:49:17,920
PUMP TEST, IT LOOKS LIKE THIS.

1312
00:49:17,920 --> 00:49:19,920
THERE'S BARELY ANY IMPAIRMENT IN

1313
00:49:19,920 --> 00:49:20,640
AMPLITUDE.

1314
00:49:20,640 --> 00:49:23,400
THE FREQUENCY IN THE

1315
00:49:23,400 --> 00:49:25,080
KNOCKOUTS -- OR KNOCK-IN MICE IS

1316
00:49:25,080 --> 00:49:26,160
ACTUALLY HIGHER, AND THERE'S NO

1317
00:49:26,160 --> 00:49:28,240
DIFFERENCE IN THE PUMP FLOW

1318
00:49:28,240 --> 00:49:28,480
CURVES.

1319
00:49:28,480 --> 00:49:31,240
BUT IF YOU LOOK AT THE VESSELS

1320
00:49:31,240 --> 00:49:33,000
WHEN THEY'RE FORCED TO PUMP

1321
00:49:33,000 --> 00:49:36,480
AGAINST A LOAD, IT'S VERY, VERY

1322
00:49:36,480 --> 00:49:37,880
CLEAR THAT THERE'S A HUGE

1323
00:49:37,880 --> 00:49:40,080
IMPAIRMENT IN THE SUR2 GAIN OF

1324
00:49:40,080 --> 00:49:40,880
FUNCTION MICE.

1325
00:49:40,880 --> 00:49:45,000
SO IN CONCLUSION, LYMPHATIC

1326
00:49:45,000 --> 00:49:46,800
DYSFUNCTION UNDER CONDITIONS OF

1327
00:49:46,800 --> 00:49:48,560
METABOLIC STRESS APPEARS TO

1328
00:49:48,560 --> 00:49:49,360
INCLUDE IMPAIRED CONTRACTILE

1329
00:49:49,360 --> 00:49:51,120
STRENGTH AND PACEMAKER

1330
00:49:51,120 --> 00:49:53,200
FREQUENCY, VALVE BACKLEAK AND

1331
00:49:53,200 --> 00:49:54,400
INCOMPETENCY, LACK OF

1332
00:49:54,400 --> 00:49:57,000
CONTRACTION WAVE ENTRAINMENT,

1333
00:49:57,000 --> 00:50:01,000
HYPERPERMEABILITY OF COLLECTING

1334
00:50:01,000 --> 00:50:04,600
VESSELS, AND THE UNDERLYING

1335
00:50:04,600 --> 00:50:07,120
MECHANISMS INCLUDE ACTIVATION OF

1336
00:50:07,120 --> 00:50:07,440
CHANNELS.

1337
00:50:07,440 --> 00:50:10,120
IN TERMS OF GAPS AND

1338
00:50:10,120 --> 00:50:10,800
OPPORTUNITIES, RELATED TO THIS

1339
00:50:10,800 --> 00:50:12,400
TALK, WE NEED TO UNDERSTAND THE

1340
00:50:12,400 --> 00:50:13,840
PRESSURES AND FLOWS IN HEALTHY

1341
00:50:13,840 --> 00:50:16,520
AND DYSFUNCTIONAL LYMPHATIC

1342
00:50:16,520 --> 00:50:17,600
NETWORKS, VIRTUALLY NOTHING IS

1343
00:50:17,600 --> 00:50:19,680
KNOWN IN MICE ABOUT THIS.

1344
00:50:19,680 --> 00:50:21,720
WE NEED TO UNDERSTAND THE

1345
00:50:21,720 --> 00:50:23,320
DEVELOP MEANT ORIGIN OF

1346
00:50:23,320 --> 00:50:26,360
LYMPHATIC MUSCLE CELLS, WHAT

1347
00:50:26,360 --> 00:50:27,920
CONTRACTILE PROTEINS THEY

1348
00:50:27,920 --> 00:50:30,120
EXPRESS, WHAT ION CHANNELS THEY

1349
00:50:30,120 --> 00:50:30,920
EXPRESS.

1350
00:50:30,920 --> 00:50:32,160
THESE TELL TELEUS HOW THE MUSCLE

1351
00:50:32,160 --> 00:50:33,760
FUNCTION IS REGULATED, AND

1352
00:50:33,760 --> 00:50:35,440
WHETHER THERE ARE REGIONAL

1353
00:50:35,440 --> 00:50:36,320
DIFFERENCES IN THESE THINGS.

1354
00:50:36,320 --> 00:50:38,160
AND THEN THE EXTENT TO WHICH

1355
00:50:38,160 --> 00:50:39,160
CONTRACTILE AND VALVE

1356
00:50:39,160 --> 00:50:43,000
DYSFUNCTION RESULT FROM, OTHER

1357
00:50:43,000 --> 00:50:44,120
PATHOLOGIES, OR CONTRIBUTE TO

1358
00:50:44,120 --> 00:50:45,000
THOSE PATHOLOGIES.

1359
00:50:45,000 --> 00:50:46,520
FINALLY, WE NEED TO DEVELOP MORE

1360
00:50:46,520 --> 00:50:50,080
RELEVANT ANIMAL MODELS OF THE

1361
00:50:50,080 --> 00:50:50,960
LYMPHATIC SYSTEM.

1362
00:50:50,960 --> 00:50:52,800
OUR CURRENT MOUSE MODELS OF

1363
00:50:52,800 --> 00:50:54,360
METABOLIC SYNDROME AND SECONDARY

1364
00:50:54,360 --> 00:50:56,160
LYMPHEDEMA ARE PRETTY

1365
00:50:56,160 --> 00:50:56,680
INADEQUATE.

1366
00:50:56,680 --> 00:50:58,360
AND SOME ASPECTS OF MOUSE

1367
00:50:58,360 --> 00:50:59,400
LYMPHATIC PHYSIOLOGY MAY NOT

1368
00:50:59,400 --> 00:51:00,760
APPLY TO HUMANS.

1369
00:51:00,760 --> 00:51:02,520
FOR EXAMPLE, VISCERAL AND

1370
00:51:02,520 --> 00:51:04,040
THORACIC CLEBTING LYMPHATICS DO

1371
00:51:04,040 --> 00:51:05,280
NOT PUMP AT ALL IN A MOUSE.

1372
00:51:05,280 --> 00:51:07,160
THEY DO IN EVERY OTHER SPECIES.

1373
00:51:07,160 --> 00:51:09,120
MICE ARE NOT EXPOSED TO CHRONIC

1374
00:51:09,120 --> 00:51:10,240
GRAVITATIONAL LOADS, WHICH IN

1375
00:51:10,240 --> 00:51:13,440
HUMANS IS ALMOST ALWAYS WHEN

1376
00:51:13,440 --> 00:51:14,440
LYMPHEDEMA DEVELOPS.

1377
00:51:14,440 --> 00:51:16,080
AND FINALLY, THERE ARE VERY FEW

1378
00:51:16,080 --> 00:51:17,360
FUNCTIONAL STUDIES OF HUMAN

1379
00:51:17,360 --> 00:51:18,640
VESSELS THAT HAVE BEEN

1380
00:51:18,640 --> 00:51:20,480
PERFORMED, ESPECIALLY HEALTHY

1381
00:51:20,480 --> 00:51:20,920
VESSELS.

1382
00:51:20,920 --> 00:51:24,920
SO I THANK MY COLLABORATORS, MY

1383
00:51:24,920 --> 00:51:27,520
CURRENT POST    POSTDOC AND FORB

1384
00:51:27,520 --> 00:51:27,840
MEMBERS.

1385
00:51:27,840 --> 00:51:38,200
THANK YOU VERY MUCH.

1386
00:51:42,840 --> 00:51:43,680
>> THANK YOU VERY MUCH,

1387
00:51:43,680 --> 00:51:44,520
DR. DAVIS.

1388
00:51:44,520 --> 00:51:46,160
NOW IT'S MY PLEASURE TO WELCOME

1389
00:51:46,160 --> 00:51:52,880
OUR MODERATOR, DR. NATASZA

1390
00:51:52,880 --> 00:51:53,440
KURPIOS, CORNELL UNIVERSITY.

1391
00:51:53,440 --> 00:51:54,920
SHE'S CONTRIBUTED SIGNIFICANTLY

1392
00:51:54,920 --> 00:51:56,720
TO OUR UNDERSTANDING OF

1393
00:51:56,720 --> 00:51:57,680
LYMPHATIC DEVELOPMENT AS WELL AS

1394
00:51:57,680 --> 00:52:01,360
THE MECHANISMS IN ORGAN

1395
00:52:01,360 --> 00:52:03,160
ACEMETERY AND SHE'LL MODERATE

1396
00:52:03,160 --> 00:52:03,440
SESSION TWO.

1397
00:52:03,440 --> 00:52:04,960
SO TAKE IT AWAY, YOU CAN

1398
00:52:04,960 --> 00:52:06,840
INTRODUCE THE NEXT SPEAKER.

1399
00:52:06,840 --> 00:52:08,360
>> ANDREA, THANKS SO MUCH.

1400
00:52:08,360 --> 00:52:09,480
CAN YOU HEAR ME?

1401
00:52:09,480 --> 00:52:10,760
>> YES, WE CAN.

1402
00:52:10,760 --> 00:52:12,240
>> OKAY, FANTASTIC.

1403
00:52:12,240 --> 00:52:14,120
SO HELLO, EVERYBODY, AND WELCOME

1404
00:52:14,120 --> 00:52:16,280
TO SESSION TWO FROM WHEREVER YOU

1405
00:52:16,280 --> 00:52:17,640
ARE IN THE WORLD.

1406
00:52:17,640 --> 00:52:21,880
WE HAVE AN OUTSTANDING SESSION

1407
00:52:21,880 --> 00:52:23,880
ENTITLED LYMPHATIC DEVELOPMENT

1408
00:52:23,880 --> 00:52:28,080
AND FUNCTION IN HOMEOSTATIC

1409
00:52:28,080 --> 00:52:29,280
DEVELOPMENT, AND OUR FIRST

1410
00:52:29,280 --> 00:52:31,120
SPEAKER OF THE SESSION IS

1411
00:52:31,120 --> 00:52:32,440
DR. OLIVER STONE.

1412
00:52:32,440 --> 00:52:33,960
WELCOME, OLI.

1413
00:52:33,960 --> 00:52:37,840
AND THE TITLE OF OLIVER'S TALK

1414
00:52:37,840 --> 00:52:40,480
WILL BE LYMPHATIC DEVELOPMENT,

1415
00:52:40,480 --> 00:52:42,000
DEVELOPMENTAL ORIGINS OF

1416
00:52:42,000 --> 00:52:43,000
LYMPHATIC ENDOTHELIAL CELLS.

1417
00:52:43,000 --> 00:52:43,920
TAKE IT AWAY.

1418
00:52:43,920 --> 00:52:46,640
>> THANK YOU VERY MUCH.

1419
00:52:46,640 --> 00:52:49,840
SO I'M A DEVELOPMENTAL BIOLOGIST

1420
00:52:49,840 --> 00:52:52,480
WORKING AT THE UNIVERSITY OF

1421
00:52:52,480 --> 00:52:53,800
OXFORD, AND WE'RE BROADLY

1422
00:52:53,800 --> 00:52:54,880
INTERESTED IN UNDERSTANDING HOW

1423
00:52:54,880 --> 00:52:57,760
AND WHEN ENDOTHELIAL CELLS ARE

1424
00:52:57,760 --> 00:52:59,320
SPECIALIZED DURING EMBRYONIC

1425
00:52:59,320 --> 00:53:00,520
DEVELOPMENT TO ESTABLISH

1426
00:53:00,520 --> 00:53:01,960
HETEROGENEITY IN THE VASCULAR

1427
00:53:01,960 --> 00:53:02,480
SYSTEM.

1428
00:53:02,480 --> 00:53:05,400
THIS IS HOW WE SERENDIPITOUSLY

1429
00:53:05,400 --> 00:53:06,200
STUMBLED INTO THE LYMPHATIC

1430
00:53:06,200 --> 00:53:11,160
FIELD.

1431
00:53:11,160 --> 00:53:12,960
DURING EMBRYONIC DEVELOPMENT,

1432
00:53:12,960 --> 00:53:17,920
ENDOTHELIAL SPELLS ARE SPECIFIED

1433
00:53:17,920 --> 00:53:21,000
INTO ANGIOBLASTS THAT IMOA ON TO

1434
00:53:21,000 --> 00:53:22,400
PROLIFERATE, FURTHER

1435
00:53:22,400 --> 00:53:24,200
DIFFERENTIATE AND MIGRATE TO

1436
00:53:24,200 --> 00:53:25,320
PERFORM PRIMITIVE VASCULAR

1437
00:53:25,320 --> 00:53:25,720
NETWORKS.

1438
00:53:25,720 --> 00:53:26,920
WE'RE INTERESTED IN

1439
00:53:26,920 --> 00:53:28,040
UNDERSTANDING IF EVENTS AT THESE

1440
00:53:28,040 --> 00:53:29,480
VERY EARLY STAGES OF DEVELOPMENT

1441
00:53:29,480 --> 00:53:30,880
IMPACT THE EVENTUAL

1442
00:53:30,880 --> 00:53:31,880
DIVERSIFICATION OF ENDOTHELIAL

1443
00:53:31,880 --> 00:53:35,400
CELLS INTO THE KIND OF

1444
00:53:35,400 --> 00:53:37,120
ENDOTHELIAL CELLS WE WOULD FIND

1445
00:53:37,120 --> 00:53:38,640
IN CORONARY CELLS, IN THE LIVER,

1446
00:53:38,640 --> 00:53:42,160
FOR EXAMPLE, IMPACTED BY EARLY

1447
00:53:42,160 --> 00:53:43,240
EVENT, AND IMPORTANTLY AS I'M

1448
00:53:43,240 --> 00:53:45,360
SPEAKING TO YOU TODAY, THE

1449
00:53:45,360 --> 00:53:47,640
LYMPHATIC VASCULATURE.

1450
00:53:47,640 --> 00:53:49,880
SO TO GIVE YOU A BRIEF OVERVIEW

1451
00:53:49,880 --> 00:53:51,840
OF THE CURRENT KIND OF MODELS

1452
00:53:51,840 --> 00:53:54,360
WHICH EXIST ON LYMPHATIC

1453
00:53:54,360 --> 00:53:55,800
DEVELOPMENT, AT LEAST THIS IS

1454
00:53:55,800 --> 00:53:58,160
SPECIFICALLY REFERRING TO MICE.

1455
00:53:58,160 --> 00:54:00,120
SO THE KIND OF EXISTING MODELS

1456
00:54:00,120 --> 00:54:02,960
SUGGEST THAT AROUND EMBRYONIC

1457
00:54:02,960 --> 00:54:04,880
DAY 9.5, ENDOTHELIAL CELLS

1458
00:54:04,880 --> 00:54:06,200
WITHIN VENOUS ENDOTHELIUM, SO

1459
00:54:06,200 --> 00:54:08,800
THIS WOULD BE NOT ONLY THE

1460
00:54:08,800 --> 00:54:11,440
CARDINAL VEIN BUT ALSO

1461
00:54:11,440 --> 00:54:13,440
INTERSEGMENTAL VESSELS OF THE

1462
00:54:13,440 --> 00:54:16,520
MICE EMBRYO, SWITCH ON IN

1463
00:54:16,520 --> 00:54:20,120
RESPONSE TO SOX18, A

1464
00:54:20,120 --> 00:54:22,440
TRANSCRIPTION FACTOR KNOWN AS

1465
00:54:22,440 --> 00:54:23,120
PROX1.

1466
00:54:23,120 --> 00:54:25,000
IT'S BELIEVED THAT FROM THIS

1467
00:54:25,000 --> 00:54:27,240
STAGE, INDUCTION OF PROX1 LEADS

1468
00:54:27,240 --> 00:54:30,720
TO MIGRATION OF LYMPHATIC

1469
00:54:30,720 --> 00:54:31,600
ENDOTHELIAL CELLS FROM THE VEIN

1470
00:54:31,600 --> 00:54:34,760
AND THEN THESE LYMPHATIC

1471
00:54:34,760 --> 00:54:35,880
PROGENITORS SUBSEQUENTLY GO ON

1472
00:54:35,880 --> 00:54:38,440
TO FORM LYMPHATIC VESSELS.

1473
00:54:38,440 --> 00:54:41,040
NOW, OVER MORE RECENT YEARS,

1474
00:54:41,040 --> 00:54:42,120
THERE HAVE ACTUALLY BEEN A

1475
00:54:42,120 --> 00:54:43,800
NUMBER OF DESCRIPTIONS OF

1476
00:54:43,800 --> 00:54:46,000
NON-VENOUS SOURCES FOR LYMPHATIC

1477
00:54:46,000 --> 00:54:47,840
ENDOTHELIAL CELLS, SO THESE HAVE

1478
00:54:47,840 --> 00:54:48,760
BEEN DESCRIBED IN THE MESENTERY

1479
00:54:48,760 --> 00:54:50,640
IN MICE, THE CARDIAC LYMPHATICS

1480
00:54:50,640 --> 00:54:53,440
AND MORE BROADLY CONTRIBUTING TO

1481
00:54:53,440 --> 00:54:55,240
LYMPHATICS WITHIN THE SKIN.

1482
00:54:55,240 --> 00:54:59,000
BUT THESE ARE SOMEWHAT -- DEEMED

1483
00:54:59,000 --> 00:54:59,680
SOMEWHAT CONTROVERSIAL WITHIN

1484
00:54:59,680 --> 00:55:01,200
THE FIELD.

1485
00:55:01,200 --> 00:55:02,720
SO TO M COME BACK TO OUR

1486
00:55:02,720 --> 00:55:04,200
ORIGINAL INTEREST, SO WE WERE

1487
00:55:04,200 --> 00:55:07,920
INTERESTED IN UNDERSTANDING IF

1488
00:55:07,920 --> 00:55:13,840
CELLS FROM DIFFERENT SUBSETS OF

1489
00:55:13,840 --> 00:55:15,400
MESODERM CONTRIBUTES TO THE

1490
00:55:15,400 --> 00:55:16,520
VASCULATURE, IF THEY MAY HAVE

1491
00:55:16,520 --> 00:55:20,400
DIFFERENT FUNCTIONS THAT COME

1492
00:55:20,400 --> 00:55:21,400
FROM AND ARE LINKED TO THEIR

1493
00:55:21,400 --> 00:55:21,800
ORIGIN.

1494
00:55:21,800 --> 00:55:23,880
SO A NUMBER OF YEARS AGO NOW, WE

1495
00:55:23,880 --> 00:55:29,320
BEGAN BY LINEAGE TRACING CELLS

1496
00:55:29,320 --> 00:55:33,120
FROM MESODERM, WE FOUND THEY DO

1497
00:55:33,120 --> 00:55:34,320
CONTRIBUTE TO SOME EXTENT TO

1498
00:55:34,320 --> 00:55:41,080
BLOOD VESSELS, THEY VERY MUCH

1499
00:55:41,080 --> 00:55:41,800
PREFERENTIALLY CONTRIBUTE TO --

1500
00:55:41,800 --> 00:55:43,880
THIS IS EMBRYONIC DAY 9.5.

1501
00:55:43,880 --> 00:55:45,280
WITHIN THIS DORSAL PORTION OF

1502
00:55:45,280 --> 00:55:47,680
THE VEIN, YOU SEE ENDOTHELIAL

1503
00:55:47,680 --> 00:55:49,640
CELLS DERIVED FROM THIS LINEAGE.

1504
00:55:49,640 --> 00:55:51,720
A DAY LATER, THESE CELLS SWITCH

1505
00:55:51,720 --> 00:55:54,600
ON PROX1 AND IF WE LOOK USING

1506
00:55:54,600 --> 00:55:58,120
FLOW CYTOMETRY AT E13.5, WHAT WE

1507
00:55:58,120 --> 00:55:59,440
SEE IS SOME DEGREE OF

1508
00:55:59,440 --> 00:56:01,880
CONTRIBUTION, THE VAST MAJORITY

1509
00:56:01,880 --> 00:56:03,200
OF LYMPHATIC ENDOTHELIAL CELLS

1510
00:56:03,200 --> 00:56:06,640
ARE DERIVED FROM THIS LINEAGE.

1511
00:56:06,640 --> 00:56:09,400
SO THIS LED US TO PROPOSE A

1512
00:56:09,400 --> 00:56:17,160
REVISED MODEL, WHEREBY -- IT'S

1513
00:56:17,160 --> 00:56:18,720
THOSE CELLS WHICH GO ON TO

1514
00:56:18,720 --> 00:56:20,320
BECOME LYMPHATICS.

1515
00:56:20,320 --> 00:56:23,840
AND ACTUALLY TO FURTHER THIS, WE

1516
00:56:23,840 --> 00:56:29,360
HAVE DELETED PROX 1 WITHIN THE

1517
00:56:29,360 --> 00:56:31,560
PAX3 LINEAGE AND WHERE WE

1518
00:56:31,560 --> 00:56:33,680
ACHIEVED RECOMBINATION OF PROX1,

1519
00:56:33,680 --> 00:56:36,840
LYMPHATIC VESSELS DON'T FORM,

1520
00:56:36,840 --> 00:56:37,840
INDICATING THERE'S A

1521
00:56:37,840 --> 00:56:39,120
PREREQUIREMENT FOR CELLS TO PASS

1522
00:56:39,120 --> 00:56:40,200
THROUGH THIS LINEAGE AND THE

1523
00:56:40,200 --> 00:56:44,120
OTHER LINEAGES DON'T APPEAR TO

1524
00:56:44,120 --> 00:56:50,040
HAVE THE CAPACITY TO DO SO.

1525
00:56:50,040 --> 00:56:53,680
TO TRY AND UNDERSTAND WHAT MIGHT

1526
00:56:53,680 --> 00:56:56,120
BE DIFFERENT DURING EMBRYONIC

1527
00:56:56,120 --> 00:56:56,880
DEVELOPMENT, WHEREAS THE REST OF

1528
00:56:56,880 --> 00:57:02,120
THE VEIN IS NOT DOING SO, WE

1529
00:57:02,120 --> 00:57:06,160
CHOSE TO PERFORM SEQUENCING

1530
00:57:06,160 --> 00:57:08,360
ACROSS THESE KEY STAGES OF

1531
00:57:08,360 --> 00:57:09,120
DEVELOPMENT FOR LYMPHATIC

1532
00:57:09,120 --> 00:57:10,200
FORMATION.

1533
00:57:10,200 --> 00:57:20,840
SO WE ISOLATED --   FACS SORTED

1534
00:57:23,560 --> 00:57:24,520
CELLS, AND A STRIKING

1535
00:57:24,520 --> 00:57:26,280
OBSERVATION THAT WE MADE

1536
00:57:26,280 --> 00:57:31,520
INITIALLY LOOKING AT EMBRYONIC

1537
00:57:31,520 --> 00:57:33,840
DAY 9.5 WAS THE PRESENCE OF A

1538
00:57:33,840 --> 00:57:35,280
NUMBER OF DIFFERENT POPULATIONS

1539
00:57:35,280 --> 00:57:38,560
OF ETV 2 EXPRESSING ANGIOBLASTS.

1540
00:57:38,560 --> 00:57:40,280
FOR ME, AT LEAST, I THOUGHT THAT

1541
00:57:40,280 --> 00:57:43,000
THE PROCESS OF ANGIOBLAST

1542
00:57:43,000 --> 00:57:44,320
DIFFERENTIATION WAS OVER AT THIS

1543
00:57:44,320 --> 00:57:45,320
STAGE.

1544
00:57:45,320 --> 00:57:48,000
SO IT WAS QUITE AN INTRIGUING

1545
00:57:48,000 --> 00:57:48,360
FINDING.

1546
00:57:48,360 --> 00:57:52,080
SO THESE ETV 2 EXPRESSING

1547
00:57:52,080 --> 00:57:55,320
ANGIOBLASTS EMERGED FROM

1548
00:57:55,320 --> 00:57:56,000
MESENCHYMAL MESODERM, AND THEY

1549
00:57:56,000 --> 00:57:58,640
DID NOT EXPRESS MATURITY

1550
00:57:58,640 --> 00:58:02,240
ENDOTHELIAL MARKERS SUCH AS

1551
00:58:02,240 --> 00:58:02,440
PECAM.

1552
00:58:02,440 --> 00:58:04,000
IF YOU LOOK AT THE EMBRYO, THIS

1553
00:58:04,000 --> 00:58:06,320
IS ETV 2 EXPRESSIONS TOGETHER

1554
00:58:06,320 --> 00:58:08,080
WITH A MATURE MARKER OF

1555
00:58:08,080 --> 00:58:09,160
ENDOTHELIUM, WE ACTUALLY SEE A

1556
00:58:09,160 --> 00:58:11,040
NUMBER OF DISTINCT POPULATIONS

1557
00:58:11,040 --> 00:58:12,400
OF ANGIOBLASTS SPREAD THROUGHOUT

1558
00:58:12,400 --> 00:58:13,880
THE EMBRYO.

1559
00:58:13,880 --> 00:58:16,600
AND INTRIGUINGLY, WE FOUND ONE

1560
00:58:16,600 --> 00:58:19,360
OF THESE POPULATIONS APPEARS TO

1561
00:58:19,360 --> 00:58:20,880
BE GIVING RISE TO LYMPHATICS.

1562
00:58:20,880 --> 00:58:23,800
SO IF WE LOOK WITHIN OUR UMAP AT

1563
00:58:23,800 --> 00:58:27,080
THE EXPRESSION OF ETV 2 AND THIS

1564
00:58:27,080 --> 00:58:28,880
MASTER REGULATOR PROX1, WE SEE

1565
00:58:28,880 --> 00:58:31,400
AN OVERLAP OF EXPRESSION WITHIN

1566
00:58:31,400 --> 00:58:34,520
THESE LESS MATURE ENDOTHELIAL

1567
00:58:34,520 --> 00:58:37,280
CELLS AS THEY'RE DIFFERENTIATING

1568
00:58:37,280 --> 00:58:38,520
FROM MESODERM, AND WE ACTUALLY

1569
00:58:38,520 --> 00:58:41,960
SEE CELLS WHICH COEXPRESS PROX1

1570
00:58:41,960 --> 00:58:45,280
AND ETV 2 WHICH WE WOULD TERM

1571
00:58:45,280 --> 00:58:49,120
LYMPH ANGIOBLASTS, EXPRESSING

1572
00:58:49,120 --> 00:58:50,640
ENDOTHELIAL DIFFERENTIATION AND

1573
00:58:50,640 --> 00:58:51,080
LYMPHATIC FATE.

1574
00:58:51,080 --> 00:58:53,280
SO IF WE LOOK ACTUALLY WITHIN AN

1575
00:58:53,280 --> 00:58:56,760
EMBRYO, THIS IS EMBRYONIC DAY

1576
00:58:56,760 --> 00:58:58,840
9.5, WE SEE -- SO THIS IS A

1577
00:58:58,840 --> 00:59:00,360
CLOSE-UP HERE OF THIS REGION

1578
00:59:00,360 --> 00:59:01,400
HERE.

1579
00:59:01,400 --> 00:59:04,880
WE SEE CELLS WHICH SIT OUTSIDE

1580
00:59:04,880 --> 00:59:07,520
OF THE VENOUS ENDOTHELIUM IN

1581
00:59:07,520 --> 00:59:09,720
BETWEEN SEGMENTAL VESSELS WHICH

1582
00:59:09,720 --> 00:59:11,880
COEXPRESS PROX1 AND ETV 2.

1583
00:59:11,880 --> 00:59:15,040
THIS IS IN SITU, WE SEE THE SAME

1584
00:59:15,040 --> 00:59:17,880
WITH MRNA -- SORRY -- WITH

1585
00:59:17,880 --> 00:59:19,200
IMMUNE STAINING, AND ACTUALLY IN

1586
00:59:19,200 --> 00:59:21,120
OTHER REGIONS OF THE EMBRYO, SO

1587
00:59:21,120 --> 00:59:24,600
THESE IMAGES ARE TAKEN FROM THE

1588
00:59:24,600 --> 00:59:25,800
PHARYNGEAL ARTERIES SHOWN TO BE

1589
00:59:25,800 --> 00:59:28,040
A SOURCE OF LYMPHATIC

1590
00:59:28,040 --> 00:59:29,280
ENDOTHELIAL CELLS BY A COUPLE OF

1591
00:59:29,280 --> 00:59:33,000
OTHER GROUPS, AGAIN, WE FIND ETV

1592
00:59:33,000 --> 00:59:35,000
2 AND PROX1 COEXPRESSING CELLS

1593
00:59:35,000 --> 00:59:36,880
WHICH DO NOT EXPRESS CELL

1594
00:59:36,880 --> 00:59:38,400
MARKERS.

1595
00:59:38,400 --> 00:59:41,040
SO DE NOVO SYNTHSIFS LYMPHATIC

1596
00:59:41,040 --> 00:59:44,080
CELLS FROM A MESODERMAL

1597
00:59:44,080 --> 00:59:44,840
PROGENITOR, WE BELIEVE.

1598
00:59:44,840 --> 00:59:46,680
WE THEN TURNED TO TRY AND

1599
00:59:46,680 --> 00:59:47,440
UNDERSTAND WHERE THESE CELLS

1600
00:59:47,440 --> 00:59:50,560
MIGHT BE ENDING UP SO WE'VE USED

1601
00:59:50,560 --> 00:59:52,520
CONDITIONAL LINEAGE APPROACH,

1602
00:59:52,520 --> 00:59:55,040
INS DUED WITH TAMOXIFEN AT

1603
00:59:55,040 --> 00:59:56,320
VARIOUS STAGES DURING EMBRYONIC

1604
00:59:56,320 --> 00:59:56,640
DEVELOPMENT.

1605
00:59:56,640 --> 01:00:00,440
WHEN WE LOOK AT BLOOD

1606
01:00:00,440 --> 01:00:02,440
ENDOTHELIAL CELL

1607
01:00:02,440 --> 01:00:03,200
DIFFERENTIATION, IT'S

1608
01:00:03,200 --> 01:00:04,680
EFFECTIVELY LOST BY EMBRYONIC

1609
01:00:04,680 --> 01:00:07,080
DAY 9, WHEREAS IF WE LOOK AT

1610
01:00:07,080 --> 01:00:08,640
LYMPHATIC ENDOTHELIAL CELLS WE

1611
01:00:08,640 --> 01:00:10,000
STILL SEE A POPULATION OF CELLS

1612
01:00:10,000 --> 01:00:11,880
EMERGING WHICH ARE LABELED BY

1613
01:00:11,880 --> 01:00:13,600
TAMOXIFEN AT THIS STAGE,

1614
01:00:13,600 --> 01:00:15,480
INDICATING THAT THERE APPEARS TO

1615
01:00:15,480 --> 01:00:16,640
BE, DURING DEVELOPMENT, THE

1616
01:00:16,640 --> 01:00:20,000
ACQUISITION OF KIND OF A

1617
01:00:20,000 --> 01:00:21,120
RESTRICTED FATE OF CELLS

1618
01:00:21,120 --> 01:00:23,000
SPECIFICALLY GIVING RISE TO

1619
01:00:23,000 --> 01:00:26,320
LYMPHATICS, PROVIDING FURTHER

1620
01:00:26,320 --> 01:00:27,600
SUPPORT FOR LYMPH ANGIOBLAST.

1621
01:00:27,600 --> 01:00:29,320
IF WE LOOK WITHIN CROSS-SECTION

1622
01:00:29,320 --> 01:00:31,960
OF AN EMBRYO, EMBRYONIC DAY

1623
01:00:31,960 --> 01:00:34,880
10.5, AND THIS IS WITH TAMOXIFEN

1624
01:00:34,880 --> 01:00:37,800
ADMINISTERED EMBRYONIC DAY 9, WE

1625
01:00:37,800 --> 01:00:41,280
SEE CLOSE TO 70 TO 80% OF CELLS

1626
01:00:41,280 --> 01:00:45,080
OUTSIDE OF THE VEIN ARE LABELED

1627
01:00:45,080 --> 01:00:46,840
WITH TAMOXIFEN AT THIS STAGE,

1628
01:00:46,840 --> 01:00:48,360
WHEREAS THE VAST MAJORITY OF

1629
01:00:48,360 --> 01:00:50,400
VENOUS ENDOTHELIAL CELLS ARE NOT

1630
01:00:50,400 --> 01:00:50,760
LABELED.

1631
01:00:50,760 --> 01:00:53,280
ALTHOUGH WE DO BELIEVE THAT THE

1632
01:00:53,280 --> 01:00:57,120
VEIN ITSELF IS STILL GROWING AT

1633
01:00:57,120 --> 01:00:58,720
THESE STAGES, SO THERE IS

1634
01:00:58,720 --> 01:01:00,560
SOME DEGREE OF CONTRIBUTION.

1635
01:01:00,560 --> 01:01:04,280
IF WE LOOK AT SLIGHTLY LATER

1636
01:01:04,280 --> 01:01:08,080
STAGES, TO LOOK AT THE KIND OF

1637
01:01:08,080 --> 01:01:11,760
MORE INITIAL LYMPHATIC

1638
01:01:11,760 --> 01:01:13,640
STRUCTURE, WITH TAMOXIFEN AT

1639
01:01:13,640 --> 01:01:15,400
THESE EARLY STAGES WE SEE BROAD

1640
01:01:15,400 --> 01:01:17,960
LABELING OF ALL LYMPHATIC

1641
01:01:17,960 --> 01:01:18,960
ENDOTHELIAL CELLS AS WELL AS

1642
01:01:18,960 --> 01:01:21,720
SOME BLOOD ENDO THELIUM.

1643
01:01:21,720 --> 01:01:24,960
AT EMBRYONIC DAY 9, WE SEE MOST

1644
01:01:24,960 --> 01:01:26,320
LYMPHATIC ENDOTHELIAL CELLS ARE

1645
01:01:26,320 --> 01:01:27,440
LABELED AND THERE IS STILL SO

1646
01:01:27,440 --> 01:01:29,600
THE MINOR LABELING OF THE

1647
01:01:29,600 --> 01:01:30,840
CARDINAL VEIN, WHEREAS THIS

1648
01:01:30,840 --> 01:01:32,760
LABELING IS COMPLETELY LOST BY

1649
01:01:32,760 --> 01:01:35,800
EMBRYONIC DAY 10.

1650
01:01:35,800 --> 01:01:39,120
SO TO KIND OF COME BACK TO THE

1651
01:01:39,120 --> 01:01:41,440
EXISTING MODEL, IF THIS MODEL

1652
01:01:41,440 --> 01:01:44,840
WERE TO, IN FACT, BE PRECISELY

1653
01:01:44,840 --> 01:01:46,080
HOW THINGS HAPPEN, ONE WOULD

1654
01:01:46,080 --> 01:01:47,360
IMAGINE THAT PROLIFERATION OF

1655
01:01:47,360 --> 01:01:49,280
CELLS WITHIN THE EXISTING VENOUS

1656
01:01:49,280 --> 01:01:51,800
ENDOTHELIUM WOULD HAVE TO BE

1657
01:01:51,800 --> 01:01:53,000
VERY RAPID IN ORDER TO FULFILL

1658
01:01:53,000 --> 01:01:56,280
THE RAPID EXPANSION OF LYMPHATIC

1659
01:01:56,280 --> 01:01:57,120
ENDOTHELIAL CELLS THAT OCCURS

1660
01:01:57,120 --> 01:01:57,960
OVER DEVELOPMENT.

1661
01:01:57,960 --> 01:02:01,960
IN COLLABORATION WITH THE LAB IN

1662
01:02:01,960 --> 01:02:03,920
MUNSTER, WE LOOKED INTO THE

1663
01:02:03,920 --> 01:02:06,360
ABSOLUTE NUMBERS OF END   ENDOTL

1664
01:02:06,360 --> 01:02:07,760
CELLS WHICH EMERGE DURING THESE

1665
01:02:07,760 --> 01:02:09,560
EARLY STAGES OF DEVELOPMENT AS

1666
01:02:09,560 --> 01:02:10,400
WELL AS THE VEIN ITSELF.

1667
01:02:10,400 --> 01:02:12,120
YOU CAN SEE THAT THERE IS VERY

1668
01:02:12,120 --> 01:02:15,560
RAPID EXPANSION OF -- SO IN

1669
01:02:15,560 --> 01:02:17,000
GREEN WE HAVE PROX1 POSITIVE

1670
01:02:17,000 --> 01:02:20,680
CELLS OUTSIDE OF THE VEIN, THEY

1671
01:02:20,680 --> 01:02:21,640
RAPIDLY INCREASE WITHIN THE

1672
01:02:21,640 --> 01:02:24,080
SPACE OF A DAY AND A HALF.

1673
01:02:24,080 --> 01:02:27,960
SO THIS WOULD SUGGEST THAT THE

1674
01:02:27,960 --> 01:02:29,800
VENOUS ENDOTHELIUM WOULD BE

1675
01:02:29,800 --> 01:02:30,600
EXTREMELY PROLIFERATIVE.

1676
01:02:30,600 --> 01:02:33,320
WHEN WE WENT BACK TO OUR SINGLE

1677
01:02:33,320 --> 01:02:34,640
CELL ANALYSIS, LOOKING

1678
01:02:34,640 --> 01:02:38,040
SPECIFICALLY AT CLUSTERS DERIVED

1679
01:02:38,040 --> 01:02:40,560
FROM VENOUS AND ANGIOBLAST

1680
01:02:40,560 --> 01:02:41,360
PROGENITOR, WE ACTUALLY SEE THIS

1681
01:02:41,360 --> 01:02:44,800
IS NOT THE CASE.

1682
01:02:44,800 --> 01:02:48,200
AND FURTHER WORK BY THE LAB OF

1683
01:02:48,200 --> 01:02:49,680
FREEDOM AND KIEFER HAS

1684
01:02:49,680 --> 01:02:51,160
DEMONSTRATED THAT, IN FACT, CELL

1685
01:02:51,160 --> 01:02:52,200
CYCLE DURATION IN CELLS WITHIN

1686
01:02:52,200 --> 01:02:55,080
THE VEIN IS ACTUALLY MUCH LOWER,

1687
01:02:55,080 --> 01:02:57,240
PROVIDING FURTHER EVIDENCE THAT

1688
01:02:57,240 --> 01:02:59,080
THE VEIN ITSELF IS UNLIKELY TO

1689
01:02:59,080 --> 01:03:03,320
PROVIDE A MASSIVE SOURCE OF

1690
01:03:03,320 --> 01:03:04,360
LYMPHATIC ENDOTHELIAL CELLS

1691
01:03:04,360 --> 01:03:05,120
DURING DEVELOPMENT.

1692
01:03:05,120 --> 01:03:06,720
SO TO COME BACK TO KIND OF THIS

1693
01:03:06,720 --> 01:03:08,240
MODEL, THERE'S A LOT OF DATA

1694
01:03:08,240 --> 01:03:09,560
THAT I HAVEN'T SHOWN WHICH IS IN

1695
01:03:09,560 --> 01:03:12,160
A PRE-PRINT THAT WE RECENTLY PUT

1696
01:03:12,160 --> 01:03:13,960
ON TO BIOARCHIVE, BUT WE NOW

1697
01:03:13,960 --> 01:03:15,160
BELIEVE THAT ACTUALLY A

1698
01:03:15,160 --> 01:03:16,600
SIGNIFICANT PROPORTION OF

1699
01:03:16,600 --> 01:03:18,880
LYMPHATIC ENDOTHELIAL CELLS

1700
01:03:18,880 --> 01:03:20,800
NEVER ENTER VENOUS ENDOTHELIUM

1701
01:03:20,800 --> 01:03:22,120
AND DIRECTLY ARE SPECIFIED TO

1702
01:03:22,120 --> 01:03:23,760
LYMPHATIC VESSELS, AND THAT

1703
01:03:23,760 --> 01:03:24,840
ACTUALLY THE PROPORTION OF CELLS

1704
01:03:24,840 --> 01:03:26,440
THAT DO LEAVE THE VEIN IS LIKELY

1705
01:03:26,440 --> 01:03:28,560
VERY LIMITED, AND PERHAPS

1706
01:03:28,560 --> 01:03:31,400
CONTRIBUTES MOSTLY TOWARDS

1707
01:03:31,400 --> 01:03:31,920
LYMPHOVENOUS VALVES.

1708
01:03:31,920 --> 01:03:33,840
IN TERMS OF WHAT I PERCEIVE IN

1709
01:03:33,840 --> 01:03:35,640
THE CONTEXT OF THIS TALK TO BE

1710
01:03:35,640 --> 01:03:40,320
GAPS, NEEDS AND OPPORTUNITIES, I

1711
01:03:40,320 --> 01:03:42,720
THINK THIS KIND OF NEW MODEL OF

1712
01:03:42,720 --> 01:03:44,240
HOW LYMPHATIC ENDOTHELIAL CELLS

1713
01:03:44,240 --> 01:03:45,360
ARE SPECIFIED EARLY IN

1714
01:03:45,360 --> 01:03:46,840
DEVELOPMENT GIVES US THE

1715
01:03:46,840 --> 01:03:49,000
OPPORTUNITY TO POTENTIALLY

1716
01:03:49,000 --> 01:03:50,960
IDENTIFY NEW GENES, CONTROLLING

1717
01:03:50,960 --> 01:03:54,240
THE EARLY STEPS OF LYMPHATIC

1718
01:03:54,240 --> 01:03:55,200
ENDOTHELIAL CELL SPECIFICATION.

1719
01:03:55,200 --> 01:03:56,680
AT THE SAME TIME, IDENTIFY

1720
01:03:56,680 --> 01:03:58,440
CAUSATIVE MUTATIONS IN NOVEL

1721
01:03:58,440 --> 01:04:00,800
GENES WHICH MIGHT UNDERPIN

1722
01:04:00,800 --> 01:04:02,280
PRIMARY LYMPHEDEMA IN HUMANS,

1723
01:04:02,280 --> 01:04:04,480
AND A GOAL OF MINE WOULD BE TO

1724
01:04:04,480 --> 01:04:06,880
DEVELOP IN VITRO SYSTEMS TO

1725
01:04:06,880 --> 01:04:08,760
DERIVE LYMPHATIC ENDOTHELIAL

1726
01:04:08,760 --> 01:04:11,600
CELLS FROM HUMAN EMBRYONIC STEM

1727
01:04:11,600 --> 01:04:12,760
CELLS ON THE BASIS OF THIS KIND

1728
01:04:12,760 --> 01:04:14,520
OF NEW PATHWAY OF

1729
01:04:14,520 --> 01:04:15,600
DIFFERENTIATION, WHICH WE

1730
01:04:15,600 --> 01:04:18,920
BELIEVE IS DOMINANT.

1731
01:04:18,920 --> 01:04:20,960
AND THAT JUST LEADS ME TO THANK

1732
01:04:20,960 --> 01:04:22,440
SOME OF THE PEOPLE THAT DID THE

1733
01:04:22,440 --> 01:04:24,080
WORK AT THE UNIVERSITY OF

1734
01:04:24,080 --> 01:04:28,440
OXFORD, AND ALSO OUR

1735
01:04:28,440 --> 01:04:34,120
COLLABORATORS, FRIEDEMANN AND

1736
01:04:34,120 --> 01:04:36,320
KIEFER'S LAB AS WELL AS SOPHIE

1737
01:04:36,320 --> 01:04:36,560
ASTROF.

1738
01:04:36,560 --> 01:04:37,600
>> THANK YOU VERY MUCH,
THAT WAS

1739
01:04:37,600 --> 01:04:38,120
FANTASTIC.

1740
01:04:38,120 --> 01:04:38,800
WE'RE GOING TO HOLD THE

1741
01:04:38,800 --> 01:04:39,880
QUESTIONS FOR THE END OF THE

1742
01:04:39,880 --> 01:04:40,680
DISCUSSION, OKAY?

1743
01:04:40,680 --> 01:04:41,040
>> SOUNDS GOOD.

1744
01:04:41,040 --> 01:04:44,040
>> SO THANKS VERY MUCH.

1745
01:04:44,040 --> 01:04:46,520
SO OUR NEXT SPEAKER IS NATASZA

1746
01:04:46,520 --> 01:04:48,040
KURPIOS, SO THIS IS ME.

1747
01:04:48,040 --> 01:04:49,360
HI, EVERYBODY, AGAIN, AND I WILL

1748
01:04:49,360 --> 01:04:57,120
JUST SHARE MY SLIDES.

1749
01:04:57,120 --> 01:04:58,600
SO OLIVER, IF YOU CAN UNSHARE

1750
01:04:58,600 --> 01:05:00,920
YOUR SLIDES.

1751
01:05:00,920 --> 01:05:01,920
>> I THINK I HAVE.

1752
01:05:01,920 --> 01:05:12,080
>> OKAY.

1753
01:05:13,120 --> 01:05:14,120
GREAT.

1754
01:05:14,120 --> 01:05:16,000
AND SO AGAIN, HELLO, EVERYBODY,

1755
01:05:16,000 --> 01:05:16,520
AND WELCOME.

1756
01:05:16,520 --> 01:05:18,080
THANKS AGAIN FOR THE ORGANIZERS

1757
01:05:18,080 --> 01:05:20,760
TO PUT TOGETHER THIS REALLY

1758
01:05:20,760 --> 01:05:21,640
WONDERFUL AND ALSO REALLY

1759
01:05:21,640 --> 01:05:22,600
IMPORTANT MEETING.

1760
01:05:22,600 --> 01:05:26,760
SO THE TITLE OF MY TALK TODAY IS

1761
01:05:26,760 --> 01:05:32,400
THE ASYMMETRIC PITX2 GENE

1762
01:05:32,400 --> 01:05:39,120
REGULATES INTESTINAL MUSCULAR

1763
01:05:39,120 --> 01:05:42,880
LYMPHATIC MORPHOGENESIS AND

1764
01:05:42,880 --> 01:05:45,280
PROTECTS AGAINST FATTY LIVER

1765
01:05:45,280 --> 01:05:49,560
DISEASE.

1766
01:05:49,560 --> 01:05:51,120
TO SPECIFY LEFT VERSUS RIGHT

1767
01:05:51,120 --> 01:05:52,040
IDENTITY OF ORGANS.

1768
01:05:52,040 --> 01:05:53,480
ONE OF OUR FAVORITE MODELS TO

1769
01:05:53,480 --> 01:05:54,920
STUDY THIS IN A LAB IS THIS

1770
01:05:54,920 --> 01:05:57,160
BEAUTIFUL LOOPING MORPHOGENESIS

1771
01:05:57,160 --> 01:05:58,360
OF THE GI TRACT, AND THE REASON

1772
01:05:58,360 --> 01:05:59,880
IS BECAUSE THE LOOPING

1773
01:05:59,880 --> 01:06:01,120
MORPHOGENESIS IS ESSENTIAL TO

1774
01:06:01,120 --> 01:06:03,680
GUT FORM AND FUNCTION, BUT ALSO

1775
01:06:03,680 --> 01:06:07,080
THAT DIRECTION IS GOVERNED BY

1776
01:06:07,080 --> 01:06:07,840
RULES OF ASYMMETRY.

1777
01:06:07,840 --> 01:06:09,240
SO ONE OF THE MOST IMPORTANT

1778
01:06:09,240 --> 01:06:12,960
GENES TO SPECIFY THIS IS A

1779
01:06:12,960 --> 01:06:14,560
TRANSCRIPTION FACTOR KNOWN AS

1780
01:06:14,560 --> 01:06:17,280
PI.  

1781
01:06:17,280 --> 01:06:18,880
PIT X2.

1782
01:06:18,880 --> 01:06:21,120
IT HAS THIS SHARP EXPRESSION

1783
01:06:21,120 --> 01:06:22,440
PATTERN RESTRICTED TO THE LEFT

1784
01:06:22,440 --> 01:06:24,200
HALF OF THE EMBRYO, AND THAT'S

1785
01:06:24,200 --> 01:06:26,600
WHERE PITX2 SPECIFIES THAT LEFT

1786
01:06:26,600 --> 01:06:28,560
SIDE IDENTITY AND THAT'S WHERE

1787
01:06:28,560 --> 01:06:30,240
PITX2'S ROLE IN LATERALITY HAS

1788
01:06:30,240 --> 01:06:31,840
BEEN EXTENSIVELY STUDIED.

1789
01:06:31,840 --> 01:06:33,360
HOWEVER, SEPARATE TO ITS ROLE IN

1790
01:06:33,360 --> 01:06:36,520
ORGAN LATERALITY, PITX2 HAS AN

1791
01:06:36,520 --> 01:06:38,160
ADDITIONAL ROLE IN ORGAN

1792
01:06:38,160 --> 01:06:38,720
MORPHOGENESIS.

1793
01:06:38,720 --> 01:06:40,400
BUT THIS FUNCTION OF PITX2 HAS

1794
01:06:40,400 --> 01:06:41,960
BEEN CHALLENGING TO STUDY

1795
01:06:41,960 --> 01:06:45,040
BECAUSE OF THE EARLY EMBRYONIC

1796
01:06:45,040 --> 01:06:45,720
LETHALITY THAT'S ASSOCIATED WITH

1797
01:06:45,720 --> 01:06:47,840
LOSS OF ALL OF PITX2 BUT HAS

1798
01:06:47,840 --> 01:06:49,280
BECOME A KEY FOCUS IN OUR LAB.

1799
01:06:49,280 --> 01:06:51,120
SO TO STUDY THIS ROLE IN

1800
01:06:51,120 --> 01:06:52,000
MORPHOGENESIS, OUR LAB SEVERAL

1801
01:06:52,000 --> 01:06:54,680
YEARS AGO HAS SHOWN THAT PITX2

1802
01:06:54,680 --> 01:06:56,520
EXPRESSION IN THE INTESTINE IS

1803
01:06:56,520 --> 01:06:59,720
SIMILARLY RESTRICTED TO THE LEFT

1804
01:06:59,720 --> 01:07:03,160
HALF OF THE DORSAL MESENTERY

1805
01:07:03,160 --> 01:07:05,280
WHERE IT FORMS THE MESENTERIC

1806
01:07:05,280 --> 01:07:07,440
TISSUE AND INITIATES THIS VERY

1807
01:07:07,440 --> 01:07:10,920
IMPORTANT ASYMMETRIC LOOPING

1808
01:07:10,920 --> 01:07:11,240
MORPHOGENESIS.

1809
01:07:11,240 --> 01:07:14,080
IN ADDITION, WE ALSO SHOWED

1810
01:07:14,080 --> 01:07:16,240
PITX2 PATTERNS THE VASCULATURE

1811
01:07:16,240 --> 01:07:17,640
LINKING THAT DEVELOPMENT TO

1812
01:07:17,640 --> 01:07:18,640
VASCULAR PA NERNING.

1813
01:07:18,640 --> 01:07:21,280
SO        PATTERNING.

1814
01:07:21,280 --> 01:07:22,680
WE WANTED TO EXPAND THESE

1815
01:07:22,680 --> 01:07:24,000
FINDINGS AND ASK THE QUESTION

1816
01:07:24,000 --> 01:07:25,640
WHETHER PITX2 ALSO PLAYS A ROLE

1817
01:07:25,640 --> 01:07:28,640
IN VILLUS VASCULATURE AND

1818
01:07:28,640 --> 01:07:30,840
PERHAPS IN GUT ABSORPTIVE ACTION

1819
01:07:30,840 --> 01:07:31,360
POSTNATALLY.

1820
01:07:31,360 --> 01:07:33,880
MY LAB USES THIS HYPOMORPHIC

1821
01:07:33,880 --> 01:07:36,840
MOUSE MODEL WE CALL PITX2-ASE.

1822
01:07:36,840 --> 01:07:38,360
THIS MODEL IS VERY IMPORTANT TO

1823
01:07:38,360 --> 01:07:39,560
US BECAUSE LOSS OF ALL OF PITX2

1824
01:07:39,560 --> 01:07:42,720
RESULTS IN VERY EARLY EMBRYONIC

1825
01:07:42,720 --> 01:07:44,160
LETHALITY AND PRECLUDES LATER

1826
01:07:44,160 --> 01:07:45,200
ANALYSIS.

1827
01:07:45,200 --> 01:07:48,480
WITH ASE MODEL, WE CAN GENERATE

1828
01:07:48,480 --> 01:07:51,000
VIABLE PITX2 IN MUTANT MICE THAT

1829
01:07:51,000 --> 01:07:52,640
CAN VIEF BEYOND BIRTH.

1830
01:07:52,640 --> 01:07:54,600
THE FIRST THING WE NOTED IS

1831
01:07:54,600 --> 01:07:56,000
DESPITE COMPARABLE BODY SIZES

1832
01:07:56,000 --> 01:08:01,680
AND WEIGHTS AT BIRTH, THESE MICE

1833
01:08:01,680 --> 01:08:02,760
FAILED TO GAIN WAIT.

1834
01:08:02,760 --> 01:08:04,600
ONE HYPOTHESIS IS MAYBE PITX2

1835
01:08:04,600 --> 01:08:05,280
REGULATES AB SORPG.

1836
01:08:05,280 --> 01:08:11,960
SO OF COURSE WE LOOKED AT

1837
01:08:11,960 --> 01:08:12,600
LACTEALS.

1838
01:08:12,600 --> 01:08:14,400
THERE WERE FEWER IN THE

1839
01:08:14,400 --> 01:08:17,480
POSTNATAL INTENSATIVE, THIS IS

1840
01:08:17,480 --> 01:08:19,360
DAY 1.5 AFTER BIRTH, THEY HAD

1841
01:08:19,360 --> 01:08:25,080
REDUCED NUMBER OF LACTEAL --

1842
01:08:25,080 --> 01:08:28,040
LACK TEALS PROLIFERATE AND THESE

1843
01:08:28,040 --> 01:08:29,720
EXTENSIONS ARE VERY IMPORTANT

1844
01:08:29,720 --> 01:08:31,760
FOR EXTENSION AND HOMEOSTASIS.

1845
01:08:31,760 --> 01:08:38,760
THIS HAS BEEN SHOWN IN 20 BEN.

1846
01:08:38,760 --> 01:08:41,480
SO THIS WAS EXCITE BUG ALSO

1847
01:08:41,480 --> 01:08:42,240
SURPRISING BECAUSE PITX2

1848
01:08:42,240 --> 01:08:43,760
EXPRESSION IS ABSENT FROM

1849
01:08:43,760 --> 01:08:46,720
LYMPHATIC AND ENDOTHELIAL CELLS

1850
01:08:46,720 --> 01:08:48,000
SO THIS BRINGS ME TO THIS

1851
01:08:48,000 --> 01:08:51,600
BEAUTIFUL PICTURE OF AXIAL

1852
01:08:51,600 --> 01:08:53,680
SMOOTH MUSCLE FIBERS THAT ARE

1853
01:08:53,680 --> 01:08:54,800
SPECIFICALLY FORMED IN THE

1854
01:08:54,800 --> 01:08:55,760
VILLUS.

1855
01:08:55,760 --> 01:08:59,440
AND THIS PICTURE IS TAKEN FROM

1856
01:08:59,440 --> 01:09:00,880
THE PAPER FROM 2015, AND IT'S

1857
01:09:00,880 --> 01:09:02,960
SHOWING US THAT LACTEALS HERE IN

1858
01:09:02,960 --> 01:09:06,760
RED ARE ACTUALLY SURROUNDED BY

1859
01:09:06,760 --> 01:09:09,120
THIS NICHE OF MUSCLE FIBERS.

1860
01:09:09,120 --> 01:09:10,560
IT'S BEEN HYPOTHESIZED THAT

1861
01:09:10,560 --> 01:09:12,440
THESE FIBERS ARE IMPORTANT FOR

1862
01:09:12,440 --> 01:09:14,920
LACTEAL HOMEOSTASIS AND LATER IN

1863
01:09:14,920 --> 01:09:17,200
THE ADULT.

1864
01:09:17,200 --> 01:09:18,360
VERY RECENTLY IT'S BEEN SHOWN

1865
01:09:18,360 --> 01:09:20,040
THAT THESE MUSCLE FIBERS ARE

1866
01:09:20,040 --> 01:09:21,320
CONTRACTILE AND THEY SQUEEZE THE

1867
01:09:21,320 --> 01:09:24,840
ADJACENT RACK    LACTEALS TO PRO

1868
01:09:24,840 --> 01:09:27,000
FACILITATE LIPID TRANSPORT.

1869
01:09:27,000 --> 01:09:29,840
WE ASKED THE QUESTION WHETHER

1870
01:09:29,840 --> 01:09:31,720
OUR PUPS ALREADY HAVE THESE

1871
01:09:31,720 --> 01:09:32,480
DIFFERENTIATED FIBERS.

1872
01:09:32,480 --> 01:09:34,240
INDEED WHEN WE LOOKED AT POST

1873
01:09:34,240 --> 01:09:38,040
DAY TALL       

1874
01:09:38,040 --> 01:09:43,960
POSTNATAL DAY 9, THESE FIBERS IN

1875
01:09:43,960 --> 01:09:45,720
RED -- WE WERE ALSO EXCITED TO

1876
01:09:45,720 --> 01:09:47,320
KNOW THAT ABOUT HALF OF THESE

1877
01:09:47,320 --> 01:09:48,760
SMOOTH MUSCLE FIBERS IN THE

1878
01:09:48,760 --> 01:09:51,040
VILLUS WERE POSITIVE FOR PITX2

1879
01:09:51,040 --> 01:09:53,560
LINEAGE, SO WE HYPOTHESIZE THAT

1880
01:09:53,560 --> 01:09:55,600
PERHAPS PITX2 REGULATES THIS

1881
01:09:55,600 --> 01:09:57,600
MUSCULAR LACTEAL CO-DEVELOPMENT

1882
01:09:57,600 --> 01:09:59,000
THROUGH THE SMOOTH MUSCLE

1883
01:09:59,000 --> 01:09:59,360
LINEAGE.

1884
01:09:59,360 --> 01:10:00,960
SO INDEED WHAT WE SHOW THAT IN

1885
01:10:00,960 --> 01:10:03,360
THE MUTANTS, THESE FIBERS FAIL

1886
01:10:03,360 --> 01:10:04,800
TO ALIGN WITH LACTEAL, SO HERE

1887
01:10:04,800 --> 01:10:07,640
IN A WILD TYPE, AGAIN, THESE ARE

1888
01:10:07,640 --> 01:10:09,240
NEONATES, I APOLOGIZE FOR THE

1889
01:10:09,240 --> 01:10:11,160
JUMPY   

1890
01:10:11,160 --> 01:10:15,160
JUMPY COMPUTER, THIS IS

1891
01:10:15,160 --> 01:10:16,920
POSTNATAL DAY 9, THIS IS

1892
01:10:16,920 --> 01:10:18,920
CONSISTENT WITH THE MUSCLE

1893
01:10:18,920 --> 01:10:20,640
FIBERS SQUEEZING THE ADJACENT

1894
01:10:20,640 --> 01:10:21,800
LACTEAL.

1895
01:10:21,800 --> 01:10:23,240
HOWEVER, IN PITX2 MUTANTS, WHAT

1896
01:10:23,240 --> 01:10:25,520
WE SAW IS SPACES BETWEEN THE

1897
01:10:25,520 --> 01:10:26,960
FIBERS, AND SPACES BETWEEN THE

1898
01:10:26,960 --> 01:10:27,960
LACTEAL.

1899
01:10:27,960 --> 01:10:30,640
SO AGAIN, A NUMBER OF QUESTIONS

1900
01:10:30,640 --> 01:10:33,160
AROSE LIKE, HOW DO THESE AXIAL

1901
01:10:33,160 --> 01:10:34,600
SMOOTH MUSCLE CELLS DEVELOP

1902
01:10:34,600 --> 01:10:37,040
ALONGSIDE LACTEALS AND DO THESE

1903
01:10:37,040 --> 01:10:38,840
LESIONS THAT WE SEE IN PITX2

1904
01:10:38,840 --> 01:10:41,040
MUTANTS HAVE ANYTHING TO DO WITH

1905
01:10:41,040 --> 01:10:42,240
DIETARY LIPID TRANSPORT?

1906
01:10:42,240 --> 01:10:43,480
SO BECAUSE WE ESSENTIALLY KNOW

1907
01:10:43,480 --> 01:10:45,560
NOTHING ABOUT THE ORIGIN OF

1908
01:10:45,560 --> 01:10:47,240
THESE VILLUS FIBERS, WE WANTED

1909
01:10:47,240 --> 01:10:49,720
TO DO TIME KINETICS TO SEE HOW

1910
01:10:49,720 --> 01:10:50,920
DO THEY FORM AND WHEN DO THEY

1911
01:10:50,920 --> 01:10:51,480
FORM.

1912
01:10:51,480 --> 01:10:53,000
SO WE FIRST NOTED CELLS THAT

1913
01:10:53,000 --> 01:10:56,400
HAVE LOW EXPRESSION OF SMOOTH

1914
01:10:56,400 --> 01:10:59,120
MUSCLE ACTIN AT EMBRYONIC DAY

1915
01:10:59,120 --> 01:11:00,200
16.5, RIGHT HERE.

1916
01:11:00,200 --> 01:11:02,080
AND THEY LOOKED LIKE STARFISH,

1917
01:11:02,080 --> 01:11:03,800
SO WE CALL THEM STAR CELLS.

1918
01:11:03,800 --> 01:11:05,360
THEN SHORTLY AFTER WITH THE

1919
01:11:05,360 --> 01:11:06,880
CO-APPEARANCE OF LACTEALS, WE

1920
01:11:06,880 --> 01:11:08,280
NOTED THAT THESE STAR CELLS

1921
01:11:08,280 --> 01:11:10,240
TRANSITION TO THESE ELONGATED

1922
01:11:10,240 --> 01:11:12,120
AXIAL SMOOTH MUSCLE-LIKE CELL

1923
01:11:12,120 --> 01:11:14,520
TYPES THAT ARE NOW VERY CLOSE TO

1924
01:11:14,520 --> 01:11:15,160
LACTEALS.

1925
01:11:15,160 --> 01:11:17,360
AND THEN BY POSTNATAL DAY 9, YOU

1926
01:11:17,360 --> 01:11:19,000
CAN SEE THESE AXIAL SMOOTH

1927
01:11:19,000 --> 01:11:21,480
MUSCLE CELLS WERE PREDOMINANT AT

1928
01:11:21,480 --> 01:11:22,720
THE EXPANSE OF LACTEALS.

1929
01:11:22,720 --> 01:11:30,120
SO WE HIGH    HYPOTHESIZE -- JUE

1930
01:11:30,120 --> 01:11:33,160
THE SMOOTH MUSCLE WE SAW TO

1931
01:11:33,160 --> 01:11:34,040
POSITIVE LINEAGE.

1932
01:11:34,040 --> 01:11:35,240
WE ALSO SHOW THIS TRANSITION

1933
01:11:35,240 --> 01:11:38,400
FROM STAR CELLS TO

1934
01:11:38,400 --> 01:11:39,280
DIFFERENTIATED -- IS DEPENDENT

1935
01:11:39,280 --> 01:11:40,600
ON PITX2 2.

1936
01:11:40,600 --> 01:11:42,000
SO HOW ABOUT LIPID TRANSPORT?

1937
01:11:42,000 --> 01:11:43,000
SO WHAT DO WE KNOW?

1938
01:11:43,000 --> 01:11:44,720
WE KNOW THAT LACTEALS OF COURSE

1939
01:11:44,720 --> 01:11:48,240
ARE THE MAJOR ROUTE THROUGH

1940
01:11:48,240 --> 01:11:50,200
WHICH LIPIDS ARE ABSORBED INTO

1941
01:11:50,200 --> 01:11:51,280
THE HOST CIRCULATION.

1942
01:11:51,280 --> 01:11:52,560
IT'S THE MAJOR BUT NOT THE ONLY

1943
01:11:52,560 --> 01:11:53,040
ONE.

1944
01:11:53,040 --> 01:11:55,880
WE ALSO KNOW THAT SHORTER CHAIN

1945
01:11:55,880 --> 01:11:58,320
SAIDZ AND NON-FATTY NUTRIENTS

1946
01:11:58,320 --> 01:12:00,520
CAN ALSO DIRECTLY ENTER THE

1947
01:12:00,520 --> 01:12:04,080
PORTAL VEIN, MATE JUROR       TD

1948
01:12:04,080 --> 01:12:08,400
SUPPLY TO THE LIVER.

1949
01:12:08,400 --> 01:12:10,040
LYMPHATIC VERSUS PORTAL

1950
01:12:10,040 --> 01:12:12,560
TRANSPORT HAVE VERY DIFFERENT

1951
01:12:12,560 --> 01:12:13,120
METABOLIC CONSEQUENCES.

1952
01:12:13,120 --> 01:12:14,840
LIPIDS ARE TAKEN UP DIRECTLY BY

1953
01:12:14,840 --> 01:12:16,240
ALL ORGANS IN THE BODY.

1954
01:12:16,240 --> 01:12:18,240
HOWEVER, IF THE LIPIDS ENTER THE

1955
01:12:18,240 --> 01:12:20,280
PORTAL VEIN, LIPIDS ARE TAKEN BY

1956
01:12:20,280 --> 01:12:22,160
THE LIVER PRIOR TO BE TAKEN UP

1957
01:12:22,160 --> 01:12:23,960
BY OTHER ORGANS, SO THIS REDUCES

1958
01:12:23,960 --> 01:12:26,920
THE AK   ACCESSIBILITY TO OTHER

1959
01:12:26,920 --> 01:12:27,280
TISSUES.

1960
01:12:27,280 --> 01:12:28,560
THE REASON WHY WE BECAME VERY

1961
01:12:28,560 --> 01:12:32,080
INTERESTED IN THESE TWO

1962
01:12:32,080 --> 01:12:32,720
INDEPENDENT PATHWAYS IS SHOWN ON

1963
01:12:32,720 --> 01:12:34,720
THIS SLIDE, BECAUSE WHENEVER WE

1964
01:12:34,720 --> 01:12:37,000
ISOLATED LIVERS FROM OUR MUTANT

1965
01:12:37,000 --> 01:12:40,040
PUPS, IT NEVER SUNK TO THE

1966
01:12:40,040 --> 01:12:41,160
BOTTOM OF THE TUBE, SUGGESTING

1967
01:12:41,160 --> 01:12:42,240
THAT THEY ARE FATTY.

1968
01:12:42,240 --> 01:12:44,960
SO WE CONFIRMED THIS WITH

1969
01:12:44,960 --> 01:12:46,480
STAINING SHOWN HERE AND ALSO

1970
01:12:46,480 --> 01:12:47,720
WITH HISTOPATHOLOGY, CONCLUDING

1971
01:12:47,720 --> 01:12:52,240
THAT OUR MU TABT PUPS        MUD

1972
01:12:52,240 --> 01:12:55,680
EARLY ONSET OF FAT EE  TY LIVER

1973
01:12:55,680 --> 01:12:59,960
DISEASE SO WHY IS THAT?

1974
01:12:59,960 --> 01:13:01,560
THIS DELETION IMPAIRS THE NORMAL

1975
01:13:01,560 --> 01:13:03,280
FATE OF DIETARY LIPID TRANSPORT

1976
01:13:03,280 --> 01:13:04,640
AND INDEED WE SHOWED THIS WITH

1977
01:13:04,640 --> 01:13:07,800
USING A FLUORESCENT LIPID

1978
01:13:07,800 --> 01:13:10,320
TRASER, THIS IS A LONG CHAIN

1979
01:13:10,320 --> 01:13:12,280
FATTY ACID LIPID TRASER.

1980
01:13:12,280 --> 01:13:15,880
SO AS EXPECTED IN WILD TYPE,

1981
01:13:15,880 --> 01:13:16,960
BODIPY ACCUMULATED IN THE

1982
01:13:16,960 --> 01:13:21,440
MESENTERY COLLECTORS, AND

1983
01:13:21,440 --> 01:13:26,480
VERY -- SIGNAL INTO THE PORTAL

1984
01:13:26,480 --> 01:13:26,840
VEIN.

1985
01:13:26,840 --> 01:13:29,440
BOTH IN THE PORTAL VEIN AND

1986
01:13:29,440 --> 01:13:30,880
LIVER PARENCHYMA SUGGESTING THAT

1987
01:13:30,880 --> 01:13:32,000
INDEED THIS LIPID TRANSPORT

1988
01:13:32,000 --> 01:13:35,080
GROUP IS ALTERED IN PITX2 MUTANT

1989
01:13:35,080 --> 01:13:35,280
MICE.

1990
01:13:35,280 --> 01:13:36,960
SO WHAT WE CAN SUMMARIZE IS THAT

1991
01:13:36,960 --> 01:13:38,840
WE THINK PITX2 IS REQUIRED FOR

1992
01:13:38,840 --> 01:13:40,600
THE NORMAL ROUTE OF DIETARY

1993
01:13:40,600 --> 01:13:42,360
LIPID TRANSPORT AND PROTECTS

1994
01:13:42,360 --> 01:13:44,320
AGAINST FATTY LIVER DISEASE.

1995
01:13:44,320 --> 01:13:46,160
AND SO OUR DATA SUPPORTS THE

1996
01:13:46,160 --> 01:13:48,440
IMPORTANCE OF THIS MUSCULAR

1997
01:13:48,440 --> 01:13:50,520
LACTEAL COMPLEX IN LIPID

1998
01:13:50,520 --> 01:13:51,400
TRANSPORT FUNCTION.

1999
01:13:51,400 --> 01:13:52,680
AND WHAT WE NEED TO UNDERSTAND

2000
01:13:52,680 --> 01:13:54,200
THOUGH AND WHAT WE REALLY WANT

2001
01:13:54,200 --> 01:13:55,840
TO DO IN THE FUTURE IS

2002
01:13:55,840 --> 01:13:58,160
UNDERSTAND TO WHAT EXTENT THIS

2003
01:13:58,160 --> 01:13:59,840
MUSCULAR LYMPHATIC DYSFUNCTION

2004
01:13:59,840 --> 01:14:01,640
ACTUALLY CONTRIBUTES TO ABNORMAL

2005
01:14:01,640 --> 01:14:03,480
LIPID TRANSPORT AND LIVER

2006
01:14:03,480 --> 01:14:04,480
PATHOLOGIES, AND JUST TO REMIND

2007
01:14:04,480 --> 01:14:07,120
YOU, THIS IS A LIVER PATHOLOGY

2008
01:14:07,120 --> 01:14:09,160
OF THE ENTERIC ORIGIN, NOT THE

2009
01:14:09,160 --> 01:14:10,160
LIVER ORIGIN.

2010
01:14:10,160 --> 01:14:13,120
AND THE MAJOR GAPS FOR US HAS

2011
01:14:13,120 --> 01:14:14,640
BEEN THE LACK OF MOLECULAR

2012
01:14:14,640 --> 01:14:15,600
INFORMATION, THE LACK OF

2013
01:14:15,600 --> 01:14:17,280
MOLECULAR MARKERS TO

2014
01:14:17,280 --> 01:14:19,880
SPECIFICALLY PERTURB THE

2015
01:14:19,880 --> 01:14:20,960
RELEVANT CELL POPULATIONS

2016
01:14:20,960 --> 01:14:21,760
BECAUSE WE DON'T KNOW ANYTHING

2017
01:14:21,760 --> 01:14:26,360
ABOUT HOW THESE VILLUS -- FORM.

2018
01:14:26,360 --> 01:14:29,480
SO TO DO THAT WE RECENTLY BECAME

2019
01:14:29,480 --> 01:14:30,400
INTERESTED IN SINGLE CELL

2020
01:14:30,400 --> 01:14:33,120
APPROACHES TO SEQUENCE THE SMALL

2021
01:14:33,120 --> 01:14:35,280
INTESTINE AT VARIOUS STAGES OF

2022
01:14:35,280 --> 01:14:36,160
DEVELOPMENT, AND WE HAVE DONE

2023
01:14:36,160 --> 01:14:41,880
THIS IN COLLABORATION WITH

2024
01:14:41,880 --> 01:14:42,920
DEVLAMINCK'S LAB HERE AT CORNELL

2025
01:14:42,920 --> 01:14:43,240
UNIVERSITY.

2026
01:14:43,240 --> 01:14:44,520
BECAUSE OF THE SAKE OF TIME, I

2027
01:14:44,520 --> 01:14:48,120
AM ONLY GOING TO FOCUS ON THE

2028
01:14:48,120 --> 01:14:49,760
MUST   

2029
01:14:49,760 --> 01:14:51,040
MUSCULARIS CLUSTER.

2030
01:14:51,040 --> 01:14:53,320
JUST WANT TO REMIND YOU THAT

2031
01:14:53,320 --> 01:14:56,280
EACH DOT ON THE MAPS REPRESENT A

2032
01:14:56,280 --> 01:14:57,680
SINGLE CELL AND EACH COLOR

2033
01:14:57,680 --> 01:14:58,560
REPRESENTS A DIFFERENT DAY.

2034
01:14:58,560 --> 01:15:03,160
SO FOR US, OUR LINEAGE TRACING

2035
01:15:03,160 --> 01:15:05,440
SPANS FROM EMBRYONIC DAY 12.5

2036
01:15:05,440 --> 01:15:10,280
ALL THE WAY TO POSTNATAL DAY 1.R

2037
01:15:10,280 --> 01:15:12,120
YOUNGEST CELLS ARE HERE IN BLUE

2038
01:15:12,120 --> 01:15:13,440
AND ORANGE AND OUR OLDER CELLS

2039
01:15:13,440 --> 01:15:15,080
ARE HERE ON THE PERIPHERY.

2040
01:15:15,080 --> 01:15:16,280
IMPORTANTLY FOR US, THE STAR

2041
01:15:16,280 --> 01:15:18,360
CELL TO ACCESS SMOOTH MUSCLE

2042
01:15:18,360 --> 01:15:19,560
TRANSITION, THIS PERINATAL

2043
01:15:19,560 --> 01:15:20,880
PERIOD IS NOTED RIGHT HERE.

2044
01:15:20,880 --> 01:15:22,960
SO WHERE ARE THE AXIAL SMOOTH

2045
01:15:22,960 --> 01:15:24,240
MUSCLE CLUSTER AND OUR STAR

2046
01:15:24,240 --> 01:15:24,560
CELLS?

2047
01:15:24,560 --> 01:15:28,400
SO WHAT WE DID IS WE FIRST USED

2048
01:15:28,400 --> 01:15:29,720
CANONICAL CELL TYPE SPECIFIC

2049
01:15:29,720 --> 01:15:31,480
MARKERS, SMOOTH MUSCLE ACTIN,

2050
01:15:31,480 --> 01:15:34,000
AND WE HAVE IDENTIFIED THREE

2051
01:15:34,000 --> 01:15:35,840
POTENTIAL CLUSTERS SMOOTH MUSCLE

2052
01:15:35,840 --> 01:15:37,840
ACTIN POSITIVE DEPICTED HERE IN

2053
01:15:37,840 --> 01:15:39,120
THE ASTERISKS.

2054
01:15:39,120 --> 01:15:41,280
ALSO THE NEXT MARKER WE USED WAS

2055
01:15:41,280 --> 01:15:43,920
A DIFFERENTIATED SMOOTH MUSCLE

2056
01:15:43,920 --> 01:15:44,800
MARKER, HEAVY CHAIN 11.

2057
01:15:44,800 --> 01:15:46,720
YOU CAN SEE WE HAVE IDENTIFIED

2058
01:15:46,720 --> 01:15:48,520
TWO OUT OF THE THREE CLUSTERS

2059
01:15:48,520 --> 01:15:50,280
THAT ARE DIFFERENTIATED SMOOTH

2060
01:15:50,280 --> 01:15:50,840
MUSCLE.

2061
01:15:50,840 --> 01:15:54,640
SO WE HIGH POTASSIUM SEISE     E

2062
01:15:54,640 --> 01:15:56,600
CLUSTER HERE, THAT SMOOTH MUSCLE

2063
01:15:56,600 --> 01:15:59,760
ACTIN LOW COULD BE OUR STAR

2064
01:15:59,760 --> 01:16:02,160
CELLS.

2065
01:16:02,160 --> 01:16:03,800
NEXT WE WANTED TO DIFFERENTIATE

2066
01:16:03,800 --> 01:16:05,240
THE SMOOT MUSCLE OF THE VILLUS

2067
01:16:05,240 --> 01:16:06,560
FROM THE SMOOTH MUSCLE OF THE

2068
01:16:06,560 --> 01:16:07,760
GUT WALL.

2069
01:16:07,760 --> 01:16:10,600
WE USED C-KIT, SPECIFIC TO THE

2070
01:16:10,600 --> 01:16:12,040
GUT WALL, AND THAT WAS VERY

2071
01:16:12,040 --> 01:16:15,080
TELLING, BECAUSE IT ONLY MARKED

2072
01:16:15,080 --> 01:16:16,840
THIS ARM OF OUR CLUSTER,

2073
01:16:16,840 --> 01:16:17,920
SUGGESTING THAT THESE ARE OUR

2074
01:16:17,920 --> 01:16:20,320
GUT WALL SMOOTH MUSCLE AND THESE

2075
01:16:20,320 --> 01:16:22,880
ARE OUR AXIAL SMOOTH MUSCLE.

2076
01:16:22,880 --> 01:16:24,360
AND SO WE THINK THAT THIS LITTLE

2077
01:16:24,360 --> 01:16:26,440
CLUSTER HERE IS OUR

2078
01:16:26,440 --> 01:16:28,840
DIFFERENTIATED SMOOTH MUSCLE --

2079
01:16:28,840 --> 01:16:30,040
AXIAL SMOOTH MUSCLE POPULATION.

2080
01:16:30,040 --> 01:16:37,280
WE ALSO USE ANOTHER MARKER KNOWN

2081
01:16:37,280 --> 01:16:38,840
AS PERIOSTIN.

2082
01:16:38,840 --> 01:16:41,800
THIS IS LIKE OUR FIBROBLAST

2083
01:16:41,800 --> 01:16:42,200
CLUSTER.

2084
01:16:42,200 --> 01:16:44,960
YOU CAN SEE IN GENERAL, THIS

2085
01:16:44,960 --> 01:16:46,400
FIBROBLAST-LIKE CLUSTER WAS

2086
01:16:46,400 --> 01:16:49,320
NEGATIVE FOR SMOOTH MUSCLE ACTIN

2087
01:16:49,320 --> 01:16:52,280
EXPRESSION WITH THE EXCEPTION OF

2088
01:16:52,280 --> 01:16:53,480
THIS SMALL LITTLE CLUSTER WE

2089
01:16:53,480 --> 01:16:56,560
THINK ARE STAR CELLS.

2090
01:16:56,560 --> 01:16:58,080
SO HERE'S OUR ROAD MAP.

2091
01:16:58,080 --> 01:16:59,160
WE BELIEVE THAT THIS CLUSTER

2092
01:16:59,160 --> 01:17:03,120
HERE IS OUR DIFFERENTIATED AXIAL

2093
01:17:03,120 --> 01:17:04,080
SMOOTH MUSCLE CELLS OF THE

2094
01:17:04,080 --> 01:17:04,840
VILLUS AND THIS CLUSTER RIGHT

2095
01:17:04,840 --> 01:17:08,120
HERE IS OUR STAR CELL-LIKE

2096
01:17:08,120 --> 01:17:12,960
CLUSTER WITHIN THIS FIBROBLAST

2097
01:17:12,960 --> 01:17:13,480
POPULATION.

2098
01:17:13,480 --> 01:17:14,760
SO NOW OF COURSE WE HAVE TO

2099
01:17:14,760 --> 01:17:16,120
VALIDATE THIS, SO HOW DO WE DO

2100
01:17:16,120 --> 01:17:17,320
THIS?

2101
01:17:17,320 --> 01:17:19,200
SO HELP US VALIDATE THIS, WE

2102
01:17:19,200 --> 01:17:20,480
HAVE IDENTIFIED ANOTHER GENE

2103
01:17:20,480 --> 01:17:21,920
THAT I HOPE YOU CAN APPRECIATE

2104
01:17:21,920 --> 01:17:23,240
WAS EXCLUSIVELY EXPRESSED AND

2105
01:17:23,240 --> 01:17:26,600
WHAT WE THINK ARE STAR CELL

2106
01:17:26,600 --> 01:17:27,760
POPULATION BUT WAS NOT EXPRESSED

2107
01:17:27,760 --> 01:17:29,800
IN THE DIFFERENTIATED SMOOTH

2108
01:17:29,800 --> 01:17:30,120
MUSCLE.

2109
01:17:30,120 --> 01:17:32,040
THIS WAS EXCITING BECAUSE WE

2110
01:17:32,040 --> 01:17:35,720
KNOW THAT TENASCIN C PLAYS A

2111
01:17:35,720 --> 01:17:42,160
REALLY IMPORTANT ROLE FROM

2112
01:17:42,160 --> 01:17:48,600
FIBROBLAST EXPRESSION.

2113
01:17:48,600 --> 01:17:51,120
OF COURSE PDGFRA IS VERY

2114
01:17:51,120 --> 01:17:54,720
IMPORTANT DURING VILIFICATION.

2115
01:17:54,720 --> 01:17:57,160
WE FOUND IN OUR FIBROBLAST-LIKE

2116
01:17:57,160 --> 01:17:58,440
CLUSTER, I HOPE YOU CAN

2117
01:17:58,440 --> 01:18:02,280
APPRECIATE EXPRESSION WAS DEVOID

2118
01:18:02,280 --> 01:18:03,560
IN THE STAR CELL-LIKE CLUSTER.

2119
01:18:03,560 --> 01:18:06,120
THIS IS CON   CONSISTENT WITH TE

2120
01:18:06,120 --> 01:18:09,080
FINDING THAT SUBEPITHELIAL ALPHA

2121
01:18:09,080 --> 01:18:11,560
POSITIVE CELLS ARE DISTINCT FROM

2122
01:18:11,560 --> 01:18:14,160
SMOOTH MUSCLE ACTIN POSITIVE

2123
01:18:14,160 --> 01:18:14,920
MYOFIBROBLASTS.

2124
01:18:14,920 --> 01:18:19,560
THIS IS WORK FROM KEN SAN   SAN'

2125
01:18:19,560 --> 01:18:20,760
LAB.

2126
01:18:20,760 --> 01:18:23,920
WE HYPOTHESIZED THAT THEY GIVE

2127
01:18:23,920 --> 01:18:27,960
RISE TO TENASCIN POSITIVE

2128
01:18:27,960 --> 01:18:29,600
MYOFIBROBLAST STAR CELLS AND

2129
01:18:29,600 --> 01:18:30,920
SUBSEQUENTLY THESE DIFFERENTIATE

2130
01:18:30,920 --> 01:18:32,880
INTO AXIAL SMOOTH MUSCLE FIBERS

2131
01:18:32,880 --> 01:18:33,560
OF THE VILLUS.

2132
01:18:33,560 --> 01:18:36,800
SO NOW WE CAN GENETICALLY TEST

2133
01:18:36,800 --> 01:18:38,800
IT WITH CRE-SPECIFIC DRIVERS.

2134
01:18:38,800 --> 01:18:39,560
SO WE DID THAT.

2135
01:18:39,560 --> 01:18:41,200
SO INITIALLY, THIS IS JUST A

2136
01:18:41,200 --> 01:18:42,840
WILD TYPE INTESTINE, AND AGAIN I

2137
01:18:42,840 --> 01:18:46,560
HOPE YOU CAN APPRECIATE THAT

2138
01:18:46,560 --> 01:18:47,760
PDGFRA POSITIVE CELLS HERE IN

2139
01:18:47,760 --> 01:18:49,840
PURPLE ARE DISTINCT FROM THE

2140
01:18:49,840 --> 01:18:51,480
DIFFERENTIATED SMOOTH MUSCLE

2141
01:18:51,480 --> 01:18:52,800
ACTIN POSITIVE CELLS HERE SHOWN

2142
01:18:52,800 --> 01:18:53,360
IN BLUE.

2143
01:18:53,360 --> 01:18:55,080
AND THIS IS BOTH IN THE

2144
01:18:55,080 --> 01:18:58,680
EMBRYONIC INTESTINE AT 14.5 AND

2145
01:18:58,680 --> 01:19:00,440
ALSO IN THE DIFFERENTIATED

2146
01:19:00,440 --> 01:19:01,440
VILLUS SMOOTH MUSCLE CELL.

2147
01:19:01,440 --> 01:19:03,520
SO YOU CAN SEE THAT THEY ARE

2148
01:19:03,520 --> 01:19:06,040
DEVOID OF PDGFRA EXPRESSION

2149
01:19:06,040 --> 01:19:06,680
HERE.

2150
01:19:06,680 --> 01:19:11,600
HOWEVER, NOW IF WE INDUCE THE

2151
01:19:11,600 --> 01:19:14,480
PDGFRA LINEAGE WITH TAMOXIFEN AT

2152
01:19:14,480 --> 01:19:16,880
POSTNATAL DAY ZERO SO JUST IN

2153
01:19:16,880 --> 01:19:18,960
THAT NEONATAL TRANSITION, WE CAN

2154
01:19:18,960 --> 01:19:22,160
SEE ROBUST LABELING OF PDGFRA

2155
01:19:22,160 --> 01:19:24,000
LINEAGE IN THESE SMOOTH MUSCLE

2156
01:19:24,000 --> 01:19:27,040
BUNDLES AND ABOUT 80 TO 90% OF

2157
01:19:27,040 --> 01:19:29,680
DIFFERENTIATED BUNDLES ARE

2158
01:19:29,680 --> 01:19:31,240
LINEAGE POSITIVE.

2159
01:19:31,240 --> 01:19:33,840
IF WE REPEAT THESE INDUCTIONS AT

2160
01:19:33,840 --> 01:19:36,040
LATER TIME POINTS THAT NUMBER

2161
01:19:36,040 --> 01:19:38,760
DRAMATICALLY INCREASES.

2162
01:19:38,760 --> 01:19:40,720
HOW ABOUT DENA SIN C?

2163
01:19:40,720 --> 01:19:44,680
WE SHOW THAT TENASCIN C IS

2164
01:19:44,680 --> 01:19:45,760
INDEED COEXPRESSED WITH STAR LN

2165
01:19:45,760 --> 01:19:47,640
LIKE SHAPED CELLS, SMOOTH MUSCLE

2166
01:19:47,640 --> 01:19:49,360
ACTIVE LOW, BUT IT IS NOT

2167
01:19:49,360 --> 01:19:50,720
EXPRESSED IN THE DIFFERENTIATED

2168
01:19:50,720 --> 01:19:54,160
AXIAL SMOOTH MUSCLE CELLS.

2169
01:19:54,160 --> 01:19:58,240
HOWEVER, IF WE INDUCE TENASCIN C

2170
01:19:58,240 --> 01:20:00,440
LINEAGE WE SEE ABOUT 80% OF OUR

2171
01:20:00,440 --> 01:20:02,280
AXIAL SMOOTH MUSCLE FIBERS ARE

2172
01:20:02,280 --> 01:20:04,840
DERIVED FROM TENASCIN POSITIVE

2173
01:20:04,840 --> 01:20:05,280
LINEAGE.

2174
01:20:05,280 --> 01:20:07,120
IF WE REPEATED THE INDUCTIONS AT

2175
01:20:07,120 --> 01:20:10,440
LATER TIME POINTS, THAT NUMBER

2176
01:20:10,440 --> 01:20:11,640
STAYED RELATIVELY HIGH,

2177
01:20:11,640 --> 01:20:15,800
CERTAINLY BY COMPARISON TO

2178
01:20:15,800 --> 01:20:18,720
PDGFRA LINEAGE -- SUGGESTING

2179
01:20:18,720 --> 01:20:20,360
STAR CELLS REMAIN IN THE ADULT

2180
01:20:20,360 --> 01:20:21,120
AND POTENTIALLY COULD HAVE A

2181
01:20:21,120 --> 01:20:23,880
ROLE IN AXIAL SMOOTH MUSCLE CELL

2182
01:20:23,880 --> 01:20:31,400
HOMEOSTASIS AND MAYBE A DISEASE.

2183
01:20:31,400 --> 01:20:32,760
I'M OUT OF TIME, PLEASE ASK ME

2184
01:20:32,760 --> 01:20:33,720
QUESTIONS DURING THE QUESTION

2185
01:20:33,720 --> 01:20:34,480
AND ANSWER PERIOD.

2186
01:20:34,480 --> 01:20:35,600
WE COULDN'T HELP TO NOTICE THAT

2187
01:20:35,600 --> 01:20:37,040
OUR AXIAL SMOOTH MUSCLE CELLS

2188
01:20:37,040 --> 01:20:41,840
WERE POSITIVE FOR NOTCH 3 AND

2189
01:20:41,840 --> 01:20:44,000
ALSO A TRANSCRIPTIONAL ACTIVATOR

2190
01:20:44,000 --> 01:20:45,000
OF NOTCH SIGNALING SMG THE

2191
01:20:45,000 --> 01:20:46,280
REASON WHY WE BECAME REALLY

2192
01:20:46,280 --> 01:20:47,640
EXCITED ABOUT HAVING NOTCH

2193
01:20:47,640 --> 01:20:49,720
3 SPECIFICALLY IN OUR AXIAL

2194
01:20:49,720 --> 01:20:53,520
SMOOTH MUSCLE CELL CLUSTER IS

2195
01:20:53,520 --> 01:20:54,720
BECAUSE IT WAS PREVIOUSLY SHOWN

2196
01:20:54,720 --> 01:20:57,560
THAT DELTA 4, A LIGAND FOR NOTCH

2197
01:20:57,560 --> 01:21:02,080
3 RECEPTOR SIGNALING, IS

2198
01:21:02,080 --> 01:21:02,800
ABSOLUTELY CRITICAL.

2199
01:21:02,800 --> 01:21:05,160
SO WE COLLABORATED AND SHOWED

2200
01:21:05,160 --> 01:21:11,600
THAT INDEED IF WE DELETE NOTCH A

2201
01:21:11,600 --> 01:21:13,040
CRE THESE SMOOTH MUSCLE FIBERS

2202
01:21:13,040 --> 01:21:14,560
ARE MUCH, MUCH SHORTER THAN

2203
01:21:14,560 --> 01:21:17,920
LACTEALS AND NOW THE LACTEALS

2204
01:21:17,920 --> 01:21:23,640
LACK -- JUST LIKE IN THE DELTA .

2205
01:21:23,640 --> 01:21:24,960
SO WE ARE NOW WORKING WITH THIS

2206
01:21:24,960 --> 01:21:28,120
MODEL THAT PERHAPS NOTCH 3 DELTA

2207
01:21:28,120 --> 01:21:28,880
4 SIGNALING CASCADE COULD BE

2208
01:21:28,880 --> 01:21:31,080
IMPORTANT FOR THE PLEE OF THESE

2209
01:21:31,080 --> 01:21:35,000
AXIAL SMOOTH MUSCLE FIBERS ALONG

2210
01:21:35,000 --> 01:21:36,120
THEIR LACTEALS.

2211
01:21:36,120 --> 01:21:38,840
SO TO QUICKLY SUMMARIZE, WE

2212
01:21:38,840 --> 01:21:45,960
THINK STAR CELLS ARE TENASCIN

2213
01:21:45,960 --> 01:21:47,720
POSITIVE MYOFIBROBLAST-LIKE

2214
01:21:47,720 --> 01:21:49,120
POPULATION THAT GIVE RISE TO

2215
01:21:49,120 --> 01:21:58,240
VILLUS AXIAL CELLS, AND GIVES

2216
01:21:58,240 --> 01:22:00,840
RISE TO MYOFIBROBLAST-LIKE STAR

2217
01:22:00,840 --> 01:22:02,360
CELLS, AND WE THINK THAT

2218
01:22:02,360 --> 01:22:03,160
POPULATION COULD BE IMPORTANT

2219
01:22:03,160 --> 01:22:05,680
FOR THAT ADULT MAINTENANCE OF

2220
01:22:05,680 --> 01:22:13,360
THIS VILLUS MUSCLE.

2221
01:22:13,360 --> 01:22:19,240
SO TO ACKNOWLEDGE AND CONCLUDE,

2222
01:22:19,240 --> 01:22:22,920
WE HAVE A COMPUTATIONAL

2223
01:22:22,920 --> 01:22:26,680
COLLABORATOR WHO HAS DONE A LOT

2224
01:22:26,680 --> 01:22:28,880
OF DATA MINING FOR OUR SINGLE

2225
01:22:28,880 --> 01:22:30,160
CELLS AND THEN ALSO COLLEAGUES

2226
01:22:30,160 --> 01:22:31,600
AT CORNEL OUTSIDE ESPECIALLY I

2227
01:22:31,600 --> 01:22:36,640
WANT TO ACKNOWLEDGE -- AND OUR

2228
01:22:36,640 --> 01:22:37,760
FUNDING AND THANKS SO MUCH FOR

2229
01:22:37,760 --> 01:22:45,960
YOUR ATTENTION.

2230
01:22:45,960 --> 01:22:55,920
OUR NEXT SPEAK SER RACHEL NIEC,

2231
01:22:55,920 --> 01:22:57,240
LYMPHATIC CAPILLARIES ACT AS A

2232
01:22:57,240 --> 01:22:59,160
SIGNALING HUB IN THE INTESTINAL

2233
01:22:59,160 --> 01:23:00,280
STEM CELL NICHE.

2234
01:23:00,280 --> 01:23:01,160
ELWELL COME, RACHEL.

2235
01:23:01,160 --> 01:23:02,320
NICE TO HAVE YOU.

2236
01:23:02,320 --> 01:23:04,880
>> THANKS.

2237
01:23:04,880 --> 01:23:06,200
I REALLY COME TO THE LYMPHATICS

2238
01:23:06,200 --> 01:23:09,480
FROM A STEM CELL PERSPECTIVE AND

2239
01:23:09,480 --> 01:23:10,760
IMMUNOLOGY PERSPECTIVE, AND IT'S

2240
01:23:10,760 --> 01:23:13,640
JUST INSPIRING TO BE HERE AMONG

2241
01:23:13,640 --> 01:23:24,040
SUCH DIVERSE COLLEAGUES.

2242
01:23:33,880 --> 01:23:35,080
ARE YOU SEEING THE RIGHT SCREEN?

2243
01:23:35,080 --> 01:23:35,720
>> LOOKS GOOD.

2244
01:23:35,720 --> 01:23:36,920
>> PERFECT.

2245
01:23:36,920 --> 01:23:39,240
SO WE'RE ON THE TITLE SLIDE

2246
01:23:39,240 --> 01:23:39,440
AGAIN?

2247
01:23:39,440 --> 01:23:39,760
>> YES.

2248
01:23:39,760 --> 01:23:40,320
>> ALL RIGHT.

2249
01:23:40,320 --> 01:23:42,120
SO THE WORK I'LL TALK TO YOU

2250
01:23:42,120 --> 01:23:43,520
ABOUT TODAY HAS REALLY BEEN A

2251
01:23:43,520 --> 01:23:52,200
TEAM EFFORT BETWEEN MYSELF,

2252
01:23:52,200 --> 01:23:56,360
SHIRISGUR-COHEN, MARINA, AND

2253
01:23:56,360 --> 01:23:58,960
TINYI CHU, A COMPUTATIONAL

2254
01:23:58,960 --> 01:24:04,880
COLLABORATOR AND POSTDOC.

2255
01:24:04,880 --> 01:24:06,720
SO ACROSS THE BODY, TISSUE STEM

2256
01:24:06,720 --> 01:24:08,200
CELLS SUPPORT TISSUE-SPECIFIC

2257
01:24:08,200 --> 01:24:09,120
DEMANDS.

2258
01:24:09,120 --> 01:24:11,040
HAIR FOLLICLE STEM CELLS SHOWN

2259
01:24:11,040 --> 01:24:12,760
HERE ARE CYCLICALLY ACTIVE TO

2260
01:24:12,760 --> 01:24:14,320
GIVE RISE TO THE HAIR CYCLE AND

2261
01:24:14,320 --> 01:24:15,960
THE HAIR ON OUR BODIES AND HEADS

2262
01:24:15,960 --> 01:24:18,320
WHEREAS IN THE INTESTINE,

2263
01:24:18,320 --> 01:24:19,480
CRYPT-BASED INTESTINAL STEM

2264
01:24:19,480 --> 01:24:22,560
CELLS ARE CONSTANTLY RENEWING

2265
01:24:22,560 --> 01:24:24,560
AND DIFFERENTIATING TO GENERATE

2266
01:24:24,560 --> 01:24:28,040
THE DIVERSE EPITHELIAL CELL

2267
01:24:28,040 --> 01:24:28,600
TYPES.

2268
01:24:28,600 --> 01:24:30,000
HOW ARE THESE DIFFERENT STEM

2269
01:24:30,000 --> 01:24:32,840
CELL ACTIVITIES COORDINATED?

2270
01:24:32,840 --> 01:24:34,240
ABUNDANT EVIDENCE HAS SHOWN THAT

2271
01:24:34,240 --> 01:24:35,840
STEM CELL ACTIVITY IS LARGELY

2272
01:24:35,840 --> 01:24:38,080
INFLUENCED BY INTERACTIONS WITH

2273
01:24:38,080 --> 01:24:39,280
THEIR LOCAL MICROENVIRONMENT,

2274
01:24:39,280 --> 01:24:39,880
THEIR NICHE.

2275
01:24:39,880 --> 01:24:41,720
AND IN RECENT YEARS, THE

2276
01:24:41,720 --> 01:24:43,800
VASCULATURE HAS EMERGED AS A

2277
01:24:43,800 --> 01:24:45,440
NICHE COMPONENT IN MULTIPLE

2278
01:24:45,440 --> 01:24:48,200
TISSUES, AND IN THE LAB FOCUSING

2279
01:24:48,200 --> 01:24:52,120
ON LYMPHATICS, SHIRI IDENTIFIED

2280
01:24:52,120 --> 01:24:53,760
LYMPHATICS VASCULATURE AS A STEM

2281
01:24:53,760 --> 01:24:56,520
CELL NICHE FOR HAIR FOLLOW KEAL

2282
01:24:56,520 --> 01:25:02,000
STEM CELLS WHEREBY THEY

2283
01:25:02,000 --> 01:25:03,640
COORDINATE THE CYCLICAL ACTIVITY

2284
01:25:03,640 --> 01:25:04,920
OF THE HAIR FOLLICLE STEM CELLS

2285
01:25:04,920 --> 01:25:06,360
IN THE HAIR CYCLE.

2286
01:25:06,360 --> 01:25:08,240
AS A GASTROENTEROLOGIST,

2287
01:25:08,240 --> 01:25:09,760
PARTICULARLY SOMEONE STUDYING

2288
01:25:09,760 --> 01:25:11,280
INFLAMMATORY BOWEL DISEASE, THIS

2289
01:25:11,280 --> 01:25:12,680
WAS INCREDIBLY INTERESTING TO

2290
01:25:12,680 --> 01:25:14,560
ME, BECAUSE OF COURSE THE

2291
01:25:14,560 --> 01:25:15,680
INTESTINAL LYMPHATICS PLAY A KEY

2292
01:25:15,680 --> 01:25:17,960
ROLE IN NUTRIENT ABSORPTION AND

2293
01:25:17,960 --> 01:25:19,520
IMMUNITY, BUT MOREOVER,

2294
01:25:19,520 --> 01:25:20,600
DISRUPTION OF LYMPHATICS HAS

2295
01:25:20,600 --> 01:25:23,880
LONG BEEN ASSOCIATED WITH

2296
01:25:23,880 --> 01:25:24,560
INFLAMMATORY BOWEL DISEASE, BUT

2297
01:25:24,560 --> 01:25:26,120
THE FUNCTION OF THIS HAS BEEN

2298
01:25:26,120 --> 01:25:28,600
REALLY UNKNOWN.

2299
01:25:28,600 --> 01:25:30,920
SO THINKING ABOUT THE INTESTINE,

2300
01:25:30,920 --> 01:25:32,600
WE DIVIDE IT INTO TWO MAIN

2301
01:25:32,600 --> 01:25:33,160
ANATOMIC UNITS.

2302
01:25:33,160 --> 01:25:35,960
THE SMALL INTESTINE COMPRISED OF

2303
01:25:35,960 --> 01:25:37,840
BOTH CRYPT AND VILLI AND THE

2304
01:25:37,840 --> 01:25:40,040
VILLI MAKE UP THE LARGE

2305
01:25:40,040 --> 01:25:41,880
ABSORPTIVE SURFACE AIR OF THIS

2306
01:25:41,880 --> 01:25:44,640
TISSUE AND CONTAIN THE LACTEALS,

2307
01:25:44,640 --> 01:25:47,120
LYMPHATIC PROTRUSIONS JUST

2308
01:25:47,120 --> 01:25:49,000
DISCUSSED AND ARE IMPORTANT FOR

2309
01:25:49,000 --> 01:25:50,720
NUTRIENT ABSORPTION AND IMMUNE

2310
01:25:50,720 --> 01:25:51,080
SURVEILLANCE.

2311
01:25:51,080 --> 01:25:52,840
THE LARGE INTESTINE DOES NOT

2312
01:25:52,840 --> 01:25:55,000
CONTAIN VILLI OR LACTEALS AND

2313
01:25:55,000 --> 01:25:56,760
INSTEAD IS JUST COMPRISED OF

2314
01:25:56,760 --> 01:25:58,400
CRYPTS ALONE DENSELY COLONIZED

2315
01:25:58,400 --> 01:25:59,400
BY MICROBES.

2316
01:25:59,400 --> 01:26:01,360
LYMPHATICS IN THIS TISSUE ARE

2317
01:26:01,360 --> 01:26:02,920
LESS WELL CHARACTERIZED YET THEY

2318
01:26:02,920 --> 01:26:04,440
ALSO PLAY AN IMPORTANT ROLE IN

2319
01:26:04,440 --> 01:26:05,400
IMMUNE SURVEILLANCE.

2320
01:26:05,400 --> 01:26:07,200
IN BOTH TISSUES, LYMPHATICS ARE

2321
01:26:07,200 --> 01:26:09,400
REALLY EXPOSED TO THE METABOLIC

2322
01:26:09,400 --> 01:26:10,680
AND IMMUNE MILIEUS OF THE

2323
01:26:10,680 --> 01:26:13,240
TISSUE, MAKING THEM AN

2324
01:26:13,240 --> 01:26:14,560
INTRIGUING CANDIDATE TO

2325
01:26:14,560 --> 01:26:15,440
TRANSLATE THESE SORTS OF SIGNALS

2326
01:26:15,440 --> 01:26:17,160
INTO THE STEM CELL NICHE TO

2327
01:26:17,160 --> 01:26:18,200
COORDINATE APPROPRIATE STEM CELL

2328
01:26:18,200 --> 01:26:18,960
ACTIVITY.

2329
01:26:18,960 --> 01:26:21,560
SO WE'VE SET OUT TO DESCRIBE THE

2330
01:26:21,560 --> 01:26:23,520
VASCULATURE AND PARTICULARLY

2331
01:26:23,520 --> 01:26:25,320
LYMPHATICS IN THE INTESTINAL

2332
01:26:25,320 --> 01:26:26,920
STEM CELL NICHE USING FIRST

2333
01:26:26,920 --> 01:26:29,120
TISSUE CLEARING AND WHOLE MOUNT

2334
01:26:29,120 --> 01:26:30,560
THREE DIMENSIONAL IMAGING.

2335
01:26:30,560 --> 01:26:32,120
SO WHAT I'M SHOWING FIRST IS A

2336
01:26:32,120 --> 01:26:33,560
PICTURE OF THE SMALL INTESTINE

2337
01:26:33,560 --> 01:26:37,920
WITH THE SCA   SCHEMATIC ON THE.

2338
01:26:37,920 --> 01:26:39,680
WE SEE THE LACTEALS AND WHAT WE

2339
01:26:39,680 --> 01:26:40,800
NOTICE RIGHT OFF WHEN WE CLEARED

2340
01:26:40,800 --> 01:26:42,320
THE TISSUE TO LOOK AT THE WHOLE

2341
01:26:42,320 --> 01:26:43,840
NETWORK WAS THAT THE LYMPHATIC

2342
01:26:43,840 --> 01:26:47,440
CAB  

2343
01:26:47,440 --> 01:26:48,680
CAPILLARIES COLLECT AND FORM

2344
01:26:48,680 --> 01:26:50,240
THIS NETWORK THAT SIT JUST BELOW

2345
01:26:50,240 --> 01:26:51,400
THE CRYPTS WHERE THE STEM CELLS

2346
01:26:51,400 --> 01:26:52,040
ARE HOUSED.

2347
01:26:52,040 --> 01:26:53,920
THIS IS A SIDE VIEW AND A

2348
01:26:53,920 --> 01:26:56,480
TOP-DOWN VIEW AND THEN LOOKING

2349
01:26:56,480 --> 01:26:57,960
AT PSEUDOCOLORRED EM IMAGES, YOU

2350
01:26:57,960 --> 01:27:00,160
CAN SEE THESE LYMPHATIC

2351
01:27:00,160 --> 01:27:01,080
CAPILLARIES ARE FORMING THIS

2352
01:27:01,080 --> 01:27:03,040
NETWORK SITTING JUST BELOW THE

2353
01:27:03,040 --> 01:27:04,000
INTESTINAL STEM CELLS WITHIN THE

2354
01:27:04,000 --> 01:27:04,400
CRYPT.

2355
01:27:04,400 --> 01:27:05,360
AND OF COURSE ONE COULD THINK

2356
01:27:05,360 --> 01:27:07,120
THAT IN THE SMALL INTESTINE, THE

2357
01:27:07,120 --> 01:27:08,320
LACTEALS NEED TO COLLECT

2358
01:27:08,320 --> 01:27:09,640
SOMEWHERE, AND SO PERHAPS THEY

2359
01:27:09,640 --> 01:27:10,800
JUST COLLECT BELOW THE BASE OF

2360
01:27:10,800 --> 01:27:11,960
THE CRYPT SO THAT THEY CAN DRAIN

2361
01:27:11,960 --> 01:27:13,600
OUT INTO THE REST OF THE BODY,

2362
01:27:13,600 --> 01:27:15,680
BUT THE LARGE INTESTINE LACKS

2363
01:27:15,680 --> 01:27:16,880
LACTEAL, AND SO WE WANTED TO

2364
01:27:16,880 --> 01:27:18,360
KNOW IF THIS WAS ALSO TRUE IN

2365
01:27:18,360 --> 01:27:20,160
THE LARGE INTESTINE, AND INDEED

2366
01:27:20,160 --> 01:27:22,600
WE FOUND THAT THE LYMPHATIC

2367
01:27:22,600 --> 01:27:23,560
CAPILLARY NETWORK SITS JUST

2368
01:27:23,560 --> 01:27:25,680
BELOW THE BASE OF THE CRYPTS

2369
01:27:25,680 --> 01:27:27,080
WHERE THE STEM CELLS ARE HOUSED

2370
01:27:27,080 --> 01:27:28,160
IN THE LARGE INTESTINE.

2371
01:27:28,160 --> 01:27:31,280
SO TO GIVE YOU A BETTER VIEW OF

2372
01:27:31,280 --> 01:27:32,240
THIS, I'VE PUT TOGETHER THIS

2373
01:27:32,240 --> 01:27:33,440
VIDEO WHERE WE HAVE LYMPHATICS

2374
01:27:33,440 --> 01:27:35,760
IN WHITE, BLOOD VESSELS IN RED,

2375
01:27:35,760 --> 01:27:39,160
CRYPTS IN GREEN AND OF COURSE

2376
01:27:39,160 --> 01:27:43,320
THERE'S GAFFE.

2377
01:27:43,320 --> 01:27:45,560
WE CONSTRUCT THE CRYPTS IN

2378
01:27:45,560 --> 01:27:46,760
PURPLE, YOU CAN SEE THIS

2379
01:27:46,760 --> 01:27:50,160
LYMPHATIC NETWORK IS NESTING AND

2380
01:27:50,160 --> 01:27:50,880
CUPPING INDIVIDUAL CRYPTS AND

2381
01:27:50,880 --> 01:27:55,960
THEIR STEM CELLS.

2382
01:27:55,960 --> 01:27:59,360
AND THIS ASSOCIATION IS ALSO

2383
01:27:59,360 --> 01:28:00,680
CONSERVED IN HUMANS.

2384
01:28:00,680 --> 01:28:02,680
HERE YOU CAN SEE THE HUMAN SMALL

2385
01:28:02,680 --> 01:28:04,200
INTESTINE, THIS IS A BIOPSY

2386
01:28:04,200 --> 01:28:06,600
SPECIMEN TAKEN FROM A PATIENT,

2387
01:28:06,600 --> 01:28:09,120
SUBJECTED TO TISSUE CLEARING.

2388
01:28:09,120 --> 01:28:11,560
YOU CAN SEE CRYPTS IN GREEN AND

2389
01:28:11,560 --> 01:28:13,400
THE LYMPHATIC CAPILLARY NETWORK

2390
01:28:13,400 --> 01:28:14,600
SITTING ALONG THE BASE OF THE

2391
01:28:14,600 --> 01:28:14,840
CRYPTS.

2392
01:28:14,840 --> 01:28:16,080
AND ALSO IN THE COLON, THIS IS

2393
01:28:16,080 --> 01:28:18,160
AGAIN THE SIDE VIEW, YOU CAN SEE

2394
01:28:18,160 --> 01:28:20,880
THIS INDIVIDUAL CRYPT ALMOST HAS

2395
01:28:20,880 --> 01:28:23,200
ITS OWN LYMPHATIC NEST FORMING

2396
01:28:23,200 --> 01:28:23,840
AROUND ITS BASE.

2397
01:28:23,840 --> 01:28:25,720
I LIKE TO THINK THAT BUY   BIOLC

2398
01:28:25,720 --> 01:28:27,040
FORM FOLLOWS FUNCTION, SO OF

2399
01:28:27,040 --> 01:28:29,560
COURSE WE WONDERED, DOES THE

2400
01:28:29,560 --> 01:28:30,760
PRESENCE OF LYMPHATIC

2401
01:28:30,760 --> 01:28:33,080
CAPILLARIES IN THE STEM CELL

2402
01:28:33,080 --> 01:28:35,600
NICHE HAVE IMPLICATIONS FOR

2403
01:28:35,600 --> 01:28:36,800
THESE STEM CELLS?

2404
01:28:36,800 --> 01:28:39,320
SO TO TEST THIS, WE TURN TODAY A

2405
01:28:39,320 --> 01:28:43,600
RATHER CRUDE LEVEL OF LYMPHATIC

2406
01:28:43,600 --> 01:28:45,040
ABLATION IN MICE, SO THAT WE

2407
01:28:45,040 --> 01:28:47,200
COULD TREAT MICE WITH TAMOXIFEN

2408
01:28:47,200 --> 01:28:49,200
TO INDUCE EXPRESSION OF

2409
01:28:49,200 --> 01:28:51,600
DIPHTHERIA TOXIN RECEPTOR ON THE

2410
01:28:51,600 --> 01:28:54,320
LYMPHATICS AND TREAT WITH DIP

2411
01:28:54,320 --> 01:29:01,240
TIER     

2412
01:29:01,240 --> 01:29:03,240
DIPHTHERIA -- THE LYMPHATICS ARE

2413
01:29:03,240 --> 01:29:05,640
GONE.

2414
01:29:05,640 --> 01:29:08,480
JUST AFTER ABLATION WE SEE A

2415
01:29:08,480 --> 01:29:14,200
PRETTY PRONOUNCED DECREASE.

2416
01:29:14,200 --> 01:29:16,600
THIS IS CORRELATED WITH A

2417
01:29:16,600 --> 01:29:18,240
CORRESPONDING ACCELERATED

2418
01:29:18,240 --> 01:29:19,960
DIFFERENTIATION AND MATURATION

2419
01:29:19,960 --> 01:29:21,360
OF THE EPITHELIAL PROGENY OF

2420
01:29:21,360 --> 01:29:22,520
THESE STEM CELLS AS SHOWN HERE

2421
01:29:22,520 --> 01:29:24,800
IN THIS PULSE CHASE EXPERIMENT,

2422
01:29:24,800 --> 01:29:26,960
WHERE YOU CAN SEE THAT IN THE DT

2423
01:29:26,960 --> 01:29:29,680
TREATED MICE, EDU INCORPORATION

2424
01:29:29,680 --> 01:29:31,680
IS MUCH HIGHER IN THE CRYPT AT

2425
01:29:31,680 --> 01:29:33,720
30 MINTS AND THESE EDU-POSITIVE

2426
01:29:33,720 --> 01:29:35,480
CELLS HAVE MOVED UP OR

2427
01:29:35,480 --> 01:29:37,040
TRANSITIONED UP THE CRYPT VILLUS

2428
01:29:37,040 --> 01:29:38,120
ACCESS MUCH MORE QUICKLY SUCH

2429
01:29:38,120 --> 01:29:39,560
THAT THEY REPRESENT A HIGHER

2430
01:29:39,560 --> 01:29:41,960
POSITION AT 48 HOURS LATER.

2431
01:29:41,960 --> 01:29:46,280
SO THIS SUGGESTS ACCELERATED

2432
01:29:46,280 --> 01:29:47,320
DIFFERENTIATION AND MATURATION

2433
01:29:47,320 --> 01:29:48,960
OF STEM CELLS INTO

2434
01:29:48,960 --> 01:29:50,320
DIFFERENTIATED EPITHELIAL CELLS

2435
01:29:50,320 --> 01:29:51,640
UPON LYMPHATIC ABLATION.

2436
01:29:51,640 --> 01:29:53,280
AND OF COURSE THIS IS AN

2437
01:29:53,280 --> 01:29:55,040
EXPERIMENT FULL OF CAVEATS.

2438
01:29:55,040 --> 01:29:57,560
WE'VE KILLED A MASSIVE

2439
01:29:57,560 --> 01:29:58,800
COMPARTMENT OF CELLS JUST BELOW

2440
01:29:58,800 --> 01:30:03,000
THE BASE OF THE STEM CELL NICHE,

2441
01:30:03,000 --> 01:30:05,360
WE'VE GOT LYMPH DRAINAGE SO WE

2442
01:30:05,360 --> 01:30:06,440
NEEDED TO KNOW IF THIS WAS A

2443
01:30:06,440 --> 01:30:07,640
DIRECT EFFECT.

2444
01:30:07,640 --> 01:30:09,480
SO TO TEST THIS, WE USED A

2445
01:30:09,480 --> 01:30:15,200
CULTURE OF 3D ORGANOIDS REMOVING

2446
01:30:15,200 --> 01:30:16,520
CELL DEATH AND DRAINAGE FROM THE

2447
01:30:16,520 --> 01:30:18,280
EQUATION SO WE COULD EXCLUSIVELY

2448
01:30:18,280 --> 01:30:20,360
STUDY CELL-CELL COMMUNICATION

2449
01:30:20,360 --> 01:30:21,480
BETWEEN THESE TWO CELL TYPES.

2450
01:30:21,480 --> 01:30:24,120
SO WE FOUND THAT LYMPHATIC

2451
01:30:24,120 --> 01:30:26,160
ENDOTHELIAL CELL CONDITIONED

2452
01:30:26,160 --> 01:30:28,800
MEDIUM BUT NOT BLOOD OR

2453
01:30:28,800 --> 01:30:30,240
FIBROBLASTED CONDITIONED MEDIUM

2454
01:30:30,240 --> 01:30:31,440
INCREASED ORGANOID PRODUCTION

2455
01:30:31,440 --> 01:30:33,760
FROM SINGLE CELLS, A SURROGATE

2456
01:30:33,760 --> 01:30:35,280
OF STEMNESS.

2457
01:30:35,280 --> 01:30:37,040
AND ALSO, THAT LYMPHATIC

2458
01:30:37,040 --> 01:30:38,040
ENDOTHELIAL CONDITION MEDIUM WAS

2459
01:30:38,040 --> 01:30:40,360
ABLE TO MAINTAIN ORGANOIDS IN A

2460
01:30:40,360 --> 01:30:42,520
LEFT DIFFERENTIATED LESS MATURE

2461
01:30:42,520 --> 01:30:43,960
PROGENITOR-LIKE STATE AS SHOWN

2462
01:30:43,960 --> 01:30:47,160
BY INCREASED EXPRESSION OF SOX

2463
01:30:47,160 --> 01:30:49,040
9, A STEM CELL MARKER, AND

2464
01:30:49,040 --> 01:30:50,240
DECREASED EXPRESSION OF MATURE

2465
01:30:50,240 --> 01:30:52,680
DIFFERENTIATION MARKERS SHOWN IN

2466
01:30:52,680 --> 01:30:52,920
YELLOW.

2467
01:30:52,920 --> 01:30:55,080
SO THESE RESULTS ARE OPPOSITE

2468
01:30:55,080 --> 01:30:57,040
AND LESS COMPLEMENTARY TO ACUTE

2469
01:30:57,040 --> 01:30:58,800
LYMPHATIC ABLATION IN MICE, AND

2470
01:30:58,800 --> 01:31:00,120
TOGETHER THIS SUGGESTS THAT

2471
01:31:00,120 --> 01:31:01,680
LYMPHATIC SIGNALS ARE PROMOTING

2472
01:31:01,680 --> 01:31:03,280
STEM CELL MAINTENANCE, SO WE

2473
01:31:03,280 --> 01:31:04,760
WANTED TO KNOW WHICH SIGNALS AND

2474
01:31:04,760 --> 01:31:07,160
WHAT'S DRIVING THESE MOLECULAR

2475
01:31:07,160 --> 01:31:07,480
INTERACTIONS.

2476
01:31:07,480 --> 01:31:09,400
AND SO TO GET AT THIS, WE WANTED

2477
01:31:09,400 --> 01:31:11,560
TO MAP LYMPHATICS AT THE

2478
01:31:11,560 --> 01:31:13,800
TRANSCRIPTIONAL LEVEL TO REALLY

2479
01:31:13,800 --> 01:31:15,040
IDENTIFY LYMPHATIC FACTORS THAT

2480
01:31:15,040 --> 01:31:17,080
ARE BEING EXPRESSED AT THE CRYPT

2481
01:31:17,080 --> 01:31:19,040
BASE THAT HAD INTESTINAL STEM

2482
01:31:19,040 --> 01:31:21,240
CELL RECEPTORS AND SO WE USED A

2483
01:31:21,240 --> 01:31:22,240
SPATIAL TRANSCRIPTOMICS APPROACH

2484
01:31:22,240 --> 01:31:23,560
AND HERE'S A PICTURE OF THE

2485
01:31:23,560 --> 01:31:25,640
SLIDE WHERE YOU CAN SEE A ZOOMED

2486
01:31:25,640 --> 01:31:32,320
IN AREA OF A COUPLE OF

2487
01:31:32,320 --> 01:31:32,960
CRYPTOVILLUS UNITS, CAPILLARIES

2488
01:31:32,960 --> 01:31:37,000
IN RED, STEM CELLS IN GREEN.

2489
01:31:37,000 --> 01:31:38,400
EACH SPOT HERE REPRESENTS A

2490
01:31:38,400 --> 01:31:39,360
CAPTURE AREA THAT'S LABELED WITH

2491
01:31:39,360 --> 01:31:42,080
PROBES, SO WE QUICKLY

2492
01:31:42,080 --> 01:31:43,080
APPRECIATED THE LIMITATION OF

2493
01:31:43,080 --> 01:31:43,840
RESOLUTION HERE.

2494
01:31:43,840 --> 01:31:45,360
EACH SPOT IS CONTAINING UP TO 10

2495
01:31:45,360 --> 01:31:52,320
CELLS OR MORE, AND SO WE ENGAGED

2496
01:31:52,320 --> 01:31:56,360
TO HELP US OVERCOME THIS BY

2497
01:31:56,360 --> 01:31:58,320
DEVELOPING AN ALGORITHM USING

2498
01:31:58,320 --> 01:32:00,120
NON-SPATIAL DATA AS PRIOR

2499
01:32:00,120 --> 01:32:05,360
INFORMATION TO DEACON     DE COE

2500
01:32:05,360 --> 01:32:07,560
EXPRESSION OF EACH SPOT ALONG

2501
01:32:07,560 --> 01:32:09,000
THE AXIS AND THEN FURTHER

2502
01:32:09,000 --> 01:32:10,440
IMPROVE RESOLUTION BY TAKING

2503
01:32:10,440 --> 01:32:12,200
ADVANTAGE OF THE STEREOTYPE

2504
01:32:12,200 --> 01:32:14,480
STRUCTURE OF THE INTESTINE,

2505
01:32:14,480 --> 01:32:15,920
THESE REPEATING CRYPT VILLUS

2506
01:32:15,920 --> 01:32:18,360
UNITS, TO THEN COMPRESS THE DATA

2507
01:32:18,360 --> 01:32:21,840
ON TO A SINGLE PSEUDOAXIS.

2508
01:32:21,840 --> 01:32:24,880
SO ONE DIMENSIONAL PSEUDOAXIS

2509
01:32:24,880 --> 01:32:26,360
REPRESENTING THE CRYPT-VILLUS

2510
01:32:26,360 --> 01:32:26,720
AXIS.

2511
01:32:26,720 --> 01:32:27,480
THIS IS WHAT THE DATA LOOKS

2512
01:32:27,480 --> 01:32:28,160
LIKE.

2513
01:32:28,160 --> 01:32:30,120
SO WHEN WE'VE REDUCED ALL THE

2514
01:32:30,120 --> 01:32:33,080
CRYPTS AND ALL THE VILLI FROM

2515
01:32:33,080 --> 01:32:34,400
THE TRANSCRIPT OMIC EXPERIMENT,

2516
01:32:34,400 --> 01:32:39,560
WE GENERATE THIS BEAUTIFUL CAR

2517
01:32:39,560 --> 01:32:40,000
CARTOGRAPH.

2518
01:32:40,000 --> 01:32:42,400
HERE WE HAVE LYMPHATICS SITTING

2519
01:32:42,400 --> 01:32:44,200
AROUND THE BASE AREA WITH THE

2520
01:32:44,200 --> 01:32:48,800
LACTEAL EXTEND     EXTENDING UPN

2521
01:32:48,800 --> 01:32:51,520
THE NICHE PANETH STEM CELLS

2522
01:32:51,520 --> 01:32:53,640
SITTING BELOW AND OTHER IMMUNE

2523
01:32:53,640 --> 01:32:54,840
AND CELL TYPES WE'RE INTERESTED

2524
01:32:54,840 --> 01:32:55,400
TO EXPLORE.

2525
01:32:55,400 --> 01:32:56,680
BUT WITH THIS IN HAND, WE WANTED

2526
01:32:56,680 --> 01:32:59,440
TO LOOK FOR A LIST OF LYMPHATIC

2527
01:32:59,440 --> 01:33:03,880
VERY CREATED       

2528
01:33:03,880 --> 01:33:04,920
SECRETED FACTORS.

2529
01:33:04,920 --> 01:33:06,920
THEN PLOT EXPRESSION OF THESE

2530
01:33:06,920 --> 01:33:09,480
LIGANDS ALONG THE CRYPT-VILLUS

2531
01:33:09,480 --> 01:33:11,120
AXIS WHICH IS NOW ON THE X AXIS

2532
01:33:11,120 --> 01:33:13,360
WITH THE CRYPT INDICATED IN THE

2533
01:33:13,360 --> 01:33:13,760
TRIANGLE.

2534
01:33:13,760 --> 01:33:15,520
SO EXCITINGLY, WE FOUND

2535
01:33:15,520 --> 01:33:17,280
LYMPHATICS WERE MAIN PRODUCERS

2536
01:33:17,280 --> 01:33:18,760
OF KEY ESTABLISHED STEM CELL

2537
01:33:18,760 --> 01:33:28,680
NICHE FACTORS SUCH AS WNTs.

2538
01:33:28,680 --> 01:33:30,400
TWO PAPERS DEMONSTRATED THE

2539
01:33:30,400 --> 01:33:36,280
IMPORTANT FUNCTION OF LYMPHATIC

2540
01:33:36,280 --> 01:33:39,120
DERIVED RSPONDIN.

2541
01:33:39,120 --> 01:33:45,680
WE WERE PARTICULARLY INTERESTED

2542
01:33:45,680 --> 01:33:47,880
IN -- BUT HAS A ROLE IN CARDIAC

2543
01:33:47,880 --> 01:33:50,520
PRO GENERATION FOLLOWING INJURY.

2544
01:33:50,520 --> 01:33:51,640
I THINK MORE WILL BE PRESENTED

2545
01:33:51,640 --> 01:33:52,520
ON THAT LATER.

2546
01:33:52,520 --> 01:33:54,360
WE WONDERED IF THIS ROLE IN

2547
01:33:54,360 --> 01:33:55,440
REGENERATION, A FEATURE OF STEM

2548
01:33:55,440 --> 01:33:58,520
CELLS, MIGHT BE CONSERVED.

2549
01:33:58,520 --> 01:34:09,240
SO THE LAB   OLIVER LAB KINDLY S

2550
01:34:12,760 --> 01:34:15,360
TISSUE, MOREOVER PROVISION OF

2551
01:34:15,360 --> 01:34:17,840
EXOGENOUS -- TO OUR ORGANOID

2552
01:34:17,840 --> 01:34:19,160
COCULTURE SYSTEM MAINTAINED

2553
01:34:19,160 --> 01:34:20,720
ORGANOIDS IN THIS LESS MATURE,

2554
01:34:20,720 --> 01:34:22,000
LESS DIFFERENTIATED PHENOTYPE

2555
01:34:22,000 --> 01:34:25,600
THAT WE SAW WITH LYMPHATIC

2556
01:34:25,600 --> 01:34:27,840
CO-CULTURE OR LYMPHATIC

2557
01:34:27,840 --> 01:34:28,720
CONDITIONED MEDIUM.

2558
01:34:28,720 --> 01:34:32,640
AND WE SEE DIRECTLY THAT

2559
01:34:32,640 --> 01:34:36,400
ADDITION OF RELN CONTRIBUTES TO

2560
01:34:36,400 --> 01:34:38,480
PHOSPHORYLATION OF DOWN

2561
01:34:38,480 --> 01:34:39,120
SIGNALING -- INDICATING DIRECT

2562
01:34:39,120 --> 01:34:39,400
SIGNALING.

2563
01:34:39,400 --> 01:34:41,080
SO I'LL CONCLUDE BY JUST SAYING

2564
01:34:41,080 --> 01:34:43,800
THAT WHAT WE FOUND IS THAT

2565
01:34:43,800 --> 01:34:44,880
LYMPHATIC CAPILLARIES ARE

2566
01:34:44,880 --> 01:34:46,600
PHYSICALLY PROXIMAL TO THE SMALL

2567
01:34:46,600 --> 01:34:48,520
INTESTINE IN BOTH THE SMALL AND

2568
01:34:48,520 --> 01:34:50,280
LARGE INTESTINE IN BOTH MICE AND

2569
01:34:50,280 --> 01:34:52,440
HUMANS, AND THAT LYMPHATIC

2570
01:34:52,440 --> 01:34:54,320
ENDOTHELIAL CELL NETWORK IS A

2571
01:34:54,320 --> 01:34:55,640
SOURCE OF NICHE FACTORS OR A

2572
01:34:55,640 --> 01:34:57,720
SIGNALING HUB FOR THE INTESTINAL

2573
01:34:57,720 --> 01:34:59,280
STEM CELL NICHE, AND IN LOOKING

2574
01:34:59,280 --> 01:35:00,920
AT THIS DATA, WE WERE ABLE TO

2575
01:35:00,920 --> 01:35:05,000
IDENTIFY A NOVEL

2576
01:35:05,000 --> 01:35:06,640
LYMPHATIC-DERIVED FACTOR,

2577
01:35:06,640 --> 01:35:09,040
REELIN, IMPORTANT FOR STEM

2578
01:35:09,040 --> 01:35:09,720
CONTROL MAINTENANCE.

2579
01:35:09,720 --> 01:35:10,760
I'LL LEAVE YOU WITH SOME

2580
01:35:10,760 --> 01:35:11,480
KNOWLEDGE GAPS AND

2581
01:35:11,480 --> 01:35:11,840
OPPORTUNITIES.

2582
01:35:11,840 --> 01:35:13,320
I THINK ONE QUESTION THAT THIS

2583
01:35:13,320 --> 01:35:15,800
BEGS, OF COURSE, THINKING ABOUT

2584
01:35:15,800 --> 01:35:19,120
LYMPHATICS AND THE HEART AND

2585
01:35:19,120 --> 01:35:20,880
SKIN AND GUT LYMPHATICS IS A

2586
01:35:20,880 --> 01:35:23,160
CONSERVED FEATURE OF STEM CELL

2587
01:35:23,160 --> 01:35:26,120
NICHES OR REGENERATIVE NICHES IN

2588
01:35:26,120 --> 01:35:27,040
GENERAL.

2589
01:35:27,040 --> 01:35:28,400
DOES LYMPHATIC COMMUNICATION

2590
01:35:28,400 --> 01:35:30,400
WITH STEM CELLS RESPOND

2591
01:35:30,400 --> 01:35:31,520
DYNAMICALLY TO CHANGES IN THE

2592
01:35:31,520 --> 01:35:31,960
TISSUE?

2593
01:35:31,960 --> 01:35:33,800
OF COURSE LYMPHATICS ARE SEEING

2594
01:35:33,800 --> 01:35:34,880
EVERYTHING THAT'S DRAINED AND SO

2595
01:35:34,880 --> 01:35:36,560
ARE THEY RESPONDING AND

2596
01:35:36,560 --> 01:35:37,640
INSTRUCTING APPROPRIATE STEM

2597
01:35:37,640 --> 01:35:39,560
CELL OR OTHER CELLULAR BEHAVIOR?

2598
01:35:39,560 --> 01:35:41,320
AND THEN WITH THIS LITTLE

2599
01:35:41,320 --> 01:35:42,280
TEASER, ONE INTERESTING QUESTION

2600
01:35:42,280 --> 01:35:45,280
THAT I HAVE IS, HOW ARE

2601
01:35:45,280 --> 01:35:47,480
LYMPHATICS REGULATING IMMUNE

2602
01:35:47,480 --> 01:35:51,120
CELL AK ES TO      ACCESS TO TH?

2603
01:35:51,120 --> 01:35:52,520
HERE YOU SEE IT GOING IN AND OUT

2604
01:35:52,520 --> 01:35:53,440
OF THE LYMPHATICS.

2605
01:35:53,440 --> 01:35:55,200
IF WE WERE TO WATCH THIS IN

2606
01:35:55,200 --> 01:35:55,840
TIME, I IMAGINE.

2607
01:35:55,840 --> 01:35:57,960
SO HOW MIGHT STEM CELLS BE

2608
01:35:57,960 --> 01:35:58,960
REGULATING THEIR LYMPHATIC NICHE

2609
01:35:58,960 --> 01:36:01,280
TO CHANGE THE IMMUNE MILIEU AND

2610
01:36:01,280 --> 01:36:02,920
OTHER SIGNALING MOLECULES IN THE

2611
01:36:02,920 --> 01:36:03,360
NICHE.

2612
01:36:03,360 --> 01:36:05,280
WITH THAT, I'LL THANK EVERYONE

2613
01:36:05,280 --> 01:36:06,120
INVOLVED IN THIS PROJECT.

2614
01:36:06,120 --> 01:36:10,600
I THINK I THANKED MY TEAM

2615
01:36:10,600 --> 01:36:16,320
ALREADY, THE PEER LAB HAS BEEN

2616
01:36:16,320 --> 01:36:17,720
AMAZING, OTHER COLLABORATORS ARE

2617
01:36:17,720 --> 01:36:19,160
SHOWN HERE AND I'LL THANK OUR

2618
01:36:19,160 --> 01:36:20,400
FUNDING SOURCES.

2619
01:36:20,400 --> 01:36:22,120
AND I'D LOVE TO HEAR YOUR

2620
01:36:22,120 --> 01:36:24,320
QUESTIONS AT THE END.

2621
01:36:24,320 --> 01:36:26,400
>> RACHEL, THANK YOU SO
MUCH.

2622
01:36:26,400 --> 01:36:28,880
I'M ENVIOUS OF YOUR SPATIAL

2623
01:36:28,880 --> 01:36:29,280
TRANSCRIPTOMICS.

2624
01:36:29,280 --> 01:36:31,480
WE'RE DYING TO DO IT IN OUR

2625
01:36:31,480 --> 01:36:32,360
EMBRYONIC INTESTINES.

2626
01:36:32,360 --> 01:36:33,360
EXPWR WE'LL BE HAPPY TO SHARE TO

2627
01:36:33,360 --> 01:36:33,640
COMPARE.

2628
01:36:33,640 --> 01:36:34,240
IT WILL BE FUN.

2629
01:36:34,240 --> 01:36:35,440
>> THANK YOU SO MUCH.

2630
01:36:35,440 --> 01:36:36,360
OKAY.

2631
01:36:36,360 --> 01:36:38,360
SO LET'S MOVE ON TO OUR NEXT

2632
01:36:38,360 --> 01:36:40,640
SPEAKER, SO OUR NEXT SPEAKER IS

2633
01:36:40,640 --> 01:36:42,280
DR. YING YANG FROM UNIVERSITY OF

2634
01:36:42,280 --> 01:36:43,720
SOUTH FLORIDA.

2635
01:36:43,720 --> 01:36:45,840
AND THE TITLE OF HER TALK IS

2636
01:36:45,840 --> 01:36:47,880
NOVEL MECHANISMS TO ENHANCE

2637
01:36:47,880 --> 01:36:58,320
LYMPHATIC VALVE FUNCTION.

2638
01:36:58,600 --> 01:37:00,280
>> HOPEFULLY EVERYONE CAN
SEE MY

2639
01:37:00,280 --> 01:37:00,720
SLIDES HERE.

2640
01:37:00,720 --> 01:37:01,800
SO VERY HAPPY TO BE HERE TO

2641
01:37:01,800 --> 01:37:03,240
PRESENT OUR WORK.

2642
01:37:03,240 --> 01:37:04,720
SO FIRST I WOULD LIKE TO THANK

2643
01:37:04,720 --> 01:37:07,000
THE ORGANIZERS FOR THIS GREAT

2644
01:37:07,000 --> 01:37:11,400
OPPORTUNITY TO SHARE OUR WORK.

2645
01:37:11,400 --> 01:37:12,800
UNDERSTANDING A NOVEL MECHANISM

2646
01:37:12,800 --> 01:37:14,760
THAT ENHANCES LYMPHATIC VALVE

2647
01:37:14,760 --> 01:37:15,480
FORMATION.

2648
01:37:15,480 --> 01:37:21,200
THIS IMMUNOSTAINING IMAGE

2649
01:37:21,200 --> 01:37:23,520
SHOWS -- IN LYMPHATIC VESSEL.

2650
01:37:23,520 --> 01:37:25,720
THE LYMPHATIC VASCULATURE IS THE

2651
01:37:25,720 --> 01:37:27,360
MAJOR TRANSPORTATION PATHWAY OF

2652
01:37:27,360 --> 01:37:29,960
TISSUE FLUIDS.

2653
01:37:29,960 --> 01:37:37,360
LYMPHATIC CAPILLARIES UPTAKE

2654
01:37:37,360 --> 01:37:40,320
FLUID -- TRANSPORT LINK.

2655
01:37:40,320 --> 01:37:42,160
AS DR. DAVIS MENTIONED EARLIER,

2656
01:37:42,160 --> 01:37:43,480
SMOOTH MUSCLE CELLS OUTSIDE OF

2657
01:37:43,480 --> 01:37:47,240
THE COLLECTING LYMPHATIC VESSELS

2658
01:37:47,240 --> 01:37:49,280
SPONTANEOUSLY CONTRIBUTE TO MOVE

2659
01:37:49,280 --> 01:37:52,480
LYMPH FORWARD AND -- ACT AS THE

2660
01:37:52,480 --> 01:37:54,600
GATE KEEPER TO PREVENT BACKFLOW

2661
01:37:54,600 --> 01:37:58,680
OF LYMPH.

2662
01:37:58,680 --> 01:38:07,960
THE FORMATION OF THE LYMPHATIC

2663
01:38:07,960 --> 01:38:09,760
VALVE IS A STEP WISE PROCESS

2664
01:38:09,760 --> 01:38:11,160
THAT STARTS AROUND EMBRYONIC DAY

2665
01:38:11,160 --> 01:38:13,800
15 TO 16.

2666
01:38:13,800 --> 01:38:15,760
THE INITIATION STEP OF VALVE

2667
01:38:15,760 --> 01:38:18,240
FORMATION IS ATTRIBUTED BY --

2668
01:38:18,240 --> 01:38:20,200
STRESS, WHICH INDUCED THE

2669
01:38:20,200 --> 01:38:21,520
UPREGULATION OF THREE

2670
01:38:21,520 --> 01:38:25,840
TRANSCRIPTION FACTORS, PROX1,

2671
01:38:25,840 --> 01:38:29,440
FOXC2 AND GATA2 IN VALVE FORMING

2672
01:38:29,440 --> 01:38:30,120
CELLS.

2673
01:38:30,120 --> 01:38:32,040
AFTER THE CONDENSATION AND

2674
01:38:32,040 --> 01:38:34,680
ELONGATION STEPS, IT HAS TWO

2675
01:38:34,680 --> 01:38:37,080
VALVE DEFECTS SHOWN HERE IN THE

2676
01:38:37,080 --> 01:38:40,920
IMAGE AT THE MATURATION STEP.

2677
01:38:40,920 --> 01:38:43,120
THEREFORE -- FLOW PLAYS AN

2678
01:38:43,120 --> 01:38:47,960
ESSENTIAL ROLE IN INDUCING VALVE

2679
01:38:47,960 --> 01:38:48,400
FORMATION.

2680
01:38:48,400 --> 01:38:50,160
THIS IS THE SHEAR STRESS

2681
01:38:50,160 --> 01:38:51,800
SIGNALING PATHWAY IN BLOOD

2682
01:38:51,800 --> 01:38:52,360
ENDOTHELIAL CELLS.

2683
01:38:52,360 --> 01:38:56,120
AS YOU CAN SEE HERE, AKT IS A

2684
01:38:56,120 --> 01:38:57,880
MAJOR DOWNSTREAM -- IN THE

2685
01:38:57,880 --> 01:39:00,640
PATHWAY AFTER SHEAR STRESS IS --

2686
01:39:00,640 --> 01:39:04,880
BY MORE MOLECULES ON THE CELL

2687
01:39:04,880 --> 01:39:05,400
SURFACE.

2688
01:39:05,400 --> 01:39:08,320
ALSO OUR PREVIOUS STUDY, WE

2689
01:39:08,320 --> 01:39:12,520
SHOWED THAT IN HUMAN ENDOTHELIAL

2690
01:39:12,520 --> 01:39:14,040
CELLS PHOSPHORYLATE AKT THE

2691
01:39:14,040 --> 01:39:16,600
ACTIVATED FORM OF AKT, WAS

2692
01:39:16,600 --> 01:39:20,200
UPREGULATED IN RESPONSE TO --

2693
01:39:20,200 --> 01:39:21,760
FLOW.

2694
01:39:21,760 --> 01:39:24,320
SO OUR QUESTION WAS, WHAT IS THE

2695
01:39:24,320 --> 01:39:27,600
DOWNSTREAM TARGET OF AKT THAT

2696
01:39:27,600 --> 01:39:32,640
CONTROLS LYMPHATIC VALVE GROWTH?

2697
01:39:32,640 --> 01:39:35,840
THE TRANSCRIPTION FACTOR

2698
01:39:35,840 --> 01:39:37,840
FOX01 AS DOWNSTREAM TARGET OF

2699
01:39:37,840 --> 01:39:39,680
AKT BECAME A CANDIDATE OF OUR

2700
01:39:39,680 --> 01:39:41,520
STUDY.

2701
01:39:41,520 --> 01:39:45,880
AS A TRANSCRIPTION FACTOR

2702
01:39:45,880 --> 01:39:47,320
FOX01 BINDS TO DNA TO REGULATE

2703
01:39:47,320 --> 01:39:49,800
GENE EXPRESSION.

2704
01:39:49,800 --> 01:39:52,360
HOWEVER, PHOSPHORYLATED AKT

2705
01:39:52,360 --> 01:39:55,560
CAN -- FOX01 AND -- OUT OF THE

2706
01:39:55,560 --> 01:39:58,520
NUCLEUS TO LOSE ITS NUCLEAR

2707
01:39:58,520 --> 01:39:59,560
ACTIVITY.

2708
01:39:59,560 --> 01:40:01,520
ALL THOAL FOX01 HAS THINGS

2709
01:40:01,520 --> 01:40:03,600
STUDIED IN MANY OTHER CELL

2710
01:40:03,600 --> 01:40:05,920
TYPES, HOWEVER, ITS ROLE IN

2711
01:40:05,920 --> 01:40:07,160
LYMPHATIC ENDOTHELIAL CELLS

2712
01:40:07,160 --> 01:40:11,640
REMAINS UNKNOWN.

2713
01:40:11,640 --> 01:40:13,480
SO THEREFORE WE DECIDED TO

2714
01:40:13,480 --> 01:40:16,080
DELETE FOX01 FROM THE LYMPHATIC

2715
01:40:16,080 --> 01:40:19,120
VASCULATURE USING PROX1 MOUSE

2716
01:40:19,120 --> 01:40:20,640
MODEL.

2717
01:40:20,640 --> 01:40:22,320
TO VISUALIZE THE LYMPHATIC

2718
01:40:22,320 --> 01:40:23,840
VASCULATURE, WE COMBINED THE

2719
01:40:23,840 --> 01:40:29,040
PROX1 GFP STRAIN TOGETHER, THE

2720
01:40:29,040 --> 01:40:30,240
ENTIRE LYMPHATIC VASCULATURE

2721
01:40:30,240 --> 01:40:35,400
WILL BE IN GFP COLOR.

2722
01:40:35,400 --> 01:40:37,840
WE DELETED FOX 01 FROM THE

2723
01:40:37,840 --> 01:40:39,280
EMBRYOS, THE POSTNATAL PUPS AND

2724
01:40:39,280 --> 01:40:41,400
THE ADULT MICE.

2725
01:40:41,400 --> 01:40:43,680
AND SINCE THE EMBRYONIC AND THE

2726
01:40:43,680 --> 01:40:46,000
ADULT DATA IS CONSISTENT WITH

2727
01:40:46,000 --> 01:40:47,200
THE POSTNATAL DATA, I WILL ONLY

2728
01:40:47,200 --> 01:40:51,600
SHOW THE POSTNATAL DATA HERE.

2729
01:40:51,600 --> 01:41:01,640
THAT MOX 15      TAMOXIFEN WAS T

2730
01:41:01,640 --> 01:41:04,280
POSTNATAL 1 AND 3.

2731
01:41:04,280 --> 01:41:07,400
AS YOU CAN SEE HERE, COMPARED TO

2732
01:41:07,400 --> 01:41:10,560
THE CONTROL VESSELS AT ALL THREE

2733
01:41:10,560 --> 01:41:15,000
STAGES, FOX01 DIVISION INDUCED

2734
01:41:15,000 --> 01:41:16,520
NEW VALVES TO GROW.

2735
01:41:16,520 --> 01:41:20,080
THESE VALVE-FORMING AREAS WERE

2736
01:41:20,080 --> 01:41:21,200
RARELY SEEN IN THE CONTROL

2737
01:41:21,200 --> 01:41:23,720
VESSELS.

2738
01:41:23,720 --> 01:41:26,240
IN OUR QUANTIFICATION DATA

2739
01:41:26,240 --> 01:41:29,840
CONFIRMED THAT, THAT NUMBER --

2740
01:41:29,840 --> 01:41:32,120
IN THE PUPS WITH FOX 01 DELETION

2741
01:41:32,120 --> 01:41:33,080
WAS SIGNIFICANTLY HIGHER THAN

2742
01:41:33,080 --> 01:41:37,000
THE CONTROL ANIMAL FLEURCHLT

2743
01:41:37,000 --> 01:41:39,720
MOREOVER, DELETION OF FOX 01 DID

2744
01:41:39,720 --> 01:41:41,880
NOT AFFECT THE DIAMETER OF THE

2745
01:41:41,880 --> 01:41:43,600
VESSELS, OR THE NUMBER OF

2746
01:41:43,600 --> 01:41:45,800
BRANCHES IN THESE ANIMALS.

2747
01:41:45,800 --> 01:41:49,400
SO FROM THESE DATA, WE CAN

2748
01:41:49,400 --> 01:41:53,320
CONCLUDE THAT FOX 01 IS A

2749
01:41:53,320 --> 01:41:54,720
REPRESSOR FOR DEFECTIVE VALVE

2750
01:41:54,720 --> 01:41:55,280
FORMATION.

2751
01:41:55,280 --> 01:41:56,360
DELETION INDUCED NEW VALVES TO

2752
01:41:56,360 --> 01:42:05,640
GROW.

2753
01:42:05,640 --> 01:42:07,320
SO YOU MIGHT WONDER HERE, SINCE

2754
01:42:07,320 --> 01:42:09,160
WE DON'T NEED TO ADD MORE VALVES

2755
01:42:09,160 --> 01:42:11,600
IN THE HEALTHY VESSELS, WHY IS

2756
01:42:11,600 --> 01:42:15,400
GROWING NEW VALVES IMPORTANT?

2757
01:42:15,400 --> 01:42:17,040
BECAUSE VALVE DEFECTS ARE

2758
01:42:17,040 --> 01:42:24,080
ASSOCIATED WITH SEVERAL TYPES OF

2759
01:42:24,080 --> 01:42:29,800
CONGENITAL LIAM    LYMPHEDEMA AX

2760
01:42:29,800 --> 01:42:39,560
01 -- IN LYMPHATIC DISEASE.

2761
01:42:39,560 --> 01:42:42,280
HETEROZYGOSITY OF FOX C2 GENE

2762
01:42:42,280 --> 01:42:44,600
CAUSES -- IN HUMAN COMPARED TO

2763
01:42:44,600 --> 01:42:48,000
THE HEALTHY DRAINAGE OF THE

2764
01:42:48,000 --> 01:42:51,960
TRASER IN CONTROL PATIENTS,

2765
01:42:51,960 --> 01:42:56,440
THERMAL BACKFLOW HERE INDICATED

2766
01:42:56,440 --> 01:42:57,840
THAT LYMPHATIC VALVES ARE

2767
01:42:57,840 --> 01:42:58,680
DEFECTIVE IN THESE PATIENTS.

2768
01:42:58,680 --> 01:43:01,320
SO WE TESTED WHETHER FOX

2769
01:43:01,320 --> 01:43:02,520
01 DELETION CAN RESTORE THE

2770
01:43:02,520 --> 01:43:06,840
VALVE DEFECTS IN FOX

2771
01:43:06,840 --> 01:43:09,280
C2 HETEROZYGOUS MICE.

2772
01:43:09,280 --> 01:43:13,400
TO DO THIS, WE DELETED FOX 01 IN

2773
01:43:13,400 --> 01:43:15,360
THE FOX C2 HETEROZYGOUS

2774
01:43:15,360 --> 01:43:15,680
BACKGROUND.

2775
01:43:15,680 --> 01:43:20,280
WE USED FOX C2 CRE 2 MOUSE

2776
01:43:20,280 --> 01:43:20,600
MODEL.

2777
01:43:20,600 --> 01:43:23,040
IN THIS PARTICULAR MOUSE MODEL,

2778
01:43:23,040 --> 01:43:25,800
ONE ALLELE OF FOX C2 WAS

2779
01:43:25,800 --> 01:43:28,040
REPLACED WITH CRE ER T2.

2780
01:43:28,040 --> 01:43:30,640
THEREFORE, THIS MOUSE MODEL IS

2781
01:43:30,640 --> 01:43:35,040
BOTH HETEROZYGOSITY FOR FOX

2782
01:43:35,040 --> 01:43:38,360
C2 AND HAS CRE ER T2 ACTIVITY.

2783
01:43:38,360 --> 01:43:42,120
WE INCREASED -- AFTER BIRTH AND

2784
01:43:42,120 --> 01:43:47,000
WAS ANALYZED THREE WEEKS LATER.

2785
01:43:47,000 --> 01:43:52,320
OUR DATA SHOW HERE THAT FOX

2786
01:43:52,320 --> 01:43:55,480
C2 HETEROZYGOUS MICE HAD ABOUT

2787
01:43:55,480 --> 01:43:57,600
50% -- VALVES AT POSTNATAL DAY

2788
01:43:57,600 --> 01:44:00,640
51 COMPARED TO THE CONTROL AND

2789
01:44:00,640 --> 01:44:02,800
DELETION OF FOX 01 COMPLETELY

2790
01:44:02,800 --> 01:44:04,200
RESTORE THE VALVE NUMBER TO THE

2791
01:44:04,200 --> 01:44:06,120
Y 

2792
01:44:06,120 --> 01:44:08,520
WILD TYPE LEVEL IN BOTH SHOWING

2793
01:44:08,520 --> 01:44:10,160
IN THE TOTAL NUMBER OF VALVE AND

2794
01:44:10,160 --> 01:44:14,600
THE VALVES PER MILLIMETER.

2795
01:44:14,600 --> 01:44:17,240
ADDITIONALLY, FOX

2796
01:44:17,240 --> 01:44:19,800
C2 HETEROZYGOUS MICE ALSO HAD A

2797
01:44:19,800 --> 01:44:22,240
SIGNIFICANT REDUCTION IN THE

2798
01:44:22,240 --> 01:44:23,760
BRANCH NUMBER.

2799
01:44:23,760 --> 01:44:26,160
AND THIS REDUCTION WAS ALSO

2800
01:44:26,160 --> 01:44:28,800
COMPLETELY RESTORED BY DELETION

2801
01:44:28,800 --> 01:44:33,080
OF FOX 01.

2802
01:44:33,080 --> 01:44:35,320
SO IN ADDITION TO RESCUING THE

2803
01:44:35,320 --> 01:44:36,840
MORPHOLOGY OF VALVES, WE ALSO

2804
01:44:36,840 --> 01:44:39,640
WANT TO TEST WHETHER FOX

2805
01:44:39,640 --> 01:44:41,720
01 DELETION CAN RESTORE THE

2806
01:44:41,720 --> 01:44:43,280
FUNCTION OF LYMPHATIC VALVES IN

2807
01:44:43,280 --> 01:44:47,920
FOX C2 HETEROZYGOUS MICE.

2808
01:44:47,920 --> 01:44:49,800
TO TEST VALVE FUNCTION, WE

2809
01:44:49,800 --> 01:44:51,320
COLLABORATED WITH DR. MICHAEL

2810
01:44:51,320 --> 01:44:57,040
DAVIS AT UNIVERSITY OF MISSOURI.

2811
01:44:57,040 --> 01:45:00,280
AFTER A SINGLE VESSEL CASS

2812
01:45:00,280 --> 01:45:02,760
CALCULATED ON TWO GLASS PIPETTES

2813
01:45:02,760 --> 01:45:04,960
THE OUTPUT PRESSURE WAS SLOWLY

2814
01:45:04,960 --> 01:45:06,600
INCREASED WHILE INPUT PRESSURE

2815
01:45:06,600 --> 01:45:09,640
REMAINS CONSTANT.

2816
01:45:09,640 --> 01:45:12,080
VALVES -- FROM A HEALTHY VALVE

2817
01:45:12,080 --> 01:45:13,560
CAN SEAL TIGHTLY TOGETHER TO

2818
01:45:13,560 --> 01:45:15,400
PREVENT BACKLEAK OF FLOAL.

2819
01:45:15,400 --> 01:45:22,200
AND ANY BACKLEAK HERE CAN BE

2820
01:45:22,200 --> 01:45:24,560
QUANTIFIED BY THE -- PIPETTE

2821
01:45:24,560 --> 01:45:28,160
RIGHT BEHIND THE VALVE LEAFLETS.

2822
01:45:28,160 --> 01:45:29,480
HERE OUR DATA SHOW SUCCESSFULLY

2823
01:45:29,480 --> 01:45:34,560
THAT THE LEAKY VALVES IN FOX

2824
01:45:34,560 --> 01:45:36,200
C2 HETEROZYGOUS MICE BECAME

2825
01:45:36,200 --> 01:45:38,040
SEALED TIGHTLY AGAINST TWO

2826
01:45:38,040 --> 01:45:39,680
DIFFERENT -- PRESSURES WHEN WE

2827
01:45:39,680 --> 01:45:41,760
DELETE EITHER ONE OR TWO ALEGALS

2828
01:45:41,760 --> 01:45:44,080
OF FOX 01.

2829
01:45:44,080 --> 01:45:46,240
THEREFORE, DELETION OF FOX

2830
01:45:46,240 --> 01:45:47,920
01 INDUCED THE NEW VALVES TO

2831
01:45:47,920 --> 01:45:50,000
GROW IN FOX C2 HETEROZYGOUS

2832
01:45:50,000 --> 01:45:56,320
MICE, AND MORE IMPORTANT -- ARE

2833
01:45:56,320 --> 01:45:58,880
FUNCTIONAL.

2834
01:45:58,880 --> 01:46:02,320
SO HOW DOES FOX 01 DELETION

2835
01:46:02,320 --> 01:46:05,400
INDUCE NEW VALVES TO GROW?

2836
01:46:05,400 --> 01:46:07,000
TO INVESTIGATE THIS, WE KNOCKED

2837
01:46:07,000 --> 01:46:11,440
DOWN FOX 01 IN HUMAN LYMPHATIC

2838
01:46:11,440 --> 01:46:12,640
ENDOTHELIAL CELLS AND TREATED

2839
01:46:12,640 --> 01:46:13,440
THESE WITH -- FLOW.

2840
01:46:13,440 --> 01:46:16,560
AS WE EXPECTED, THE EXPRESSION

2841
01:46:16,560 --> 01:46:19,080
LEVELS OF FLOW RESPONSIVE GENE

2842
01:46:19,080 --> 01:46:20,600
AND VALVE FORMING GENES

2843
01:46:20,600 --> 01:46:28,320
INCLUDING FOX C2, GATA2,

2844
01:46:28,320 --> 01:46:33,320
KLF4 AND KLF2 WAS -- MORE

2845
01:46:33,320 --> 01:46:34,760
IMPORTANTLY, THE EXPRESSION OF

2846
01:46:34,760 --> 01:46:36,160
ALL THESE GENES WAS

2847
01:46:36,160 --> 01:46:41,520
SIGNIFICANTLY INCREASED IN FOX

2848
01:46:41,520 --> 01:46:43,560
01 KNOCKDOWN CELLS ON BOTH MRNA

2849
01:46:43,560 --> 01:46:44,880
AND PROTEIN LEVELS.

2850
01:46:44,880 --> 01:46:49,880
IN THE PRESENCE OF -- FLOW, FOX

2851
01:46:49,880 --> 01:46:51,880
01 WAS EXCRETED OUT OF THE

2852
01:46:51,880 --> 01:46:53,800
NUCLEUS, SHOWN HERE IN

2853
01:46:53,800 --> 01:46:56,760
IMMUNOSTAINING, AND   UNDER THEE

2854
01:46:56,760 --> 01:46:58,040
FLOW CONDITION ON POTASSIUM THE

2855
01:46:58,040 --> 01:47:03,640
LEVEL OF PHOSPHOAKT AND -- FOX

2856
01:47:03,640 --> 01:47:04,320
01 WERE UPREGULATED.

2857
01:47:04,320 --> 01:47:06,880
WHEN WE TREATED CELLS WITH AN

2858
01:47:06,880 --> 01:47:14,760
AKT ACTIVATOR SC-79, BOTH WERE

2859
01:47:14,760 --> 01:47:15,400
REGULATED.

2860
01:47:15,400 --> 01:47:16,880
SO ALL THESE DATA LEAD US TO

2861
01:47:16,880 --> 01:47:18,880
THIS MODEL THAT IN RESPONSE TO

2862
01:47:18,880 --> 01:47:22,800
SHEAR STRESS, ACTIVATED AKT AT10

2863
01:47:22,800 --> 01:47:24,520
WAITS THE NUCLEAR ACTIVITY OF

2864
01:47:24,520 --> 01:47:28,200
FOX 01 AND AS A VALVE GENE REPRE

2865
01:47:28,200 --> 01:47:31,440
SER IN      

2866
01:47:31,440 --> 01:47:34,320
REPRESSOR IN THE NUCLEUS --

2867
01:47:34,320 --> 01:47:35,320
WHICH ALLOWS NEW VALVES TO GROW.

2868
01:47:35,320 --> 01:47:39,840
TO FURTHER SUPPORT OUR MODEL,

2869
01:47:39,840 --> 01:47:46,120
THE IMMUNO -- THE ASSAY SHOWED

2870
01:47:46,120 --> 01:47:49,240
THAT FOX 01 CAN DIRECTLY BIND TO

2871
01:47:49,240 --> 01:47:52,360
THE PROMOTER AREA OF FOX C2 AND

2872
01:47:52,360 --> 01:47:55,800
REG LAYING LATHE         

2873
01:47:55,800 --> 01:47:56,560
REGULATE EXPRESSION.

2874
01:47:56,560 --> 01:48:00,760
RECENTLY WE TESTED -- IN

2875
01:48:00,760 --> 01:48:02,680
ADDITION TO GENETIC METHODS.

2876
01:48:02,680 --> 01:48:04,800
AS YOU CAN SEE HERE, AFTER 48

2877
01:48:04,800 --> 01:48:07,760
HOURS OF TREATMENT, FOX

2878
01:48:07,760 --> 01:48:10,920
01 INHIBITOR IS SIGNIFICANTLY

2879
01:48:10,920 --> 01:48:13,240
INCREASING THE LEVELS OF VALVE

2880
01:48:13,240 --> 01:48:14,320
FORMING GENES AND FLOW

2881
01:48:14,320 --> 01:48:15,800
RESPONSIVE GENES ON BOTH MRNA

2882
01:48:15,800 --> 01:48:17,920
AND THE PROTEIN LEVELS.

2883
01:48:17,920 --> 01:48:20,520
IN ADDITION TO THE INDIVIDUAL

2884
01:48:20,520 --> 01:48:23,120
DATA, IN VIVO INJECTION OF THIS

2885
01:48:23,120 --> 01:48:25,280
FOX 01 INHIBITOR SIGNIFICANTLY

2886
01:48:25,280 --> 01:48:29,440
INCREASED THE VALVE NUMBER IN

2887
01:48:29,440 --> 01:48:31,840
FOX C2 HETEROZYGOUS MICE.

2888
01:48:31,840 --> 01:48:33,600
ALTHOUGH THE VALVE NUMBER WAS

2889
01:48:33,600 --> 01:48:35,040
NOT RESTORED COMPLETELY TO WILD

2890
01:48:35,040 --> 01:48:37,560
TYPE LEVEL, THE FOX

2891
01:48:37,560 --> 01:48:40,320
01 INHIBITORS DO SHOW A PARTIAL

2892
01:48:40,320 --> 01:48:42,360
RESCUE OF THE VALVE NUMBER IN

2893
01:48:42,360 --> 01:48:47,960
FOX C2 HETEROSIGH DWUS.  ZYGOUS.

2894
01:48:47,960 --> 01:48:51,600
SO TON CLEUD MY THOUGHT TODAY,

2895
01:48:51,600 --> 01:48:52,800
TRANSCRIPTION FACTOR THAT

2896
01:48:52,800 --> 01:48:53,360
REPRESSES LYMPHATIC VALVE

2897
01:48:53,360 --> 01:48:56,080
FORMATION, WE WERE ABLE TO SHOW

2898
01:48:56,080 --> 01:48:59,240
THAT AKT-FOX 01 SIGNALING

2899
01:48:59,240 --> 01:49:00,240
PATHWAY IS CRITICAL FOR

2900
01:49:00,240 --> 01:49:02,080
LYMPHATIC VALVE FORMATION, AND

2901
01:49:02,080 --> 01:49:04,280
FOX 01 DIRECTLY REPRESSES THE

2902
01:49:04,280 --> 01:49:07,960
EXPRESS OF THE KEY VALVE-FORMING

2903
01:49:07,960 --> 01:49:10,040
GENE FOX C2 TO REGULATE VALVE

2904
01:49:10,040 --> 01:49:10,720
FORMATION.

2905
01:49:10,720 --> 01:49:15,120
LASTLY, WE SHOWED LOSS OF FOX 0,

2906
01:49:15,120 --> 01:49:16,640
MORPHOLOGY AND FUNCTION OF

2907
01:49:16,640 --> 01:49:18,480
VALVES IN A LYMPHEDEMA MOUSE

2908
01:49:18,480 --> 01:49:20,360
MODEL.

2909
01:49:20,360 --> 01:49:23,720
SO THERE IS STILL MANY GAPS THAT

2910
01:49:23,720 --> 01:49:24,320
NEED MORE RESEARCH.

2911
01:49:24,320 --> 01:49:27,080
FOR EXAMPLE, WHICH TYPES OF

2912
01:49:27,080 --> 01:49:28,800
CONGENITAL LYMPHEDEMA CAN BE

2913
01:49:28,800 --> 01:49:32,840
RESTORED BY DELETION OF FOX 01?

2914
01:49:32,840 --> 01:49:36,240
ARE THERE ANY OTHER GENES ALSO

2915
01:49:36,240 --> 01:49:37,320
REPRESSING LYMPHATIC VALVE

2916
01:49:37,320 --> 01:49:38,840
FORMATION OTHER THAN FOX 01?

2917
01:49:38,840 --> 01:49:40,400
ARE THERE ANY OTHER LYMPHATIC

2918
01:49:40,400 --> 01:49:43,000
DISEASES BESIDES LYMPHEDEMA IN

2919
01:49:43,000 --> 01:49:45,280
WHICH INHIBITION OF FOX 01 CAN

2920
01:49:45,280 --> 01:49:48,000
IMPROVE LYMPHATIC FUNCTION?

2921
01:49:48,000 --> 01:49:49,760
NEVERTHELESS, OUR RESEARCH HAS

2922
01:49:49,760 --> 01:49:52,720
PROVIDED A POTENTIAL TARGET FOR

2923
01:49:52,720 --> 01:49:54,240
CONGENITAL LYMPHEDEMA.

2924
01:49:54,240 --> 01:49:56,600
WE THINK THE ABILITY TO

2925
01:49:56,600 --> 01:49:58,040
STIMULATE THE GROWTH OF

2926
01:49:58,040 --> 01:50:00,440
LYMPHATIC VALVES DE NOVO IN A

2927
01:50:00,440 --> 01:50:02,000
PHYSIOLOGICAL MANNER PROVIDES

2928
01:50:02,000 --> 01:50:04,480
OPPORTUNITIES TO FIND BE

2929
01:50:04,480 --> 01:50:07,200
POTENTIAL TARGETS FOR LYMPHATIC

2930
01:50:07,200 --> 01:50:09,680
DISEASES WHERE VALVES REGRESS OR

2931
01:50:09,680 --> 01:50:10,840
DISINTEGRATE, INCLUDING SEVERAL

2932
01:50:10,840 --> 01:50:13,520
TYPES OF PRIMARY LYMPHEDEMA AND

2933
01:50:13,520 --> 01:50:14,840
THE LYMPHATIC MALFORMATIONS.

2934
01:50:14,840 --> 01:50:16,680
SO LASTLY, I WOULD LIKE TO THANK

2935
01:50:16,680 --> 01:50:19,720
ALL OF MOUNTAIN BERMS FROM MY

2936
01:50:19,720 --> 01:50:21,520
LAB AND ALL MY COLLABORATORS FOR

2937
01:50:21,520 --> 01:50:22,760
SHARING THEIR MOUSE MODEL AND

2938
01:50:22,760 --> 01:50:24,320
FOR THEIR AMAZING TECHNICAL

2939
01:50:24,320 --> 01:50:25,160
SUPPORT.

2940
01:50:25,160 --> 01:50:27,320
I'D ALSO WANT TO THANK THE

2941
01:50:27,320 --> 01:50:30,480
SUPPORTERS FROM MY DEPARTMENT,

2942
01:50:30,480 --> 01:50:33,160
THE IMAGING CO-FACILITY AND THE

2943
01:50:33,160 --> 01:50:34,960
FACILITY AT USF, AND I ALSO WANT

2944
01:50:34,960 --> 01:50:37,440
TO THANK NIH FOR FUNDING

2945
01:50:37,440 --> 01:50:38,000
SUPPORT.

2946
01:50:38,000 --> 01:50:39,760
THANK YOU VERY MUCH FOR YOUR

2947
01:50:39,760 --> 01:50:40,880
ATTENTION.

2948
01:50:40,880 --> 01:50:43,600
AND I'M HAPPY TO TAKE QUESTIONS

2949
01:50:43,600 --> 01:50:45,040
LATER.

2950
01:50:45,040 --> 01:50:47,400
>> THANK YOU VERY MUCH,
YANG.

2951
01:50:47,400 --> 01:50:48,360
>> THANK YOU.

2952
01:50:48,360 --> 01:50:49,320
>> THANK YOU.

2953
01:50:49,320 --> 01:50:54,480
AND OUR NEXT SPEAKER IS XIAOLEI

2954
01:50:54,480 --> 01:50:59,600
LIU, FROM TEMPLE UNIVERSITY.

2955
01:50:59,600 --> 01:51:01,320
TALKING ABOUT TARGETING CARDIAC

2956
01:51:01,320 --> 01:51:03,080
LYMPHATICS FOR TREATMENT OF

2957
01:51:03,080 --> 01:51:07,440
ISCHEMIC HEART DISEASE.

2958
01:51:07,440 --> 01:51:08,840
>> THANK YOU SO MUCH FOR
THE

2959
01:51:08,840 --> 01:51:09,760
INTRODUCTION AND THANK YOU SO

2960
01:51:09,760 --> 01:51:12,240
MUCH FOR INVITING ME TO THIS

2961
01:51:12,240 --> 01:51:12,480
WORKSHOP.

2962
01:51:12,480 --> 01:51:14,640
IT HAS BEEN FANTASTIC.

2963
01:51:14,640 --> 01:51:16,880
SO WE HAVE JUST HEARD SO MANY

2964
01:51:16,880 --> 01:51:19,920
AWESOME TALKS ABOUT THE

2965
01:51:19,920 --> 01:51:21,360
DEVELOPMENT, ANATOMY AND

2966
01:51:21,360 --> 01:51:22,680
PHYSIOLOGIC CONDITION OF THE

2967
01:51:22,680 --> 01:51:24,160
LYMPH SYSTEM, AND WE KNOW THAT

2968
01:51:24,160 --> 01:51:28,760
IN GENERAL, LYMPHATICS PLAY A

2969
01:51:28,760 --> 01:51:30,920
MAJOR ROLE FOR TISSUE FLUID

2970
01:51:30,920 --> 01:51:36,600
BALANCE FOR IMMUNE SURVEILLANCE

2971
01:51:36,600 --> 01:51:40,640
AND LIPID ABSORPTION AT THE GUT

2972
01:51:40,640 --> 01:51:41,200
AREA.

2973
01:51:41,200 --> 01:51:45,040
INCREASING STUDIES SHOW THERE'S

2974
01:51:45,040 --> 01:51:46,200
NOVEL LYMPHATIC FUNCTIONS

2975
01:51:46,200 --> 01:51:46,760
IDENTIFIED.

2976
01:51:46,760 --> 01:51:49,160
MAINLY, I HAVE TO MENTION THAT

2977
01:51:49,160 --> 01:51:51,120
THESE FUNCTIONS ARE IN

2978
01:51:51,120 --> 01:51:53,080
ORGAN-SPECIFIC MANNER,

2979
01:51:53,080 --> 01:51:54,480
ESPECIALLY FINDING IN THE EYES,

2980
01:51:54,480 --> 01:51:57,640
IN THE CARDIOVASCULAR, IN THE

2981
01:51:57,640 --> 01:51:59,720
NEURAL AREA AND MORE TO BE

2982
01:51:59,720 --> 01:52:01,520
COMING IN THE FUTURE.

2983
01:52:01,520 --> 01:52:05,280
SO IN THE CASE OF THE HEART,

2984
01:52:05,280 --> 01:52:07,440
WHERE I AMPHOCUSSING ON, I HOPE

2985
01:52:07,440 --> 01:52:08,560
YOU CAN APPRECIATE THAT, THE

2986
01:52:08,560 --> 01:52:10,800
HEART IS ALSO ENRICHED BY A

2987
01:52:10,800 --> 01:52:12,640
COMPLEX NETWORK OF THE LYMPHATIC

2988
01:52:12,640 --> 01:52:16,600
VESSEL, HERE HIGHLIGHTED IN RED.

2989
01:52:16,600 --> 01:52:18,240
A STUDY IN THE PAST SEVERAL

2990
01:52:18,240 --> 01:52:20,880
YEARS HAS SHOWED THAT LYMPHATIC

2991
01:52:20,880 --> 01:52:23,360
VESSEL PLAY A FUNDAMENTAL ROLE

2992
01:52:23,360 --> 01:52:25,520
IN CARDIOVASCULAR DISEASE IN

2993
01:52:25,520 --> 01:52:28,280
TERMS OF ATHEROSCLEROSIS AND

2994
01:52:28,280 --> 01:52:29,120
MYOCARDIAL INFARCTION.

2995
01:52:29,120 --> 01:52:31,240
AS WE KNOW, THOSE ARE THE TWO

2996
01:52:31,240 --> 01:52:32,040
MAJOR DISEASE CONDITIONS THAT

2997
01:52:32,040 --> 01:52:33,480
LEAD TO HEART FAILURE, AND IT'S

2998
01:52:33,480 --> 01:52:36,120
STILL THE NUMBER ONE KILLER

2999
01:52:36,120 --> 01:52:36,720
WORLDWIDE.

3000
01:52:36,720 --> 01:52:38,360
SO UNDERSTANDING THE FUNCTIONAL

3001
01:52:38,360 --> 01:52:40,080
ROLE IN CARDIOVASCULAR DISEASE

3002
01:52:40,080 --> 01:52:44,120
IS REALLY A KEY AND RISING IN

3003
01:52:44,120 --> 01:52:44,400
THIS FIELD.

3004
01:52:44,400 --> 01:52:50,080
SO I HAVE TO MENTION PIONEER

3005
01:52:50,080 --> 01:52:51,640
WORK SEVERAL YEARS AGO FROM

3006
01:52:51,640 --> 01:52:52,720
DR. PAUL REILLY'S GROUP HAS

3007
01:52:52,720 --> 01:52:57,160
SHOWN THAT IN THE MOUSE MODEL,

3008
01:52:57,160 --> 01:52:58,160
AFTER MYOCARDIAL INFARCTION, YOU

3009
01:52:58,160 --> 01:53:01,720
CAN SEE THERE'S INCREASED

3010
01:53:01,720 --> 01:53:02,280
LYMPHOANGIOGENESIS IN THE

3011
01:53:02,280 --> 01:53:03,200
INFARCTED AREA.

3012
01:53:03,200 --> 01:53:05,680
AND IMPORTANTLY, WHEN YOU GIVE

3013
01:53:05,680 --> 01:53:10,880
VEGF C, A MAJOR FACTOR TO INDUCE

3014
01:53:10,880 --> 01:53:12,080
LYMPHOANGIOGENESIS, YOU CAN

3015
01:53:12,080 --> 01:53:13,520
CLEARLY SEE THAT COMPARED TO

3016
01:53:13,520 --> 01:53:18,080
CONTROL, THERE'S INCREASE IN --

3017
01:53:18,080 --> 01:53:21,360
GENESIS AND ALSO THERE'S

3018
01:53:21,360 --> 01:53:22,360
IMPROVED CARDIAC FUNCTION.

3019
01:53:22,360 --> 01:53:27,160
SO INDICATING THERAPEUTIC

3020
01:53:27,160 --> 01:53:29,080
POTENTIAL OF LYMPHATIC VESSEL IN

3021
01:53:29,080 --> 01:53:31,040
CARDIAC DISEASE.

3022
01:53:31,040 --> 01:53:33,040
I'M WORKING ON THIS FIELD.

3023
01:53:33,040 --> 01:53:34,720
I ALWAYS WONDER WHAT IS THE

3024
01:53:34,720 --> 01:53:36,480
MECHANISM, WHAT IS THE MECHANISM

3025
01:53:36,480 --> 01:53:40,680
TO HELP WITH THIS RECOVERY?

3026
01:53:40,680 --> 01:53:43,440
SO MANY OF THE STUDY CONCLUDE IT

3027
01:53:43,440 --> 01:53:45,760
LIKELY BY TRANSPORT OR BY REMOVE

3028
01:53:45,760 --> 01:53:47,960
THE DEBRIS OR IMMUNE CELLS FROM

3029
01:53:47,960 --> 01:53:50,640
THE INJURY SITE.

3030
01:53:50,640 --> 01:53:54,120
SO WHEN WE PER NORM MYOCARDIAL

3031
01:53:54,120 --> 01:53:55,400
INFARCTION TO THE HEART AND YOU

3032
01:53:55,400 --> 01:54:01,040
CAN SEE THE LYVE1 STAIN TO THE

3033
01:54:01,040 --> 01:54:03,480
VESSEL IS CLEARLY INCREASED AND

3034
01:54:03,480 --> 01:54:04,160
INFARCT THE AREA.

3035
01:54:04,160 --> 01:54:05,880
SO WE WONDER WHAT ARE THE

3036
01:54:05,880 --> 01:54:07,280
FUNCTIONS RELEVANT TO THIS

3037
01:54:07,280 --> 01:54:10,480
DISEASE RECOVERY?

3038
01:54:10,480 --> 01:54:12,720
SINCE I'M A DEVELOPMENTAL

3039
01:54:12,720 --> 01:54:13,640
BIOLOGIST, I WONDER WHETHER WE

3040
01:54:13,640 --> 01:54:16,320
CAN SORT OUT THIS MECHANISM FROM

3041
01:54:16,320 --> 01:54:17,760
DEVELOPMENTAL POINT OF VIEW, AND

3042
01:54:17,760 --> 01:54:20,720
TO ASK, DO WE KNOW THE

3043
01:54:20,720 --> 01:54:21,680
FUNCTIONAL ROLE OF THE

3044
01:54:21,680 --> 01:54:22,520
LYMPHATICS DURING HEART

3045
01:54:22,520 --> 01:54:23,760
DEVELOPMENT?

3046
01:54:23,760 --> 01:54:27,880
SO TO DO THIS, WE USE SEVERAL

3047
01:54:27,880 --> 01:54:31,080
GENETIC MOUSE MODEL LIKE IN

3048
01:54:31,080 --> 01:54:33,440
LYMPHATIC DEVELOPMENT AND WE ARE

3049
01:54:33,440 --> 01:54:34,840
USING CONDITIONAL DELETION TRAN

3050
01:54:34,840 --> 01:54:36,600
SCRIP TORE FACTOR, PROX1, AND

3051
01:54:36,600 --> 01:54:38,560
YOU CAN APPRECIATE HERE THAT

3052
01:54:38,560 --> 01:54:42,160
THIS EMBRYO SHOWS SEVERE EDEMA,

3053
01:54:42,160 --> 01:54:47,440
IN THE EMBRYO, AND IN THE HEART,

3054
01:54:47,440 --> 01:54:49,040
THERE'S -- TO OUR SURPRISE IS,

3055
01:54:49,040 --> 01:54:52,200
WE FOUND THAT THE HEART SIZE IS

3056
01:54:52,200 --> 01:54:54,800
DRAMATICALLY REDUCED COMPARED TO

3057
01:54:54,800 --> 01:54:55,480
THE CONTROL.

3058
01:54:55,480 --> 01:55:00,120
SO SUGGESTING THERE IS A ROLE OF

3059
01:55:00,120 --> 01:55:01,920
THE LYMPHATIC -- REGULATING

3060
01:55:01,920 --> 01:55:03,000
CARDIAC GROWTH, HOWEVER, BY

3061
01:55:03,000 --> 01:55:03,320
WHAT?

3062
01:55:03,320 --> 01:55:04,600
WHAT IS THE MECHANISM?

3063
01:55:04,600 --> 01:55:06,840
AND UNDERSTANDING THE HEART

3064
01:55:06,840 --> 01:55:09,080
ANATOMY, WE KNOW THAT ALTHOUGH

3065
01:55:09,080 --> 01:55:12,480
CARDIO -- IS CRITICAL, BUT IS

3066
01:55:12,480 --> 01:55:14,640
ONLY 30% OF THE MASS OF THE

3067
01:55:14,640 --> 01:55:17,600
HEART, AS AN INTERACTION BETWEEN

3068
01:55:17,600 --> 01:55:20,080
OTHER CELL TYPES WITH

3069
01:55:20,080 --> 01:55:21,600
CARDIOMYOCYTE HAS BEEN NO

3070
01:55:21,600 --> 01:55:23,680
CRITICAL IN THE

3071
01:55:23,680 --> 01:55:24,320
PHYSIOPATHOLOGICAL CONDITION OF

3072
01:55:24,320 --> 01:55:25,960
THE HEART DEVELOPMENT.

3073
01:55:25,960 --> 01:55:27,760
AND ONE OF THE MAJOR FOCUS IN

3074
01:55:27,760 --> 01:55:33,320
THE FIELD WE HAVE KNOWN IS

3075
01:55:33,320 --> 01:55:35,200
THAT -- FACTOR FROM ENDOTHELIAL

3076
01:55:35,200 --> 01:55:36,680
CELLS HAS BEEN TREMENDOUSLY

3077
01:55:36,680 --> 01:55:38,400
CRITICAL FOR THE CARDIAC

3078
01:55:38,400 --> 01:55:41,120
DEVELOPMENT AND DISEASE.

3079
01:55:41,120 --> 01:55:45,520
HOWEVER IN THIS PICTURE,

3080
01:55:45,520 --> 01:55:46,720
SOMETHING THAT'S LACKING IS

3081
01:55:46,720 --> 01:55:48,560
WHETHER THERE'S SUCH A SIGNAL

3082
01:55:48,560 --> 01:55:55,240
FROM LYMPHATICS THAT COULD ALSO

3083
01:55:55,240 --> 01:55:56,520
REGULATE CARDIO -- SO WE SET OUT

3084
01:55:56,520 --> 01:55:57,720
TO UNDERSTANDING WHETHER THERE

3085
01:55:57,720 --> 01:56:01,080
IS SUCH A ROLE BY USING IN VITRO

3086
01:56:01,080 --> 01:56:05,040
CELL CULTURE SYSTEM AND HAS

3087
01:56:05,040 --> 01:56:07,120
ALREADY MENTIONED A LITTLE BIT

3088
01:56:07,120 --> 01:56:07,560
ABOUT THAT.

3089
01:56:07,560 --> 01:56:09,800
WHAT WE DID IS COLLECT

3090
01:56:09,800 --> 01:56:12,640
COMMISSION MEDIUM AND USING

3091
01:56:12,640 --> 01:56:16,560
COCULTURE SYSTEM TO CULTURE THE

3092
01:56:16,560 --> 01:56:17,800
PRIMARY CARDIOMYOCYTE IN VITRO,

3093
01:56:17,800 --> 01:56:20,200
AND TO OUR SURPRISES, BY

3094
01:56:20,200 --> 01:56:22,920
CULTURING THE CARDIOMYOCYTE WITH

3095
01:56:22,920 --> 01:56:24,760
CONDITIONED MEDIUM, IT'S

3096
01:56:24,760 --> 01:56:27,400
SIGNIFICANTLY INCREASED THE

3097
01:56:27,400 --> 01:56:28,720
CARDIOMYOCYTE PROLIFERATION, AND

3098
01:56:28,720 --> 01:56:31,760
IT'S REDUCED THE CARDIOMYOCYTE

3099
01:56:31,760 --> 01:56:33,160
APOPTOSIS UNDER THE HYPOXIA

3100
01:56:33,160 --> 01:56:33,920
CONDITION.

3101
01:56:33,920 --> 01:56:36,760
SO SUGGESTING THERE IS INDEED

3102
01:56:36,760 --> 01:56:39,680
THERE IS A SIGNAL FROM THE

3103
01:56:39,680 --> 01:56:42,000
LYMPHATIC ENDOTHELIAL CELLS THAT

3104
01:56:42,000 --> 01:56:44,040
CAN REGULATE CARDIOMYOCYTE

3105
01:56:44,040 --> 01:56:47,840
PROLIFERATION AND SURVIVAL.

3106
01:56:47,840 --> 01:56:49,080
SO WHAT IS INSIDE OF THE

3107
01:56:49,080 --> 01:56:51,160
CONDITION MEDIUM?

3108
01:56:51,160 --> 01:56:53,960
WE USE MASS SPEC TO SCREEN THIS

3109
01:56:53,960 --> 01:56:55,960
CANDIDATE, AND WE FOUND LIKE

3110
01:56:55,960 --> 01:56:58,680
OVER 300 CANDIDATES, AND ONE OF

3111
01:56:58,680 --> 01:57:03,600
THE TOP ENRICHED FACTOR IS

3112
01:57:03,600 --> 01:57:04,040
REELIN.

3113
01:57:04,040 --> 01:57:05,760
YOU SEE WE DID IMMUNOSTAINING IN

3114
01:57:05,760 --> 01:57:07,960
THE HEART, YOU CAN CLEARLY SEE

3115
01:57:07,960 --> 01:57:11,560
THAT REELIN IS ENRICHED OR

3116
01:57:11,560 --> 01:57:13,080
EXPRESSED BY LYMPHATIC

3117
01:57:13,080 --> 01:57:14,120
ENDOTHELIAL CELLS IN THE HEART.

3118
01:57:14,120 --> 01:57:18,440
MOST IMPORTANTLY, WHEN WE DELETE

3119
01:57:18,440 --> 01:57:19,240
REELINUSING LYMPHATIC CRE AND

3120
01:57:19,240 --> 01:57:23,040
WHAT WE FOUND, IT'S KIND OF

3121
01:57:23,040 --> 01:57:24,440
RECAPTURED WHAT WE'VE SEEN IN

3122
01:57:24,440 --> 01:57:27,880
THE LYMPHATIC DEPLETION MUTANT

3123
01:57:27,880 --> 01:57:29,280
MICE SHOWN EARLIER AS THE HEART

3124
01:57:29,280 --> 01:57:31,560
SIZE IS DRAMATICALLY REDUCED

3125
01:57:31,560 --> 01:57:36,920
COMPARING TO THE CONTROL, AND IN

3126
01:57:36,920 --> 01:57:37,960
CONSISTENCY WITH THE SMALLER

3127
01:57:37,960 --> 01:57:40,360
HEART, WE ALSO SEE THE

3128
01:57:40,360 --> 01:57:42,360
CARDIOMYOCYTE PROLIFERATION IS

3129
01:57:42,360 --> 01:57:45,000
REDUCED, AND INSTEAD APOPTOSIS

3130
01:57:45,000 --> 01:57:46,280
IS INCREASED.

3131
01:57:46,280 --> 01:57:47,920
SO WITH THIS DEVELOPMENTAL

3132
01:57:47,920 --> 01:57:50,320
FINDING, WE WONDER WHETHER THE

3133
01:57:50,320 --> 01:57:53,040
SIGNAL ARE SIGNIFICANT IN TERMS

3134
01:57:53,040 --> 01:57:54,640
OF CARDIAC REPAIR.

3135
01:57:54,640 --> 01:57:58,800
SO WHAT WE DID IS WE USED THIS

3136
01:57:58,800 --> 01:58:01,080
IDENTIFIED FACTOR AND WE PUT

3137
01:58:01,080 --> 01:58:04,480
INTO THE HEART IMMEDIATELY AFTER

3138
01:58:04,480 --> 01:58:05,680
MYOCARDIAL INFARCTION AND TO SEE

3139
01:58:05,680 --> 01:58:08,200
WHETHER THIS FACTOR IS

3140
01:58:08,200 --> 01:58:09,120
BENEFICIAL.

3141
01:58:09,120 --> 01:58:11,560
AND IT'S SURPRISINGLY, YOU CAN

3142
01:58:11,560 --> 01:58:13,320
TELL THAT COMPARED TO THE

3143
01:58:13,320 --> 01:58:15,160
CONTROL PATCH, WHICH IS A

3144
01:58:15,160 --> 01:58:17,480
COLLAGEN PATCH INCORPORATED WITH

3145
01:58:17,480 --> 01:58:21,800
THIS FACTOR REELIN AND WE'VE

3146
01:58:21,800 --> 01:58:25,000
FOUND WITH REELIN THAT GREATLY

3147
01:58:25,000 --> 01:58:26,040
IMPROVED THE CARDIAC FUNCTION

3148
01:58:26,040 --> 01:58:28,040
THE DAYS AFTER M.I. AND WE ALSO

3149
01:58:28,040 --> 01:58:30,240
SEE THAT IS CLEARLY -- IT'S

3150
01:58:30,240 --> 01:58:34,680
RESORBED THE CARDIAC FIBROSIS AS

3151
01:58:34,680 --> 01:58:36,000
REELIN-TREATED GROUP SHOWS

3152
01:58:36,000 --> 01:58:37,160
REDUCED CARDIAC FIBROSIS

3153
01:58:37,160 --> 01:58:41,000
COMPARED TO THE CONTROL GROUP.

3154
01:58:41,000 --> 01:58:43,320
SO IT'S SUGGESTING THAT THIS

3155
01:58:43,320 --> 01:58:45,280
FACTOR WE FOUND FROM THE

3156
01:58:45,280 --> 01:58:48,880
DEVELOPMENTAL POINT OF VIEW IS

3157
01:58:48,880 --> 01:58:49,160
BENEFICIAL.

3158
01:58:49,160 --> 01:58:52,600
NOW THE NEXT QUESTION IS, DO WE

3159
01:58:52,600 --> 01:58:56,000
KNOW THAT LYMPHATIC DERIVED

3160
01:58:56,000 --> 01:58:57,960
RELIN IS CRITICAL DURING CARDIAC

3161
01:58:57,960 --> 01:58:58,200
REPAIR.

3162
01:58:58,200 --> 01:59:01,040
SO WE FIRST PERFORMED

3163
01:59:01,040 --> 01:59:03,640
IMMUNOSTAINING TO CHECK THE

3164
01:59:03,640 --> 01:59:04,640
REELIN EXPRESSION.

3165
01:59:04,640 --> 01:59:07,320
SURPRISINGLY IN A NON-INFARCTED

3166
01:59:07,320 --> 01:59:08,240
AREA REALLY EXPRESSION IS VERY

3167
01:59:08,240 --> 01:59:10,320
LOW, IT'S BARELY DETECTED.

3168
01:59:10,320 --> 01:59:11,840
HOWEVER, AFTER INFARCTION,

3169
01:59:11,840 --> 01:59:14,560
THERE'S NEWLY FORMED LYMPHATIC

3170
01:59:14,560 --> 01:59:17,080
VESSEL, THERE'S UPREGULATED OF

3171
01:59:17,080 --> 01:59:21,440
REELIN EXPRESSION IN THE HEART.

3172
01:59:21,440 --> 01:59:22,880
SO IT'S VERY INTERESTING, NOW WE

3173
01:59:22,880 --> 01:59:27,560
WANT TO ASK WHETHER THOSE REELIN

3174
01:59:27,560 --> 01:59:34,840
IN THIS -- ARE FUNCTIONAL.

3175
01:59:34,840 --> 01:59:40,000
WE PERFORMED -- -- WE PERFORM

3176
01:59:40,000 --> 01:59:42,600
M.I. AND WE CHECK THE CARDIAC

3177
01:59:42,600 --> 01:59:44,280
FUNCTION FOUR WEEKS AFTER, WHAT

3178
01:59:44,280 --> 01:59:47,120
WE HAVE FOUND IS THAT INDEED,

3179
01:59:47,120 --> 01:59:52,560
CARDIAC FUNCTION IS DRAMATICALLY

3180
01:59:52,560 --> 01:59:54,600
REDUCED BY LACKING OF THE REAL

3181
01:59:54,600 --> 01:59:58,360
ENIN THE LYMPHATIC AND WE SEE

3182
01:59:58,360 --> 02:00:00,320
CARDIAC FIBROSIS IS DRAMATICALLY

3183
02:00:00,320 --> 02:00:01,960
INCREASED IN THIS HEART POST

3184
02:00:01,960 --> 02:00:07,440
M.I. TOO.

3185
02:00:07,440 --> 02:00:12,000
SO WE FOUND REELIN LYMPHATIC

3186
02:00:12,000 --> 02:00:13,400
DERIVED FACTOR IS REQUIRED FOR

3187
02:00:13,400 --> 02:00:15,920
CARDIAC GROWTH BY IMPROVING

3188
02:00:15,920 --> 02:00:17,320
CARDIAC PROLIFERATION AND

3189
02:00:17,320 --> 02:00:22,640
SURVIVAL, AND WE ALSO SHOWED YOU

3190
02:00:22,640 --> 02:00:23,920
THAT -- IS REQUIRED FOR ADULT

3191
02:00:23,920 --> 02:00:24,400
CARDIAC REPAIR.

3192
02:00:24,400 --> 02:00:26,560
SO NOW WE PUT THE WHOLE PICTURE

3193
02:00:26,560 --> 02:00:30,720
TOGETHER AS WHEN WE CONSIDER

3194
02:00:30,720 --> 02:00:32,680
ABOUT LYMPHOANGIOGENESIS IN

3195
02:00:32,680 --> 02:00:35,320
CARDIAC REPAIR, WE ALWAYS THINK

3196
02:00:35,320 --> 02:00:38,400
LYMPHATIC HAS A ROLE TO CLEAR

3197
02:00:38,400 --> 02:00:42,240
THE IMMUNE CELLS.

3198
02:00:42,240 --> 02:00:44,040
NOW, WE IDENTIFY A NEW FUNCTION

3199
02:00:44,040 --> 02:00:47,120
THAT ACTIVELY SECRETES THIS

3200
02:00:47,120 --> 02:00:48,880
SIGNAL TO IMPROVE CARDIAC

3201
02:00:48,880 --> 02:00:49,120
SURVIVAL.

3202
02:00:49,120 --> 02:00:52,040
SO THE FUTURE DIRECTION ON TOP

3203
02:00:52,040 --> 02:00:55,440
OF THIS IS KIND OF TO DISSECT

3204
02:00:55,440 --> 02:00:57,320
THE CONTRIBUTION OF THE TWO

3205
02:00:57,320 --> 02:00:59,040
FUNCTIONS GIVEN THE CARDIAC

3206
02:00:59,040 --> 02:01:01,640
REPAIR, WHETHER THERE'S TEMPO

3207
02:01:01,640 --> 02:01:03,960
SPATIAL REGULATION, AND WHETHER

3208
02:01:03,960 --> 02:01:06,360
WE CAN OPTIMIZE BOTH OF THE

3209
02:01:06,360 --> 02:01:09,640
FUNCTION IN THE FUTURE CARDIAC

3210
02:01:09,640 --> 02:01:11,160
THERAPEUTIC STRATEGY FOR THE

3211
02:01:11,160 --> 02:01:15,640
CARDIAC REPAIR.

3212
02:01:15,640 --> 02:01:17,040
SO I THINK ANOTHER KEY POINT

3213
02:01:17,040 --> 02:01:19,880
ABOUT THIS FINDING IS NOT JUST

3214
02:01:19,880 --> 02:01:21,640
ONE FACTOR IDENTIFIED.

3215
02:01:21,640 --> 02:01:27,000
I THINK IT'S PROVIDE MOTIVATE --

3216
02:01:27,000 --> 02:01:28,520
TO THINK LYMPHATIC FUNCTION AS A

3217
02:01:28,520 --> 02:01:31,480
WHOLE IS NOT JUST A DRAINAGE BUT

3218
02:01:31,480 --> 02:01:33,200
ALSO TAKE INTO CONSIDERATION OF

3219
02:01:33,200 --> 02:01:34,560
THE LYMPHATIC SIGNAL.

3220
02:01:34,560 --> 02:01:37,560
AND I'M VERY EXCITED TO SAY THAT

3221
02:01:37,560 --> 02:01:39,440
AFTER THE PAPER CAME OUT, THERE

3222
02:01:39,440 --> 02:01:43,000
IS MANY, MANY -- THERE'S TWO

3223
02:01:43,000 --> 02:01:46,440
MAJOR FINDINGS THAT HAS BEEN

3224
02:01:46,440 --> 02:01:47,960
SHOWN IN ADIPOSE TISSUE, AND WE

3225
02:01:47,960 --> 02:01:49,600
HAVE JUST HEARD FROM RACHEL FROM

3226
02:01:49,600 --> 02:01:52,440
THE INTESTINE, AND WE ARE MORE

3227
02:01:52,440 --> 02:01:54,920
CONFIDENT ABOUT THAT THE

3228
02:01:54,920 --> 02:01:56,360
SIGNALING ARE IN AN

3229
02:01:56,360 --> 02:01:57,800
ORGAN-SPECIFIC MANNER BECAUSE A

3230
02:01:57,800 --> 02:02:01,600
DIFFERENT SIGNAL HAS BEEN

3231
02:02:01,600 --> 02:02:03,120
IDENTIFIED FROM DIFFERENT

3232
02:02:03,120 --> 02:02:04,320
LYMPHATIC NICHE.

3233
02:02:04,320 --> 02:02:06,200
BASED ON THIS, I THINK THERE IS

3234
02:02:06,200 --> 02:02:08,600
STILL GAPS AND A NEED AND

3235
02:02:08,600 --> 02:02:11,760
OPPORTUNITIES IN THIS FIELD IS

3236
02:02:11,760 --> 02:02:13,520
TO KIND OF DISSECT THIS

3237
02:02:13,520 --> 02:02:17,160
LYMPHATIC SIGNALING VERSUS

3238
02:02:17,160 --> 02:02:18,640
LYMPH -- FUNCTION DURING CARDIAC

3239
02:02:18,640 --> 02:02:20,480
REPAIR AND THE SECOND IS BL

3240
02:02:20,480 --> 02:02:22,360
THERE'S OTHER LYMPHATIC

3241
02:02:22,360 --> 02:02:23,360
SIGNALING AFFECT OTHER CELL

3242
02:02:23,360 --> 02:02:24,600
TYPES STILL IN THE HEART THAT IS

3243
02:02:24,600 --> 02:02:29,600
GOING TO BE CONTRIBUTED TO

3244
02:02:29,600 --> 02:02:31,880
DEVELOPMENT AND DISEASE.

3245
02:02:31,880 --> 02:02:32,960
WE'VE HEARD FROM OLIVER STONE

3246
02:02:32,960 --> 02:02:34,360
AND OTHER STUDIES IN THE FIELD

3247
02:02:34,360 --> 02:02:38,200
ABOUT THE ORIGIN ABOUT LYMPHATIC

3248
02:02:38,200 --> 02:02:40,160
VESSEL, AND WE WONDER WHETHER

3249
02:02:40,160 --> 02:02:41,960
THERE'S OTHER CONTRIBUTION TO

3250
02:02:41,960 --> 02:02:42,800
THIS DISEASE MODEL.

3251
02:02:42,800 --> 02:02:47,160
SO I'M GOING TO -- BASED ON

3252
02:02:47,160 --> 02:02:47,600
THOSE OPTION -- THIS

3253
02:02:47,600 --> 02:02:49,880
OPPORTUNITIES, I WANT TO

3254
02:02:49,880 --> 02:02:53,720
INTRODUCE TWO PROJECTS THAT IS

3255
02:02:53,720 --> 02:02:55,680
GOING ON IN MY LAB AT TEMPLE

3256
02:02:55,680 --> 02:02:56,320
UNIVERSITY.

3257
02:02:56,320 --> 02:02:59,920
THE FIRST ONE IS WE HAVE

3258
02:02:59,920 --> 02:03:03,440
IDENTIFIED THIS PAIR ALCRINE

3259
02:03:03,440 --> 02:03:06,600
SIGNALS TO CARDIOMYOCYTES NOW WE

3260
02:03:06,600 --> 02:03:08,440
ASK WHETHER THERE'S OTHER

3261
02:03:08,440 --> 02:03:10,400
SIGNALING FROM LYMPHATIC

3262
02:03:10,400 --> 02:03:11,320
ENDOTHELIAL CELLS TO OTHER CELL

3263
02:03:11,320 --> 02:03:12,760
TYPES DURING THE PATHOLOGIC PRO

3264
02:03:12,760 --> 02:03:15,440
GRETION OF THE          

3265
02:03:15,440 --> 02:03:16,520
PROGRESSION OF THE CARDIAC

3266
02:03:16,520 --> 02:03:19,800
REPAIR AND USING IN VIVO AND IN

3267
02:03:19,800 --> 02:03:21,680
VITRO MODEL TO DISSECT THIS.

3268
02:03:21,680 --> 02:03:23,080
THE SECOND PROJECT IS, AS A

3269
02:03:23,080 --> 02:03:24,080
DEVELOPMENTAL BIOLOGIST, I

3270
02:03:24,080 --> 02:03:25,960
ALWAYS VALUE THE IMPORTANT AND

3271
02:03:25,960 --> 02:03:27,560
THE CRITICAL OF THE EARLY STEPS

3272
02:03:27,560 --> 02:03:31,040
OF THE LYMPHATIC DEVELOPMENT.

3273
02:03:31,040 --> 02:03:33,160
WE KNOW THAT THERE'S MANY KEY

3274
02:03:33,160 --> 02:03:35,240
GENES, NOW IT'S ALSO IMPORTANT

3275
02:03:35,240 --> 02:03:37,520
MARKERS IN THIS FIELD, HAS BEEN

3276
02:03:37,520 --> 02:03:40,800
IDENTIFIED TO CONTROL THE EARLY

3277
02:03:40,800 --> 02:03:42,760
SPROUTING MIGRATION AT

3278
02:03:42,760 --> 02:03:44,080
DEVELOPMENT OF THIS VESSEL.

3279
02:03:44,080 --> 02:03:45,600
COMPARED TO THE BLOOD VESSEL OR

3280
02:03:45,600 --> 02:03:48,120
OTHER SYSTEMS, THE UNDERSTANDING

3281
02:03:48,120 --> 02:03:49,640
IS FAR LESS UNDERSTOOD.

3282
02:03:49,640 --> 02:03:52,040
SO IDENTIFYING NOVEL PLAYER IS

3283
02:03:52,040 --> 02:03:54,000
STILL A NEED, AND IS A PART OF

3284
02:03:54,000 --> 02:03:56,400
MY PASSION TO IDENTIFY.

3285
02:03:56,400 --> 02:03:57,600
SO ONE OF THE CANDIDATES I

3286
02:03:57,600 --> 02:04:00,840
WANTED TO SHOW YOU HERE IS WE

3287
02:04:00,840 --> 02:04:01,640
IDENTIFIED ANOTHER GENE.

3288
02:04:01,640 --> 02:04:04,240
THAT IS VERY INTERESTINGLY

3289
02:04:04,240 --> 02:04:06,680
HIGHLY EXPRESSED IN THE

3290
02:04:06,680 --> 02:04:08,760
SPROUTING PART OF THE LYMPHATIC

3291
02:04:08,760 --> 02:04:10,640
VESSEL, AND IN THE LAB WE'RE

3292
02:04:10,640 --> 02:04:13,480
USING TRANSGENIC -- MOUSE MODEL

3293
02:04:13,480 --> 02:04:15,440
TO FURTHER IDENTIFY THE

3294
02:04:15,440 --> 02:04:16,720
FUNCTIONAL ROLE DURING THE

3295
02:04:16,720 --> 02:04:17,840
DEVELOPMENT.

3296
02:04:17,840 --> 02:04:21,200
AND WITH THE ULTIMATE GOAL IS TO

3297
02:04:21,200 --> 02:04:23,800
MODULATE THIS SIGNALING FOR THE

3298
02:04:23,800 --> 02:04:25,440
TREATMENT OF LYMPHATIC-RELATED

3299
02:04:25,440 --> 02:04:25,960
DISEASE.

3300
02:04:25,960 --> 02:04:28,000
SO WITH ALL OF THAT, I WOULD

3301
02:04:28,000 --> 02:04:32,240
LIKE TO ANNOUNCE THAT MY LAB IS

3302
02:04:32,240 --> 02:04:33,800
OFFICIALLY ESTABLISHED EARLY

3303
02:04:33,800 --> 02:04:39,880
THIS YEAR IN THE LEMOLE CENTER

3304
02:04:39,880 --> 02:04:40,440
FOR TEMPLE UNIVERSITY.

3305
02:04:40,440 --> 02:04:42,840
RIGHT NOW I HAVE A POSTDOC AND

3306
02:04:42,840 --> 02:04:43,920
PH.D. CANDIDATE IN THE LAB.

3307
02:04:43,920 --> 02:04:45,320
WE ARE STILL HIRING, SO ANYBODY

3308
02:04:45,320 --> 02:04:46,840
WHO ARE INTERESTED IN THIS PART

3309
02:04:46,840 --> 02:04:51,120
OF THE WORK, PLEASE FEEL FREE TO

3310
02:04:51,120 --> 02:04:53,200
CONTACT US, AND SO AT THE FIRST

3311
02:04:53,200 --> 02:04:55,520
PART OF THE WORK I HAVE

3312
02:04:55,520 --> 02:04:56,280
PRESENTED HAS BEEN DONE WHEN I

3313
02:04:56,280 --> 02:04:58,440
WAS A POSTDOC IN DR. OLIVER'S

3314
02:04:58,440 --> 02:05:01,080
LAB, RIGHT NOW WE STILL HAVE

3315
02:05:01,080 --> 02:05:03,360
ACTING COLLABORATION ON SOME OF

3316
02:05:03,360 --> 02:05:05,200
THE ONGOING PROJECT.

3317
02:05:05,200 --> 02:05:06,640
SINCE I JOINED TEMPLE, I HAVE

3318
02:05:06,640 --> 02:05:08,720
ESTABLISHED MY OWN COLLABORATION

3319
02:05:08,720 --> 02:05:11,440
WITH A NUMBER OF WONDERFUL

3320
02:05:11,440 --> 02:05:12,880
SCIENTISTS LISTED HERE, AND A

3321
02:05:12,880 --> 02:05:14,400
COLLABORATION OUTSIDE OF THE

3322
02:05:14,400 --> 02:05:14,640
TEMPLE.

3323
02:05:14,640 --> 02:05:16,480
THANK YOU SO MUCH FOR YOUR

3324
02:05:16,480 --> 02:05:16,720
ATTENTION.

3325
02:05:16,720 --> 02:05:17,920
I'M LOOKING FORWARD TO ANSWER

3326
02:05:17,920 --> 02:05:18,400
QUESTIONS AT THE END.

3327
02:05:18,400 --> 02:05:21,960
THANK YOU.

3328
02:05:21,960 --> 02:05:26,120
>> THANK YOU, THAT WAS
VERY

3329
02:05:26,120 --> 02:05:27,120
EXCITING.

3330
02:05:27,120 --> 02:05:31,240
SO OUR NEXT AND FINAL SPEAKER OF

3331
02:05:31,240 --> 02:05:33,000
SESSION TWO IS JOSH SCALLAN FROM

3332
02:05:33,000 --> 02:05:34,240
UNIVERSITY OF SOUTH FLORIDA.

3333
02:05:34,240 --> 02:05:36,400
SO WELL    WELCOME, JOSH.

3334
02:05:36,400 --> 02:05:38,600
JOSH IS GOING TO TALK TO US

3335
02:05:38,600 --> 02:05:40,640
ABOUT THE REGULATION OF BUTTON

3336
02:05:40,640 --> 02:05:42,240
JUNCTIONS IN THE LYMPHATIC

3337
02:05:42,240 --> 02:05:52,440
VASCULATURE.

3338
02:05:56,360 --> 02:05:57,360
>> THANK YOU FOR THE

3339
02:05:57,360 --> 02:05:59,880
INTRODUCTION AND THANK YOU TO

3340
02:05:59,880 --> 02:06:03,600
THE ORGANIZERS FOR INVITING US

3341
02:06:03,600 --> 02:06:04,080
TODAY.

3342
02:06:04,080 --> 02:06:05,240
THIS IS A NEW PROJECT IN OUR

3343
02:06:05,240 --> 02:06:07,880
LAB, WHICH IS FOCUSED ON BUTTON

3344
02:06:07,880 --> 02:06:09,200
JUNCTIONS IN THE LYMPHATIC

3345
02:06:09,200 --> 02:06:10,280
VASCULATURE AND JUST REAL

3346
02:06:10,280 --> 02:06:11,920
QUICKLY TO INTRODUCE WHAT A

3347
02:06:11,920 --> 02:06:16,200
BUTTON JUNCTION IS, IF YOU

3348
02:06:16,200 --> 02:06:16,920
IMMUNOSTAIN LYMPHATIC

3349
02:06:16,920 --> 02:06:17,920
VASCULATURE LIKE SHOWN HERE FOR

3350
02:06:17,920 --> 02:06:19,480
A JUNCTION PROTEIN IN BLOOD

3351
02:06:19,480 --> 02:06:20,760
VESSELS, YOU WILL SEE THE ENTIRE

3352
02:06:20,760 --> 02:06:23,760
CELL PERIPHERY OF EACH

3353
02:06:23,760 --> 02:06:24,160
INDIVIDUAL CELL.

3354
02:06:24,160 --> 02:06:26,120
AS YOU CAN NOTE HERE IN

3355
02:06:26,120 --> 02:06:27,880
LYMPHATIC VESSELS, THE JUNCTION

3356
02:06:27,880 --> 02:06:28,960
PATTERN LOOKS A LITTLE

3357
02:06:28,960 --> 02:06:30,120
DISCONTINUE WITH US AND BROKEN

3358
02:06:30,120 --> 02:06:31,520
AND WE REFER TO THESE AS

3359
02:06:31,520 --> 02:06:34,720
BUTTONS.

3360
02:06:34,720 --> 02:06:36,240
BEFORE I CONTINUE TALKING ABOUT

3361
02:06:36,240 --> 02:06:37,200
BUTTONS, I'D LIKE TO INTRODUCE

3362
02:06:37,200 --> 02:06:40,480
HOW WE GOT INTERESTED IN

3363
02:06:40,480 --> 02:06:42,240
MOLECULAR REGULATION OF BUTTONS.

3364
02:06:42,240 --> 02:06:44,800
SO THIS WAS A SLIDE THAT WAS

3365
02:06:44,800 --> 02:06:46,040
PRESENTED IN DR. YING YANG'S

3366
02:06:46,040 --> 02:06:47,440
TALK BUT REAL QUICK JUST TO GO

3367
02:06:47,440 --> 02:06:58,240
OVER IT, THIS IS A LIN PITOCIN G

3368
02:06:59,920 --> 02:07:05,800
ROW FEE, WHEN YOU INJECT RADIO

3369
02:07:05,800 --> 02:07:07,920
TRASER INTO FEET -- THAT TRAVELS

3370
02:07:07,920 --> 02:07:10,400
UP TO THE GROIN WHERE IT

3371
02:07:10,400 --> 02:07:14,800
ACCUMULATES IN LYMPH NODES.

3372
02:07:14,800 --> 02:07:17,600
IN FOX C2 PATIENTS, IT DOES

3373
02:07:17,600 --> 02:07:18,840
BACKFLOW INTO THE DERMAL CAB

3374
02:07:18,840 --> 02:07:19,920
LARRYS WHICH CAN ONLY HAPPEN

3375
02:07:19,920 --> 02:07:21,480
WHEN YOU HAVE EITHER MISSING OR

3376
02:07:21,480 --> 02:07:22,640
DYSFUNCTIONAL VALVES.

3377
02:07:22,640 --> 02:07:23,840
BUT WE WERE ACTUALLY REALLY

3378
02:07:23,840 --> 02:07:25,600
INTRIGUED BY ANOTHER PANEL IN

3379
02:07:25,600 --> 02:07:30,320
THIS PAPER WHICH SHOWED A

3380
02:07:30,320 --> 02:07:31,160
DIFFERENT LYMPHEDEMA FLOW

3381
02:07:31,160 --> 02:07:33,720
PATTERN WHICH OCCURS IN PATIENTS

3382
02:07:33,720 --> 02:07:36,560
WITH MISS ANS MUTATIONS IN THE

3383
02:07:36,560 --> 02:07:44,240
GENE VEGFR3, THE MOST

3384
02:07:44,240 --> 02:07:45,360
COMMONLY -- RADIO TRASER IS

3385
02:07:45,360 --> 02:07:47,200
SIMPLY NOT ABSORBED AT ALL BY

3386
02:07:47,200 --> 02:07:47,480
LYMPHATICS.

3387
02:07:47,480 --> 02:07:48,720
SO WE WANTED TO KNOW A LITTLE

3388
02:07:48,720 --> 02:07:51,560
BIT MORE ABOUT WHAT COULD BE

3389
02:07:51,560 --> 02:07:55,040
CAUSING THAT AND WHY IT'S

3390
02:07:55,040 --> 02:07:56,040
OCCURRING.

3391
02:07:56,040 --> 02:08:00,000
THERE ARE THREE VEGF RECEPTORS,

3392
02:08:00,000 --> 02:08:03,400
1, 2 AND 3, AND THESE RECEPTORS

3393
02:08:03,400 --> 02:08:05,080
ARE RECEPTOR TYROSINE KINASES

3394
02:08:05,080 --> 02:08:09,640
THAT FORM DIMERS -- EITHER HOMO

3395
02:08:09,640 --> 02:08:11,640
OR HETERODIMERS AND THE END

3396
02:08:11,640 --> 02:08:13,720
EFFECT OF BINDING THEIR LIGANDS

3397
02:08:13,720 --> 02:08:18,400
SUCH AS VEGF A OR VEGF C IS TO

3398
02:08:18,400 --> 02:08:21,600
NICHE YAIF LYMPH ANGIOGENESIS OR

3399
02:08:21,600 --> 02:08:23,240
ANGIOGENESIS, THE GROWTH OF

3400
02:08:23,240 --> 02:08:25,120
LYMPHATIC OR BLOOD VESSELS.

3401
02:08:25,120 --> 02:08:29,160
SO THE WAY WILD TYPE -- WHEN

3402
02:08:29,160 --> 02:08:31,880
VEGF C BINDS IT, THEY'LL AUTO

3403
02:08:31,880 --> 02:08:33,320
PHOSPHORYLATE ONE ANOTHER AND

3404
02:08:33,320 --> 02:08:34,640
INITIATE A BUNCH OF DIFFERENT

3405
02:08:34,640 --> 02:08:36,080
SIGNALING PATHWAYS WHICH WILL

3406
02:08:36,080 --> 02:08:40,680
ALL ACT TO INITIATE LYMPH

3407
02:08:40,680 --> 02:08:42,560
ANGIOGENESIS.

3408
02:08:42,560 --> 02:08:49,000
HOWEVER, IN MILL    MILROY DISEE

3409
02:08:49,000 --> 02:08:52,280
THIS INACTIVATES THE TAIL SO

3410
02:08:52,280 --> 02:08:53,600
EVEN IF YOU HAVE A MUTATED

3411
02:08:53,600 --> 02:08:54,800
PROTEIN THAT PAIRS UP WITH A

3412
02:08:54,800 --> 02:08:57,000
WILD TYPE PROTEIN, YOU WILL NOT

3413
02:08:57,000 --> 02:08:59,840
GET ANY AUTO PHOSPHORYLATION

3414
02:08:59,840 --> 02:09:01,280
CYTOPLASMIC TAILS AND YOU WILL

3415
02:09:01,280 --> 02:09:02,240
HAVE ABLATED SIGNALING WHICH

3416
02:09:02,240 --> 02:09:05,680
WILL IN THIS DIAGRAM LEAD TO

3417
02:09:05,680 --> 02:09:08,520
DISRUPTED LYMPH ANGIOGENESIS.

3418
02:09:08,520 --> 02:09:10,160
SO TO EXPLAIN THE FLOW PATTERN I

3419
02:09:10,160 --> 02:09:11,480
SHOWED IN THE BEGINNING OF MY

3420
02:09:11,480 --> 02:09:15,520
TALK YOU MAY THINK MILROY

3421
02:09:15,520 --> 02:09:16,720
PATIENTS DON'T -- THEY DON'T

3422
02:09:16,720 --> 02:09:18,000
HAVE ANY LYMPHATIC VESSELS IN

3423
02:09:18,000 --> 02:09:19,560
THE FEET AT ALL.

3424
02:09:19,560 --> 02:09:20,800
THIS WAS ACTUALLY THE CONCLUSION

3425
02:09:20,800 --> 02:09:24,240
THAT MANY CAME TO, YOU KNOW, IN

3426
02:09:24,240 --> 02:09:25,480
THE LITERATURE.

3427
02:09:25,480 --> 02:09:27,920
JUST REAL QUICK, I WANT TO

3428
02:09:27,920 --> 02:09:29,880
HIGHLIGHT THAT VEG RECEPTOR 3 IS

3429
02:09:29,880 --> 02:09:32,400
THE KEY REGULATOR IN -- ANGIO16

3430
02:09:32,400 --> 02:09:32,720
CYST.

3431
02:09:32,720 --> 02:09:35,440
IF YOU DO A PUBMED SEARCH FOR

3432
02:09:35,440 --> 02:09:39,640
VEG RECEPTOR 3 OR VEG RECEPTOR A

3433
02:09:39,640 --> 02:09:42,160
STRONG DEGREE OF OVERLAP HERE,

3434
02:09:42,160 --> 02:09:45,880
INDICATING IT'S REALLY STUDIED

3435
02:09:45,880 --> 02:09:47,800
PRIMARILY IN THE CONTEXT OF

3436
02:09:47,800 --> 02:09:49,280
ANGIOGENESIS AND NOT ANYTHING

3437
02:09:49,280 --> 02:09:49,920
ELSE.

3438
02:09:49,920 --> 02:09:50,920
HOWEVER A MORE RECENT PAPER

3439
02:09:50,920 --> 02:09:52,760
SHOWED IT WASN'T ANY LACK OF

3440
02:09:52,760 --> 02:09:55,240
LYMPHATIC VESSELS BUT VESSELS

3441
02:09:55,240 --> 02:09:58,240
WITH DYSFUNCTION THAT CAUSES

3442
02:09:58,240 --> 02:10:01,120
MILROY DISEASE AND THEY TOOK

3443
02:10:01,120 --> 02:10:05,840
STUDIES FROM MILROY PATIENTS AND

3444
02:10:05,840 --> 02:10:06,840
IMMUNOSTAIN FOR BLOOD VESSELS

3445
02:10:06,840 --> 02:10:10,840
SHOWN IN RED, LYMPHATIC VESSELS

3446
02:10:10,840 --> 02:10:15,200
SHOWN IN GREE FROM CONTROL AND

3447
02:10:15,200 --> 02:10:18,880
MILROY PATIENTS.

3448
02:10:18,880 --> 02:10:20,840
FROM BOTH CONTROL IN MILROY

3449
02:10:20,840 --> 02:10:22,080
PATIENTS IN THE ARM AND IN THE

3450
02:10:22,080 --> 02:10:23,480
FEET, AND WHILE THERE IS A

3451
02:10:23,480 --> 02:10:25,120
SIGNIFICANT REDUCTION OF ALMOST

3452
02:10:25,120 --> 02:10:27,200
LYMPHATIC CAPILLARY DENSITY IN

3453
02:10:27,200 --> 02:10:28,400
MILROY PATIENTS AS YOU GO DEEPER

3454
02:10:28,400 --> 02:10:29,800
INTO THE SKIN, THIS DIFFERENCE

3455
02:10:29,800 --> 02:10:31,920
TENDS TO DISAPPEAR AND SO YOU

3456
02:10:31,920 --> 02:10:34,000
CAN APPRECIATE THAT MILROY

3457
02:10:34,000 --> 02:10:35,200
PATIENTS DEFINITELY HAVE A

3458
02:10:35,200 --> 02:10:36,520
NON-ZERO NUMBER OF LYMPHATIC

3459
02:10:36,520 --> 02:10:37,920
VESSELS THAT ARE PRESENT BUT

3460
02:10:37,920 --> 02:10:39,360
MUST BE DYSFUNCTIONAL IN SOME

3461
02:10:39,360 --> 02:10:40,160
WAY.

3462
02:10:40,160 --> 02:10:43,440
SO TO TRY TO GET AT THIS -- FOR

3463
02:10:43,440 --> 02:10:45,360
THE POSSIBLE CAUSE OF MISS

3464
02:10:45,360 --> 02:10:47,280
FUNCTION WE TURN TO

3465
02:10:47,280 --> 02:10:48,720
HYPOTHESIZING THAT MAYBE THE

3466
02:10:48,720 --> 02:10:49,480
LYMPHATIC CAPILLARIES ARE

3467
02:10:49,480 --> 02:10:50,560
PRESENT BUT THEY HAVE SOME KIND

3468
02:10:50,560 --> 02:10:54,640
OF A PROBLEM WITH THEIR BUTTON

3469
02:10:54,640 --> 02:10:54,920
JUNCTIONS.

3470
02:10:54,920 --> 02:10:57,200
THIS IS A TIME COURSE OF BUTTON

3471
02:10:57,200 --> 02:11:00,000
JUNCTION DEVELOPMENT FROM --

3472
02:11:00,000 --> 02:11:01,680
16 1/2, SO TWO MONTHS

3473
02:11:01,680 --> 02:11:05,520
POSTNATALLY IN THE TRACHEA.

3474
02:11:05,520 --> 02:11:08,240
IMMUNOSTAIN FOR -- YOU CAN SEE

3475
02:11:08,240 --> 02:11:09,920
THE CELL JUNCTIONS IN THE EMBRYO

3476
02:11:09,920 --> 02:11:11,640
ARE LARGELY CONTINUOUS BUT RIGHT

3477
02:11:11,640 --> 02:11:15,160
AROUND BIRTH, AND FOR SEVERAL

3478
02:11:15,160 --> 02:11:16,520
WEEKS AFTER BIRTH, YOU ARE

3479
02:11:16,520 --> 02:11:17,800
DEVELOPING MORE BUTTONS OVER

3480
02:11:17,800 --> 02:11:18,800
TIME AND THESE BUTTONS ARE

3481
02:11:18,800 --> 02:11:21,200
BECOMING MORE MATURE AND MORE

3482
02:11:21,200 --> 02:11:21,480
DISCRETE.

3483
02:11:21,480 --> 02:11:23,080
THIS IS A CARTOON SCHEMATIC

3484
02:11:23,080 --> 02:11:28,520
SHOWING THAT BUTTONS OCCUR IN --

3485
02:11:28,520 --> 02:11:29,520
THE PURPOSE OF THE BUTTON

3486
02:11:29,520 --> 02:11:31,040
JUNCTIONS IS TO FORM LARGE FLAPS

3487
02:11:31,040 --> 02:11:34,160
THAT ARE HIGHLY PERMEABLE WHICH

3488
02:11:34,160 --> 02:11:35,560
ALLOW THE LYMPHATIC CAPILLARIES

3489
02:11:35,560 --> 02:11:37,560
TO ABSORB LARGE AMOUNTS OF

3490
02:11:37,560 --> 02:11:38,760
FLUIDS, MACRO MOLECULES AND

3491
02:11:38,760 --> 02:11:42,800
LIPIDS.

3492
02:11:42,800 --> 02:11:44,680
SO WHAT DO WE KNOW ABOUT THE

3493
02:11:44,680 --> 02:11:47,080
MICRO REGULATION OF LYMPHATIC

3494
02:11:47,080 --> 02:11:47,720
BUTTON JUNCTIONS?

3495
02:11:47,720 --> 02:11:56,960
WE NODELL TA      WE KNOW THAT D

3496
02:11:56,960 --> 02:12:02,120
4 PROMOTES CONTINUOUS LACTEAL

3497
02:12:02,120 --> 02:12:03,240
REGENERATION, NEVER FORM BUTTONS

3498
02:12:03,240 --> 02:12:04,720
IN THE FIRST PLACE DOWN HERE,

3499
02:12:04,720 --> 02:12:06,200
AND THIS IS QUANTIFIED HERE, YOU

3500
02:12:06,200 --> 02:12:08,080
CAN SEE THAT THERE ARE VERY FEW

3501
02:12:08,080 --> 02:12:09,480
CONTINUOUS ZIPPER-LIKE JUNCTIONS

3502
02:12:09,480 --> 02:12:11,600
IN HEALTHY WILD TYPE LACTEALS

3503
02:12:11,600 --> 02:12:14,200
BUT YOU HAVE EXPANSION OF

3504
02:12:14,200 --> 02:12:19,120
ZIPPERED UP JUNCTIONS IN DELTA

3505
02:12:19,120 --> 02:12:20,200
LIGAND 4 KNOCKOUTS.

3506
02:12:20,200 --> 02:12:22,200
IN THE SAME PAPER, IF YOU LOOK

3507
02:12:22,200 --> 02:12:23,840
AT SUBMUCOSAL LYMPHATIC

3508
02:12:23,840 --> 02:12:26,480
CAPILLARIES AND YOU DELETE DELTA

3509
02:12:26,480 --> 02:12:29,000
LIGHT LIGAND 4 THERE REALLY IS

3510
02:12:29,000 --> 02:12:30,760
NO DIFFERENCE IN THE NUMBER OF

3511
02:12:30,760 --> 02:12:34,160
BUTTON JUNCTIONS -- REGULATION

3512
02:12:34,160 --> 02:12:36,240
OF BUTTON JUNCTION DEVELOPMENT.

3513
02:12:36,240 --> 02:12:44,360
WE ALSO KNOW ANGIOPOIETIN

3514
02:12:44,360 --> 02:12:47,000
2 REGULATES THE TRANSFORMATION

3515
02:12:47,000 --> 02:12:49,840
AND INTEGRITY OF LYMPHATIC

3516
02:12:49,840 --> 02:12:55,440
ENDOTHELIAL CELL JUNCTIONS.

3517
02:12:55,440 --> 02:13:00,480
MORE RECENTLY, THEY SHOWED THAT

3518
02:13:00,480 --> 02:13:01,880
MICE ARE PROTECTED FROM A HIGH

3519
02:13:01,880 --> 02:13:04,640
FAT DIET FOR 16 WEEKS DUE TO

3520
02:13:04,640 --> 02:13:09,800
LACTEAL ZIPPERING, SO IF YOU

3521
02:13:09,800 --> 02:13:12,120
DELETE BOTH WHICH BIND VEGF A

3522
02:13:12,120 --> 02:13:14,720
THEN THE LACTEALS GO TO BEING

3523
02:13:14,720 --> 02:13:16,040
LARGELY ZIPPERED UP.

3524
02:13:16,040 --> 02:13:21,760
AND THE MECHANISM FOR HOW THIS

3525
02:13:21,760 --> 02:13:23,720
WORKS IS THAT RECEPTORS ON BLOOD

3526
02:13:23,720 --> 02:13:26,160
VESSELS THAT SEQUESTER VEGF A

3527
02:13:26,160 --> 02:13:27,160
AND PREVENT IT FROM ACCUMULATING

3528
02:13:27,160 --> 02:13:27,880
THE TISSUE.

3529
02:13:27,880 --> 02:13:29,000
WHEN YOU KNOCK THEM OUT YOU HAVE

3530
02:13:29,000 --> 02:13:31,480
A HIGH LEVEL IN THE TISSUE THAT

3531
02:13:31,480 --> 02:13:35,000
THEN HYPERACTIVATES -- R2,

3532
02:13:35,000 --> 02:13:36,440
ACTING AS A PRO ZIPPERING

3533
02:13:36,440 --> 02:13:36,680
PATHWAY.

3534
02:13:36,680 --> 02:13:39,200
THIS WAS CONFIRMED THIS YEAR IN

3535
02:13:39,200 --> 02:13:41,920
A PAPER WHERE MICE WERE INFECTED

3536
02:13:41,920 --> 02:13:43,600
WITH VACCINIA VIRUS WHICH TURNS

3537
02:13:43,600 --> 02:13:45,960
BUTTON JUNCTIONS INTO ZIPPER

3538
02:13:45,960 --> 02:13:47,080
JUNCTIONS, AND THAT COULD BE

3539
02:13:47,080 --> 02:13:49,280
RESCUED BY ANTIBODIES AGAINST

3540
02:13:49,280 --> 02:13:57,720
VEGF R2 OR VEGF A OR KNOCKING

3541
02:13:57,720 --> 02:14:02,200
OUT -- SHOWING THAT VEGF

3542
02:14:02,200 --> 02:14:03,440
R2 INDUCES ZIPPERING.

3543
02:14:03,440 --> 02:14:11,720
WE ON   AT THE SAME TIME WITH PP

3544
02:14:11,720 --> 02:14:13,400
REPORTER SO WE CAN SEE ALL

3545
02:14:13,400 --> 02:14:13,720
LYMPHATICS.

3546
02:14:13,720 --> 02:14:15,920
WE INDUCED A LESION AT P1, RIGHT

3547
02:14:15,920 --> 02:14:17,120
WHEN BUTTONS ARE STARTING TO

3548
02:14:17,120 --> 02:14:19,760
BECOME FORMED, AND CONTINUED

3549
02:14:19,760 --> 02:14:22,160
DELETION UNTIL P21 BY INJECTING

3550
02:14:22,160 --> 02:14:23,800
TAMOXIFEN EVERY OTHER DAY.

3551
02:14:23,800 --> 02:14:26,360
SHOWN HERE, WE EFFECTIVELY

3552
02:14:26,360 --> 02:14:30,200
DELETED VEGF RECEPTOR 3, IF YOU

3553
02:14:30,200 --> 02:14:32,000
LOOK AT A HIGHER MAGNIFICATION,

3554
02:14:32,000 --> 02:14:34,680
YOU CAN SEE THERE ARE BUTTON

3555
02:14:34,680 --> 02:14:36,360
JUNCTIONS IN THE CONTROLS.

3556
02:14:36,360 --> 02:14:37,440
HOWEVER, KNOCKOUTS, THEY WERE

3557
02:14:37,440 --> 02:14:39,920
ALL ZIPPERED UP, AND THAT IS

3558
02:14:39,920 --> 02:14:40,480
QUANTIFIED HERE.

3559
02:14:40,480 --> 02:14:42,880
SO ZIPPERS IN BLUE AND BUTTONS

3560
02:14:42,880 --> 02:14:43,240
IN GREY.

3561
02:14:43,240 --> 02:14:45,800
SO WE HAD AN ALMOST COMPLETE

3562
02:14:45,800 --> 02:14:47,880
DISAPPEARANCE OF BUTTONS AND A

3563
02:14:47,880 --> 02:14:49,400
VERY BIG INCREASE IN NUMBER OF

3564
02:14:49,400 --> 02:14:52,560
ZIPPERS, JUST BY DELETING ZIPPER

3565
02:14:52,560 --> 02:14:56,160
3, INDICATING IT IS IMPORTANT

3566
02:14:56,160 --> 02:15:03,920
FOR BUTTER JUNCTION         BUT.

3567
02:15:03,920 --> 02:15:05,360
WE ENSURED THIS WAS NOT SPECIFIC

3568
02:15:05,360 --> 02:15:06,640
TO THE DIAPHRAGM, THIS IS

3569
02:15:06,640 --> 02:15:08,080
MULTIPLE TISSUES WHERE WE HAVE

3570
02:15:08,080 --> 02:15:09,400
ZIPPERING.

3571
02:15:09,400 --> 02:15:10,960
I JUST WANTED TO POINT OUT THAT

3572
02:15:10,960 --> 02:15:15,560
WE DO NOT HAVE IMPAIRED LYMPH

3573
02:15:15,560 --> 02:15:17,080
ANGIOGENESIS BY -- POSE NATALLY

3574
02:15:17,080 --> 02:15:18,080
IN EITHER THE DIAPHRAGM OR THE

3575
02:15:18,080 --> 02:15:19,280
EAR.

3576
02:15:19,280 --> 02:15:20,720
THIS IS NOT THAT SURPRISING, BUT

3577
02:15:20,720 --> 02:15:22,280
IT MIGHT BE SURPRISING TO SOME

3578
02:15:22,280 --> 02:15:24,800
PEOPLE    

3579
02:15:24,800 --> 02:15:25,560
PEOPLE.

3580
02:15:25,560 --> 02:15:30,360
IF YOU DELETE -- AFTER BUTTON

3581
02:15:30,360 --> 02:15:34,440
JUNCTIONS HAVE ALL BEEN    BEEN

3582
02:15:34,440 --> 02:15:35,400
ESTABLISHED WE WANTED TO KNOW IF

3583
02:15:35,400 --> 02:15:37,000
IT WAS REQUIRED FOR MAINTENANCE

3584
02:15:37,000 --> 02:15:39,000
OF BUTTONS SORT OF LIKE HOW

3585
02:15:39,000 --> 02:15:41,240
OTHER GENES ARE REQUIRED FOR

3586
02:15:41,240 --> 02:15:42,720
MAINTENANCE OF OTHER LYMPHATIC

3587
02:15:42,720 --> 02:15:43,200
VALVES.

3588
02:15:43,200 --> 02:15:45,240
IF YOU LOOK AT   AT THE BUTTONSW

3589
02:15:45,240 --> 02:15:45,840
THERE'S NO DIFFERENCE IN THE

3590
02:15:45,840 --> 02:15:47,240
NUMBER OF BUTTONS INDICATING

3591
02:15:47,240 --> 02:15:49,680
THAT VEGF RECEPTOR 3 IS

3592
02:15:49,680 --> 02:15:50,880
DISPENSABLE AFTER A SHORT

3593
02:15:50,880 --> 02:15:52,520
CRITICAL POSTNATAL WIN DOLE, WE

3594
02:15:52,520 --> 02:15:54,800
HAVE BUTTONS DEVELOPING SOMETIME

3595
02:15:54,800 --> 02:15:56,040
IN THE FIRST THREE WEEKS OF

3596
02:15:56,040 --> 02:15:56,520
LIFE.

3597
02:15:56,520 --> 02:15:58,160
AT LEAST IN MICE.

3598
02:15:58,160 --> 02:15:58,480
OKAY.

3599
02:15:58,480 --> 02:16:01,560
SO I ALREADY TOLD YOU THAT VEGF

3600
02:16:01,560 --> 02:16:02,280
R2 CAN INDUCE ZIPPERING.

3601
02:16:02,280 --> 02:16:04,200
SO IS IT POSSIBLE THAT SHOWM

3602
02:16:04,200 --> 02:16:05,960
WHEN WE DELETE VEG RECEPTOR 3,

3603
02:16:05,960 --> 02:16:12,640
DO WE HYPERACTIVATE VEGF R2 --

3604
02:16:12,640 --> 02:16:15,240
IF YOU ADDRESS WHETHER VEGF

3605
02:16:15,240 --> 02:16:19,240
RESPECT TORE 2 CAN REDUCE

3606
02:16:19,240 --> 02:16:20,720
ZIPPERING -- THIS IS SHOWING YOU

3607
02:16:20,720 --> 02:16:21,880
VEG RECEPTOR 2 WHICH IS

3608
02:16:21,880 --> 02:16:26,400
EXPRESSED IN MANY CELL TYPES AND

3609
02:16:26,400 --> 02:16:27,320
DIAPHRAGMS -- EPITHELIAL CELLS

3610
02:16:27,320 --> 02:16:28,560
AND AGAIN WE GET THE SAME

3611
02:16:28,560 --> 02:16:30,680
RESULTS, WE HAVE BUTTONS IN THE

3612
02:16:30,680 --> 02:16:31,680
CONTROLS AND ZIPPERS IN THE

3613
02:16:31,680 --> 02:16:32,880
DOUBLE KNOCKOUTS NOW, WHICH

3614
02:16:32,880 --> 02:16:34,200
REALLY LOOKS NO DIFFERENT THAN

3615
02:16:34,200 --> 02:16:36,320
OUR SINGLE VEG RECEPTOR

3616
02:16:36,320 --> 02:16:37,840
3 KNOCKOUTS, INDICATING THAT

3617
02:16:37,840 --> 02:16:39,280
DELETION OF VEG RECEPTOR 2 IS

3618
02:16:39,280 --> 02:16:41,520
NOT SUFFICIENT TO RESCUE LOSS OF

3619
02:16:41,520 --> 02:16:43,640
VEG RECEPTOR 3.

3620
02:16:43,640 --> 02:16:46,200
IT'S PROBABLY NOT PLAYING A

3621
02:16:46,200 --> 02:16:46,520
ROLE.

3622
02:16:46,520 --> 02:16:49,520
SO IT FIGURE OUT WHAT THE

3623
02:16:49,520 --> 02:16:51,040
MECHANISM WAS BEHIND WHY WE'RE

3624
02:16:51,040 --> 02:16:56,400
GETTING ZIPPERING, WE CULTURE

3625
02:16:56,400 --> 02:16:58,360
HD -- VEG RECEPTOR 2 DOES NOT

3626
02:16:58,360 --> 02:17:01,920
CHANGE WHEN WE DO THIS BUT NOTCH

3627
02:17:01,920 --> 02:17:05,520
SIGNALING IS STRONGLY -- AGAIN

3628
02:17:05,520 --> 02:17:09,520
THE PROTEIN LEVEL TOTAL VEGF

3629
02:17:09,520 --> 02:17:10,880
R2 AND PHOSPHORYLATED LEVELS

3630
02:17:10,880 --> 02:17:12,480
WE'RE NOT SEEING SIGNIFICANTLY

3631
02:17:12,480 --> 02:17:14,800
ALTERED BY KNOCKING DOWN VEG

3632
02:17:14,800 --> 02:17:16,200
RECEPTOR 3 AND PHOSPHORYLATED IS

3633
02:17:16,200 --> 02:17:18,480
VERY LOW IN LEZs, HOWEVER,

3634
02:17:18,480 --> 02:17:20,720
WHEN WE USE ANTIBODIES AGAINST

3635
02:17:20,720 --> 02:17:22,480
CLEAVES, NOTCH 1 OR NOTCH 4,

3636
02:17:22,480 --> 02:17:24,120
THEN NOTCH 1 WAS FOUND TO BE

3637
02:17:24,120 --> 02:17:25,880
HIGHLY EXPRESSED AND STRONGLY

3638
02:17:25,880 --> 02:17:27,320
DOWN REGULATED WHEN WE KNOCKED

3639
02:17:27,320 --> 02:17:30,680
DOWN VEG RECEPTOR 3 AND

3640
02:17:30,680 --> 02:17:32,000
NICD4 WAS REALLY NOT EXPRESSED

3641
02:17:32,000 --> 02:17:33,080
VERY HIGHLY AT ALL AND DIDN'T

3642
02:17:33,080 --> 02:17:33,840
CHANGE.

3643
02:17:33,840 --> 02:17:36,680
SO WHAT IS NOTCH SIGNALING?

3644
02:17:36,680 --> 02:17:37,840
NOTCH SIGNALING IS A SIGNALING

3645
02:17:37,840 --> 02:17:41,640
PATHWAY ACTIVATED BY CELL

3646
02:17:41,640 --> 02:17:42,600
MEMBRANE -- LIGANDS.

3647
02:17:42,600 --> 02:17:44,240
SO WHEN ONE CELL COMES INTO

3648
02:17:44,240 --> 02:17:45,520
CLOSE PROXIMITY TO ANOTHER CELL

3649
02:17:45,520 --> 02:17:47,160
EXPRESSING THE NOTCH RECEPTORS,

3650
02:17:47,160 --> 02:17:49,280
THE LIGAND COMBINES THE RECEPTOR

3651
02:17:49,280 --> 02:17:53,320
WHICH ACTIVATES CLEAVAGE OF THE

3652
02:17:53,320 --> 02:17:54,520
INTERCELLULAR DOMAIN OF NOTCH

3653
02:17:54,520 --> 02:17:57,160
WHICH THEN ALLOWS TO FREELY

3654
02:17:57,160 --> 02:17:59,480
TRANS LOCATE TO ACTIVATE GENE

3655
02:17:59,480 --> 02:18:01,040
TRANS KRIPTION AND IN THE

3656
02:18:01,040 --> 02:18:03,200
ABSENCE OF NICD, YOU USUALLY GET

3657
02:18:03,200 --> 02:18:04,520
GENE REPRESSION.

3658
02:18:04,520 --> 02:18:06,200
SO TO TEST WHETHER OR NOT WE

3659
02:18:06,200 --> 02:18:09,120
COULD OVEREXPRESS A

3660
02:18:09,120 --> 02:18:11,120
CONSTITUTIVELY ACTIVELY

3661
02:18:11,120 --> 02:18:13,160
NICD1 FRAG MANAGEMENT TO BETTER

3662
02:18:13,160 --> 02:18:15,960
RES KEUL     

3663
02:18:15,960 --> 02:18:18,160
RESCUE KNOCKOUTS -- AND AGAIN,

3664
02:18:18,160 --> 02:18:19,640
I'M SHOWING YOU WE HAVE BUTTONS

3665
02:18:19,640 --> 02:18:23,400
IN THE CONTROLS, WE HAVE ZIPPERS

3666
02:18:23,400 --> 02:18:25,360
IN THE VEG RECEPTOR 3 KNOCK

3667
02:18:25,360 --> 02:18:27,880
YOWLTS BUT SURPRISINGLY IN THE

3668
02:18:27,880 --> 02:18:31,080
ABSENCE OF VEG RECEPTOR 3 BY

3669
02:18:31,080 --> 02:18:33,600
ACTIVATING NICD1, WE'RE ABLE TO

3670
02:18:33,600 --> 02:18:34,520
ACTIVATE -- BACK TO CONTROL

3671
02:18:34,520 --> 02:18:36,160
LEVELS INDICATING NOTCH 1 IS

3672
02:18:36,160 --> 02:18:38,120
SIGNIFICANT TO RESCUE THE LOGS

3673
02:18:38,120 --> 02:18:43,600
OF VEG RECEPTOR 3.

3674
02:18:43,600 --> 02:18:46,160
SO WE WANTED TO ALSO ADDRESS

3675
02:18:46,160 --> 02:18:46,880
FUNCTION.

3676
02:18:46,880 --> 02:18:54,600
WE INJECTED EVANS BLUE DYE.

3677
02:18:54,600 --> 02:18:59,120
IN THE R3 KNOCKOUTS IT MOVES

3678
02:18:59,120 --> 02:19:01,320
INTERSTISHLY BUT DOES NOT FILL

3679
02:19:01,320 --> 02:19:03,040
UP VASCULAR STRUCTURES.

3680
02:19:03,040 --> 02:19:08,400
HOWEVER IN NICD REGS    RESCUESE

3681
02:19:08,400 --> 02:19:11,560
IS NOT ABLE TO FILL -- BY

3682
02:19:11,560 --> 02:19:12,480
RESTORING BUTTONS.

3683
02:19:12,480 --> 02:19:15,120
SO TO GO OVER MY CONCLUSIONS.

3684
02:19:15,120 --> 02:19:16,960
WHAT I SHOWED YOU TODAY IS THAT

3685
02:19:16,960 --> 02:19:19,280
VEG REACCEPT PORE 3 IS REQUIRED

3686
02:19:19,280 --> 02:19:21,520
FOR POSTNATAL BUTTON JUNCTION

3687
02:19:21,520 --> 02:19:22,280
FORMATION DURING A CRITICAL

3688
02:19:22,280 --> 02:19:23,280
WINDOW.

3689
02:19:23,280 --> 02:19:24,560
NOTCH 1 SIGNALING CAN RESCUE

3690
02:19:24,560 --> 02:19:25,880
BUTTON JUNCTION FORMATION AND

3691
02:19:25,880 --> 02:19:27,360
FUNCTION IN THE ABSENCE OF VEG

3692
02:19:27,360 --> 02:19:27,880
RECEPTOR 3.

3693
02:19:27,880 --> 02:19:30,400
WE PROPOSE THERE'S A VEG

3694
02:19:30,400 --> 02:19:32,760
RECEPTOR 3/DLL4 NOTCH SIGNALING

3695
02:19:32,760 --> 02:19:33,960
AXIS RESPONSIBLE FOR BUTTON

3696
02:19:33,960 --> 02:19:36,440
JUNCTION FORMATION AND BUTTON

3697
02:19:36,440 --> 02:19:37,240
JUNCTIONS FACILITATE

3698
02:19:37,240 --> 02:19:38,680
INTERSTITIAL FLUID ABSORPTION

3699
02:19:38,680 --> 02:19:43,200
AND FILE FAILURE TO FORM -- SO

3700
02:19:43,200 --> 02:19:44,480
FOR GAPS, NEEDS AND

3701
02:19:44,480 --> 02:19:45,600
OPPORTUNITIES, HOW DO WE

3702
02:19:45,600 --> 02:19:47,040
CLINICALLY TARGET AND INDUCE

3703
02:19:47,040 --> 02:19:49,440
BUTTON JUNCTION DEVELOPMENT IN

3704
02:19:49,440 --> 02:19:50,320
MILLROY PATIENTS AND OTHER

3705
02:19:50,320 --> 02:19:51,720
PATIENTS THAT MAYBE HAVE

3706
02:19:51,720 --> 02:19:52,960
DEFECTIVE BUTTON JUNCTION

3707
02:19:52,960 --> 02:19:53,320
FORMATION?

3708
02:19:53,320 --> 02:19:54,960
AND CAN WE TARGET NOTCH

3709
02:19:54,960 --> 02:19:56,360
SIGNALING SOMEHOW IN PATIENTS?

3710
02:19:56,360 --> 02:19:58,320
ARE THERE OTHER CONGENITAL GENE

3711
02:19:58,320 --> 02:19:59,600
MUTATIONS THAT CAUSE LYMPHEDEMA

3712
02:19:59,600 --> 02:20:01,360
BY INHIBITING BUTTON JUNCTION

3713
02:20:01,360 --> 02:20:02,560
DEVELOPMENT AND CAN THESE BE

3714
02:20:02,560 --> 02:20:04,000
RESCUED BY TARGETING THE NOTCH

3715
02:20:04,000 --> 02:20:04,760
PATHWAY?

3716
02:20:04,760 --> 02:20:06,000
IT'S WORTH NOTING THAT IN

3717
02:20:06,000 --> 02:20:07,840
ACQUIRED LYMPHEDEMA PATIENTS,

3718
02:20:07,840 --> 02:20:09,880
THERE IS A STRONG DOWNREGULATION

3719
02:20:09,880 --> 02:20:12,800
OF VEG RECEPTOR 3 AND NOTCH

3720
02:20:12,800 --> 02:20:13,640
1 ACTIVITY, SO MAYBE THERE COULD

3721
02:20:13,640 --> 02:20:19,200
BE A POTENTIAL ROLE FOR

3722
02:20:19,200 --> 02:20:20,720
DEFECTIVE BUTTON JUNCTIONS IN

3723
02:20:20,720 --> 02:20:21,360
SECONDARY LYMPHEDEMA.

3724
02:20:21,360 --> 02:20:24,720
AND FINALLY WHAT PROTEINS DOES

3725
02:20:24,720 --> 02:20:26,240
NOTCH COOPERATE WITH TO INDUCE

3726
02:20:26,240 --> 02:20:28,760
BUTTON DEVELOPMENT IN VIC

3727
02:20:28,760 --> 02:20:30,360
CAPILLARIES BUT NOT IN

3728
02:20:30,360 --> 02:20:31,320
COLLECTING VIC VESSELS?

3729
02:20:31,320 --> 02:20:34,240
WE COULD ACCELERATE BUTTON

3730
02:20:34,240 --> 02:20:36,120
FUNCTION EVEN EARLIER BUT

3731
02:20:36,120 --> 02:20:37,080
COLLECTING LYMPHATICS NEVER

3732
02:20:37,080 --> 02:20:37,520
DEVELOPED BUTTONS.

3733
02:20:37,520 --> 02:20:38,440
SO I'D LIKE TO ACKNOWLEDGE THE

3734
02:20:38,440 --> 02:20:40,080
PEOPLE IN MY LAB.

3735
02:20:40,080 --> 02:20:44,080
MY POSTDOC, MELANIE JANNAWAY WHO

3736
02:20:44,080 --> 02:20:45,400
DID A LOT OF WORK ON THIS

3737
02:20:45,400 --> 02:20:48,480
PROJECT, OTHER COLLABORATORS AND

3738
02:20:48,480 --> 02:20:48,800
NSF.

3739
02:20:48,800 --> 02:20:51,520
I'D LIKE TO THANK NIH FOR

3740
02:20:51,520 --> 02:20:53,640
FUNDING AS WELL AS DHA AND

3741
02:20:53,640 --> 02:20:55,520
OTHERS KIND ENOUGH TO SHARE

3742
02:20:55,520 --> 02:20:56,600
MOUSE MODELS, WITH THAT, I'D

3743
02:20:56,600 --> 02:21:01,120
LIKE TO TAKE ANY QUESTIONS.

3744
02:21:01,120 --> 02:21:01,360
THANK YOU.

3745
02:21:01,360 --> 02:21:02,400
>> JOSH, THANK YOU SO
MUCH.

3746
02:21:02,400 --> 02:21:03,880
I WANT TO TAKE A SECOND TO THANK

3747
02:21:03,880 --> 02:21:08,600
ALL OF THE SPEAKERS FOR REALLY

3748
02:21:08,600 --> 02:21:09,880
ENERGETIC AND IMPORTANT TALKS.

3749
02:21:09,880 --> 02:21:14,320
SO I THINK WE WILL OFFICIALLY

3750
02:21:14,320 --> 02:21:15,400
START OUR Q & A DISCUSSION.

3751
02:21:15,400 --> 02:21:17,440
SO I ENCOURAGE THAT PANELISTS

3752
02:21:17,440 --> 02:21:18,720
AND THE SPEAKERS TO JUST RAISE

3753
02:21:18,720 --> 02:21:22,080
YOUR HAND OR JUST TO SHOUT IF

3754
02:21:22,080 --> 02:21:23,640
YOU HAVE -- OR NOT TOO LOUD --

3755
02:21:23,640 --> 02:21:25,640
IF YOU HAVE A QUESTION TO ANY OF

3756
02:21:25,640 --> 02:21:28,360
THE SPEAKERS, THIS INCLUDES

3757
02:21:28,360 --> 02:21:32,840
QUESTIONS TO MIKE DAVIS AS WELL

3758
02:21:32,840 --> 02:21:34,200
AND ALSO WHAT I'M GOING TO START

3759
02:21:34,200 --> 02:21:35,840
IS FOR ALL OF OUR PARTICIPANTS,

3760
02:21:35,840 --> 02:21:38,040
JUST PLACE YOUR QUESTIONS ON THE

3761
02:21:38,040 --> 02:21:40,000
CHAT AND I WILL TRY TO DO MY

3762
02:21:40,000 --> 02:21:42,000
BEST TO GO THROUGH ALL OF THEM.

3763
02:21:42,000 --> 02:21:45,600
SO WHAT I AM GOING TO DO IS I AM

3764
02:21:45,600 --> 02:21:46,880
GOING TO START WITH JUST THE

3765
02:21:46,880 --> 02:21:47,640
ORDER OF THE QUESTIONS THAT THEY

3766
02:21:47,640 --> 02:21:54,920
WERE POSTED.

3767
02:21:54,920 --> 02:21:57,320
SO WE WILL START WITH OLIVER

3768
02:21:57,320 --> 02:21:59,000
STONE, FROM SATESH.

3769
02:21:59,000 --> 02:22:00,320
THE QUESTION IS, HAVE YOU,

3770
02:22:00,320 --> 02:22:03,320
OLIVER, LOOKED AT ORGAN-SPECIFIC

3771
02:22:03,320 --> 02:22:04,560
LYMPHATIC VESSELS?

3772
02:22:04,560 --> 02:22:10,640
>> SO WE'VE LOOKED AT THIS
WITH

3773
02:22:10,640 --> 02:22:16,640
A CONSTITUTIVE CRE AND ALSO WITH

3774
02:22:16,640 --> 02:22:17,840
CONDITIONAL LINEAGE LABELING AT

3775
02:22:17,840 --> 02:22:19,640
DIFFERENT STAGES.

3776
02:22:19,640 --> 02:22:21,040
WITH CONSTITUTIVE CRE, WE SEE

3777
02:22:21,040 --> 02:22:22,600
LABELING WITH A SIGNIFICANT

3778
02:22:22,600 --> 02:22:24,840
PROPORTION, THE MAJORITY OF

3779
02:22:24,840 --> 02:22:26,040
ENDOTHELIAL CELLS IN MOST

3780
02:22:26,040 --> 02:22:26,680
ORGANS.

3781
02:22:26,680 --> 02:22:30,480
WE DON'T SEE LABELING WITHIN THE

3782
02:22:30,480 --> 02:22:31,160
HEAD REGION.

3783
02:22:31,160 --> 02:22:32,880
THIS IS PURELY A CONSEQUENCE OF

3784
02:22:32,880 --> 02:22:37,320
THE FACT THAT PACKS 3 IS NOT

3785
02:22:37,320 --> 02:22:38,320
EXPRESSED IN MEES YOE DETERMINE

3786
02:22:38,320 --> 02:22:41,800
IN THE HEAD NOR IN THE

3787
02:22:41,800 --> 02:22:50,520
PHARYNGEAL MESOYOE     MESODERM.

3788
02:22:50,520 --> 02:22:51,800
WE'RE ATTEMPTING TO UNDERSTAND

3789
02:22:51,800 --> 02:22:53,120
WHAT THIS MEANS AT THIS POINT IN

3790
02:22:53,120 --> 02:22:58,240
TIME.

3791
02:22:58,240 --> 02:23:00,680
SO WE WERE INITIALLY FOCUSED ON

3792
02:23:00,680 --> 02:23:01,760
THE EARLY STEPS OF

3793
02:23:01,760 --> 02:23:03,000
DIFFERENTIATION BUT WE ARE

3794
02:23:03,000 --> 02:23:05,400
CERTAINLY GOING BACK AND LOOKING

3795
02:23:05,400 --> 02:23:07,280
MORE INTO HOW CELLS END UP IN

3796
02:23:07,280 --> 02:23:09,920
DIFFERENT ORGANS.

3797
02:23:09,920 --> 02:23:10,920
>> OKAY.

3798
02:23:10,920 --> 02:23:13,560
OLIVER, THANKS SO MUCH.

3799
02:23:13,560 --> 02:23:17,240
SATESH, FEEL FREE TO EMAIL

3800
02:23:17,240 --> 02:23:21,440
OLIVER IF YOU WANT TO UNCOUNTER

3801
02:23:21,440 --> 02:23:22,920
THAT.

3802
02:23:22,920 --> 02:23:25,480
FOR RACHEL I'M WONDERING HOW YOU

3803
02:23:25,480 --> 02:23:27,360
THINK THAT IMPAIRED LYMPHATIC

3804
02:23:27,360 --> 02:23:29,840
FLOW WITH INTACT LYMPHATIC

3805
02:23:29,840 --> 02:23:31,520
ENDOTHELIUM MAY AFFECT THESE

3806
02:23:31,520 --> 02:23:32,840
INTERACTIONS WITH THE STEM CELL

3807
02:23:32,840 --> 02:23:33,320
NICHE?

3808
02:23:33,320 --> 02:23:34,240
THANKS VERY MUCH.

3809
02:23:34,240 --> 02:23:35,920
>> THANK YOU.

3810
02:23:35,920 --> 02:23:38,080
YOU'RE RIGHT ACROSS THE STREET,

3811
02:23:38,080 --> 02:23:39,520
WE SHOULD BE WAVING AT EACH

3812
02:23:39,520 --> 02:23:41,120
OTHER, THAT'S SO FUNNY.

3813
02:23:41,120 --> 02:23:42,200
I THINK IT'S A REALLY

3814
02:23:42,200 --> 02:23:42,920
FASCINATING QUESTION AND I THINK

3815
02:23:42,920 --> 02:23:45,240
A QUESTION THAT I'D REALLY LOVE

3816
02:23:45,240 --> 02:23:47,800
TO POSE TO SOME OF MY COLLEAGUES

3817
02:23:47,800 --> 02:23:50,640
HERE STUDYING LYMPHATIC FLOW,

3818
02:23:50,640 --> 02:23:53,200
WHAT WE KNOW ABOUT THE

3819
02:23:53,200 --> 02:23:55,760
TRANSCRIPTOME AND THE SECRETEOME

3820
02:23:55,760 --> 02:23:57,600
DURING FLOW OR STATIC STATES.

3821
02:23:57,600 --> 02:23:59,480
PERHAPS IT CHANGES, PERHAPS

3822
02:23:59,480 --> 02:24:00,640
THEY'RE SENSITIVE TO PRESSURE

3823
02:24:00,640 --> 02:24:01,640
AND HOW MUCH THEY'RE SECRETING

3824
02:24:01,640 --> 02:24:05,200
OR THE GEEBS    GENES THEY'RE

3825
02:24:05,200 --> 02:24:06,240
TRANSCRIBING OR CHANGING AND

3826
02:24:06,240 --> 02:24:08,080
THAT WAY THEY CAN AFFECT CELLS

3827
02:24:08,080 --> 02:24:09,480
IN THEIR MICROENVIRONMENT.

3828
02:24:09,480 --> 02:24:10,560
ALSO OF COURSE ONE THING WE

3829
02:24:10,560 --> 02:24:12,880
THINK ABOUT IS IF THE LYMPHATICS

3830
02:24:12,880 --> 02:24:14,880
ARE FLOWING, IF THEY'RE DRAINING

3831
02:24:14,880 --> 02:24:16,680
FACTOR, THEY CAN BE DRAINING

3832
02:24:16,680 --> 02:24:20,360
IMPORTANT SIGNALING QUEUES OF

3833
02:24:20,360 --> 02:24:21,440
INFLAMMATION -- FROM THE STEM

3834
02:24:21,440 --> 02:24:22,960
CELL NICHE, EITHER LEAVING THEM

3835
02:24:22,960 --> 02:24:24,520
THERE TO PROMOTE APPROPRIATE

3836
02:24:24,520 --> 02:24:26,200
BEHAVIOR AND DRAINING THEM TO

3837
02:24:26,200 --> 02:24:27,080
CHANGE BEHAVIOR, SO THAT'S

3838
02:24:27,080 --> 02:24:28,600
SOMETHING THAT I'M REALLY

3839
02:24:28,600 --> 02:24:31,000
FASCINATED TO LOOK AT IN

3840
02:24:31,000 --> 02:24:32,360
INFLAMMATORY DISEASE

3841
02:24:32,360 --> 02:24:33,560
PARTICULARLY INFLAMMATORY BOWEL

3842
02:24:33,560 --> 02:24:33,800
DISEASE.

3843
02:24:33,800 --> 02:24:35,120
>> OKAY, RACHEL.

3844
02:24:35,120 --> 02:24:37,720
THANK YOU SO MUCH.

3845
02:24:37,720 --> 02:24:39,560
THERE'S A QUESTION FOR DR. YANG.

3846
02:24:39,560 --> 02:24:47,520
DO YOU THINK VAIR YATION IN    N

3847
02:24:47,520 --> 02:24:48,360
VARIABLE PHENOTYPE IN LYMPHEDEMA

3848
02:24:48,360 --> 02:24:50,720
AND HAVE YOU LOOKED FOR EVIDENCE

3849
02:24:50,720 --> 02:24:51,800
OF THIS?

3850
02:24:51,800 --> 02:24:55,240
>> SO WE DID ACTUALLY.

3851
02:24:55,240 --> 02:24:57,800
FOX 02 IS IDENTICAL TO FOX 03.

3852
02:24:57,800 --> 02:25:01,280
SO WE ACTUALLY KNOCKED OUT FOX

3853
02:25:01,280 --> 02:25:02,600
03 FROM THE LYMPHATIC

3854
02:25:02,600 --> 02:25:06,440
ENDOTHELIAL CELLS USING THE SAME

3855
02:25:06,440 --> 02:25:09,840
CRE -- AND THEY LOOKED AT

3856
02:25:09,840 --> 02:25:11,640
WHETHER FOX 03 WOULD HAVE A

3857
02:25:11,640 --> 02:25:13,360
SIMILAR FUNCTION AS FOX

3858
02:25:13,360 --> 02:25:16,240
01 DELETION.

3859
02:25:16,240 --> 02:25:21,120
AND WHEN WE LOOK AT THE VALVE

3860
02:25:21,120 --> 02:25:22,280
NUMBER, WE CANNOT SEE AN

3861
02:25:22,280 --> 02:25:24,560
INCREASE OR DECREASE IN VALVE

3862
02:25:24,560 --> 02:25:26,800
NUMBER WHEN WE DELETED FOX 03.

3863
02:25:26,800 --> 02:25:31,280
SO IN THIS CASE, I THINK FOX

3864
02:25:31,280 --> 02:25:33,680
01 IS THE MAJOR FOX

3865
02:25:33,680 --> 02:25:35,600
0 TRANSCRIPTION FACTORS THAT

3866
02:25:35,600 --> 02:25:38,960
REGULATES LYMPHATIC VALVE

3867
02:25:38,960 --> 02:25:39,960
FORMATION.

3868
02:25:39,960 --> 02:25:41,400
AND ALSO FOX 03 EXPRESSION LEVEL

3869
02:25:41,400 --> 02:25:43,800
IS VERY LOW IN THE LYMPHATIC

3870
02:25:43,800 --> 02:25:45,440
ENDOTHELIAL CELLS THAT COULD

3871
02:25:45,440 --> 02:25:49,080
ALSO EXPLAIN THE REASON.

3872
02:25:49,080 --> 02:25:50,280
>> OKAY.

3873
02:25:50,280 --> 02:25:51,080
THERE'S ONE MORE QUESTION

3874
02:25:51,080 --> 02:25:55,200
WHETHER YOU THINK -- I THINK

3875
02:25:55,200 --> 02:25:56,280
IT'S FROM JIM MOORE.

3876
02:25:56,280 --> 02:25:57,720
I'M JUST WONDERING WHETHER THERE

3877
02:25:57,720 --> 02:26:01,360
ARE ANY SIMILARITIES BETWEEN

3878
02:26:01,360 --> 02:26:02,400
LYMPH ANGIOGENESIS, PARTICULARLY

3879
02:26:02,400 --> 02:26:04,680
VALVE FORMATION AND THE VALVE

3880
02:26:04,680 --> 02:26:07,000
FORMATION IN NEOANGIOGENESIS.

3881
02:26:07,000 --> 02:26:08,000
CAN YOU COMMENT ON THAT?

3882
02:26:08,000 --> 02:26:12,520
>> THANK YOU FOR THE
QUESTION.

3883
02:26:12,520 --> 02:26:18,440
SO YES, THERE ARE SIM LAIRMTS.

3884
02:26:18,440 --> 02:26:19,640
 SIMILARITIES.

3885
02:26:19,640 --> 02:26:21,800
FOX 01 IS A REPRESSOR FOR ALL

3886
02:26:21,800 --> 02:26:27,040
THREE PROCESS, INCLUDING

3887
02:26:27,040 --> 02:26:28,320
ANGIOGENESIS -- AND -- VALVE

3888
02:26:28,320 --> 02:26:30,360
FORMATION.

3889
02:26:30,360 --> 02:26:32,160
AND -- BUT THAT BECAUSE FOX

3890
02:26:32,160 --> 02:26:36,560
01 DELETION CAN CAUSE INCREASED

3891
02:26:36,560 --> 02:26:38,400
PROLIFERATION IN BOTH BLOOD

3892
02:26:38,400 --> 02:26:41,680
ENDOTHELIAL CELLS SHOWN BY

3893
02:26:41,680 --> 02:26:45,200
MICHAEL --'S LAB AND

3894
02:26:45,200 --> 02:26:46,840
INCREASED -- IN -- GENESIS SHOWN

3895
02:26:46,840 --> 02:26:56,360
BY MY LAB AND ALSO BY -- LAB,

3896
02:26:56,360 --> 02:26:59,440
BUT THE DIFFERENCE IS THAT WHEN

3897
02:26:59,440 --> 02:27:04,160
WE LOOKED AT PROLIFERATION

3898
02:27:04,160 --> 02:27:06,400
STATUS PARTICULARLY DURING

3899
02:27:06,400 --> 02:27:07,360
LYMPHATIC VALVE FORMATION, WE

3900
02:27:07,360 --> 02:27:09,280
DID NOT SEE A CHANGE IN

3901
02:27:09,280 --> 02:27:13,400
PROLIFERATION OF PARTICULARLY IN

3902
02:27:13,400 --> 02:27:14,400
POSTNATAL VESSELS.

3903
02:27:14,400 --> 02:27:17,320
SO WE RULED OUT ROW LIVE RANGE

3904
02:27:17,320 --> 02:27:22,640
OF MOTION FUNCTION IN

3905
02:27:22,640 --> 02:27:24,320
INDUCING -- GROWTH.

3906
02:27:24,320 --> 02:27:25,280
>> THANK YOU SO MUCH.

3907
02:27:25,280 --> 02:27:29,320
THERE IS A QUESTION FROM THE

3908
02:27:29,320 --> 02:27:29,920
AUDIENCE.

3909
02:27:29,920 --> 02:27:30,720
ASK YOUR QUESTION.

3910
02:27:30,720 --> 02:27:30,960
>> YES.

3911
02:27:30,960 --> 02:27:32,920
I WOULD LIKE TO ASK -- AND ALSO

3912
02:27:32,920 --> 02:27:36,080
REMIND EVERYONE THAT FOR MIKE

3913
02:27:36,080 --> 02:27:37,040
DAVIS AND -- THIS WOULD BE THE

3914
02:27:37,040 --> 02:27:38,520
TIME TO ASK QUESTIONS AND I HAVE

3915
02:27:38,520 --> 02:27:42,560
A QUESTION TO MIKE.

3916
02:27:42,560 --> 02:27:45,360
I WAS WONDERING IF YOU SEE ANY

3917
02:27:45,360 --> 02:27:46,200
EXTRACELLULAR MATRIX CHANGES IN

3918
02:27:46,200 --> 02:27:49,800
THOSE ANIMALS OF THE OBESE MICE,

3919
02:27:49,800 --> 02:27:52,480
ESPECIALLY, CAUSING THE

3920
02:27:52,480 --> 02:27:55,240
FUNCTIONAL CHANGES LIKE IN

3921
02:27:55,240 --> 02:27:56,400
ARTERIAL CONDITIONS, THEY BECOME

3922
02:27:56,400 --> 02:27:59,080
STIFF AND ARE NOT CONTRACTILE.

3923
02:27:59,080 --> 02:28:01,880
SO I WAS WONDERING IF YOU SEE

3924
02:28:01,880 --> 02:28:02,720
ANYTHING IN THE LYMPHATIC

3925
02:28:02,720 --> 02:28:03,640
VESSELS.

3926
02:28:03,640 --> 02:28:07,960
>> THAT'S A GOOD QUESTION.

3927
02:28:07,960 --> 02:28:08,920
WE HAVEN'T SPECIFICALLY LOOKED

3928
02:28:08,920 --> 02:28:10,720
AT THAT, BUT IF YOU DO PASSING

3929
02:28:10,720 --> 02:28:12,920
PRESSURE DIAMETER CURVES IN SOME

3930
02:28:12,920 --> 02:28:14,560
OF THOSE ANIMAL MODELS, THE

3931
02:28:14,560 --> 02:28:15,960
LYMPHATIC VESSELS DO SHOW

3932
02:28:15,960 --> 02:28:17,160
DIFFERENCES.

3933
02:28:17,160 --> 02:28:19,640
I THINK JORGE MAY BE ABLE TO

3934
02:28:19,640 --> 02:28:20,960
ADDRESS THAT LATER ON IN HIS

3935
02:28:20,960 --> 02:28:23,440
TALK.

3936
02:28:23,440 --> 02:28:27,240
>> IF I CAN FOLLOW UP JUST
A

3937
02:28:27,240 --> 02:28:28,440
LITTLE BIT MORE THAT IF ALL

3938
02:28:28,440 --> 02:28:30,560
THOSE SMOOTH MUSCLE CELLS IN THE

3939
02:28:30,560 --> 02:28:32,200
LYMPHATIC VASCULATURE, BECAUSE

3940
02:28:32,200 --> 02:28:34,400
WE KNOW THAT IN ARTERIAL SMOOTH

3941
02:28:34,400 --> 02:28:38,520
MUSCLES, THEY CHANGE THEIR

3942
02:28:38,520 --> 02:28:40,840
RECEPTORS AND RECEPTOR

3943
02:28:40,840 --> 02:28:44,080
SIGNALING, AND THOSE CHANGES TO

3944
02:28:44,080 --> 02:28:47,040
REFLECT INTO THE -- FOR EXAMPLE,

3945
02:28:47,040 --> 02:28:48,800
CALCIUM SIGNALING CHANNELS AND

3946
02:28:48,800 --> 02:28:50,040
HOW THEY'RE EXPRESSED, SO I

3947
02:28:50,040 --> 02:28:53,240
WONDER IF -- I KNOW I'M ASKING A

3948
02:28:53,240 --> 02:28:55,800
LOT OF -- TO THE VERY BEGINNING

3949
02:28:55,800 --> 02:28:58,040
OF THIS WORK THAT YOU ARE

3950
02:28:58,040 --> 02:28:59,040
INITIATING, BUT MAYBE THOSE

3951
02:28:59,040 --> 02:29:02,120
MIGHT BE THE CHANGES THAT ARE

3952
02:29:02,120 --> 02:29:04,520
AFFECTING INITIALLY THE

3953
02:29:04,520 --> 02:29:06,080
LYMPHATIC VESSELS AND IN TURN

3954
02:29:06,080 --> 02:29:07,480
LYMPHATIC VESSELS INITIATE THE

3955
02:29:07,480 --> 02:29:10,240
CHANGES IN THE ARTERIAL VESSELS.

3956
02:29:10,240 --> 02:29:11,360
I WAS WONDERING WHAT YOU THINK

3957
02:29:11,360 --> 02:29:12,080
ABOUT THAT.

3958
02:29:12,080 --> 02:29:14,200
>> IT'S POSSIBLE.

3959
02:29:14,200 --> 02:29:15,320
I DON'T KNOW THE ANSWER TO THAT.

3960
02:29:15,320 --> 02:29:16,240
>> OKAY.

3961
02:29:16,240 --> 02:29:19,760
THANK YOU.

3962
02:29:19,760 --> 02:29:20,960
>> THANKS VERY MUCH, MIKE.

3963
02:29:20,960 --> 02:29:21,280
OKAY.

3964
02:29:21,280 --> 02:29:24,960
SO THERE IS A QUESTION FROM

3965
02:29:24,960 --> 02:29:26,480
JAMES MOORE TO YING.

3966
02:29:26,480 --> 02:29:27,240
HI, YING.

3967
02:29:27,240 --> 02:29:28,240
THANKS FOR THE NICE TALK.

3968
02:29:28,240 --> 02:29:31,520
DO YOU HAVE ANY ESTIMATE OF THE

3969
02:29:31,520 --> 02:29:32,800
OSCILLATORY SHEAR STRESS BEING

3970
02:29:32,800 --> 02:29:37,880
APPLIED IN THE TEST TUBE ROCKER

3971
02:29:37,880 --> 02:29:38,200
EXPERIMENT?

3972
02:29:38,200 --> 02:29:39,080
>> YES, THANK YOU FOR THE

3973
02:29:39,080 --> 02:29:41,720
QUESTION.

3974
02:29:41,720 --> 02:29:46,320
SO THE ESTIMATED OSCILLATORY

3975
02:29:46,320 --> 02:29:48,440
STRESS ON THE TEST TUBE ROCKER

3976
02:29:48,440 --> 02:29:55,960
WAS ABOUT 0.3 CENTIMETERS --

3977
02:29:55,960 --> 02:29:56,760
SQUARE CENTIMETER.

3978
02:29:56,760 --> 02:30:00,400
ALTHOUGH IT IS LOWER THAN THE

3979
02:30:00,400 --> 02:30:03,360
SHEAR STRESS IN THE LYMPHATIC

3980
02:30:03,360 --> 02:30:06,200
VESSELS IN VIVO EXPERIENCING

3981
02:30:06,200 --> 02:30:12,640
WHICH IS BETWEEN 1 TO 12

3982
02:30:12,640 --> 02:30:15,680
SQUARE CENTIMETER, BUT WE WERE

3983
02:30:15,680 --> 02:30:19,480
ABLE TO SEE THE UPREGULATION OF

3984
02:30:19,480 --> 02:30:22,760
VALVE GENES AND FOR RESPONSIVE

3985
02:30:22,760 --> 02:30:26,040
GENES, AND WE ALSO WERE ABLE TO

3986
02:30:26,040 --> 02:30:29,360
SEE THE NUCLEAR TRANSLOCATION OF

3987
02:30:29,360 --> 02:30:31,120
FOX 01 UNDER THAT CONDITION.

3988
02:30:31,120 --> 02:30:32,360
THANK YOU.

3989
02:30:32,360 --> 02:30:33,320
>> THANK YOU.

3990
02:30:33,320 --> 02:30:36,040
OKAY.

3991
02:30:36,040 --> 02:30:42,800
AND SO THERE'S A QUESTION FROM

3992
02:30:42,800 --> 02:30:44,360
ESTA STERNECK, FOR YOU AND OTHER

3993
02:30:44,360 --> 02:30:49,400
INVESTIGATORS USING LYMPHATIC

3994
02:30:49,400 --> 02:30:50,320
ENDOTHELIAL CONDITIONED MEDIA.

3995
02:30:50,320 --> 02:30:54,040
DO YOU USE OR   ORGAN-SPECIFIC

3996
02:30:54,040 --> 02:30:55,720
PRIMARY ISOLATES AND IF NOT WHAT

3997
02:30:55,720 --> 02:30:58,520
IS THE STATUS OF YOUR

3998
02:30:58,520 --> 02:30:59,080
ENDOTHELIAL CELLS.

3999
02:30:59,080 --> 02:31:01,400
>> FOR MY STUDY WHAT WE
HAVE

4000
02:31:01,400 --> 02:31:03,360
USED, IT'S NOT THE ENDOTHELIAL

4001
02:31:03,360 --> 02:31:04,240
CELL FROM THE HEART.

4002
02:31:04,240 --> 02:31:07,680
WE HAVE USED A COMMERCIALLY

4003
02:31:07,680 --> 02:31:09,320
AVAILABLE HUMAN DERMAL

4004
02:31:09,320 --> 02:31:10,200
ENDOTHELIAL CELLS.

4005
02:31:10,200 --> 02:31:13,160
SO ACCORDING TO THE SCREEN OF

4006
02:31:13,160 --> 02:31:14,360
CANDIDATES WHAT WE HAVE DONE IS

4007
02:31:14,360 --> 02:31:16,320
TO CONFIRM BY IMMUNOSTAINING

4008
02:31:16,320 --> 02:31:18,800
WHETHER THOSE MARKERS ORTHOS

4009
02:31:18,800 --> 02:31:20,520
CANDIDATES ARE HIGHLY EXPRESSED

4010
02:31:20,520 --> 02:31:23,080
IN CARDIAC AND LYMPHATIC

4011
02:31:23,080 --> 02:31:24,400
ENDOTHELIAL CELLS OR NOT.

4012
02:31:24,400 --> 02:31:26,000
I THINK THIS IS A VERY VALUABLE

4013
02:31:26,000 --> 02:31:27,560
QUESTION AS IN THE FUTURE, IT'S

4014
02:31:27,560 --> 02:31:32,520
VERY HELPFUL TO DO RN SEQ OR

4015
02:31:32,520 --> 02:31:36,480
SINGLE CELL RN SEQ FROM ORGAN

4016
02:31:36,480 --> 02:31:37,480
SPECIFIC LYMPHATIC AND TO

4017
02:31:37,480 --> 02:31:38,560
VALIDATE MAYBE THERE'S SOME

4018
02:31:38,560 --> 02:31:40,240
INFORMATION MISSING BY USING

4019
02:31:40,240 --> 02:31:49,040
THIS COMMERCIAL AVAILABLE -- OR

4020
02:31:49,040 --> 02:31:50,080
ORGAN SPECIFIC LECs.

4021
02:31:50,080 --> 02:31:54,960
THANK YOU FOR THE QUESTION.

4022
02:31:54,960 --> 02:31:55,640
>> THANK YOU.

4023
02:31:55,640 --> 02:31:57,600
JOSH, THERE'S A QUESTION FROM

4024
02:31:57,600 --> 02:32:05,160
YOU FROM MATTHEW BURCHILL.

4025
02:32:05,160 --> 02:32:09,560
IF YOU INDUCE LYMPHOANG GENESIS

4026
02:32:09,560 --> 02:32:11,760
IN CAPILLARIES IN WHICH YOU

4027
02:32:11,760 --> 02:32:15,600
DELETE VEGF RECEPTOR 3 AFTER

4028
02:32:15,600 --> 02:32:15,960
DEVELOPMENT --

4029
02:32:15,960 --> 02:32:19,240
>> AND THEN INDUCE WITH

4030
02:32:19,240 --> 02:32:20,800
ANGIOGENESIS DO I SEE GREATER

4031
02:32:20,800 --> 02:32:22,000
ZIPPERING THAN CONTROL, I DON'T

4032
02:32:22,000 --> 02:32:23,160
THINK THERE WILL BE A DIFFERENCE

4033
02:32:23,160 --> 02:32:28,080
BECAUSE EVEN IN CONTROL MICE --

4034
02:32:28,080 --> 02:32:29,680
I THINK THEY'RE ALL ZIPPERED UP

4035
02:32:29,680 --> 02:32:32,480
SO I DON'T THINK DELETION OF VEG

4036
02:32:32,480 --> 02:32:33,800
RECEPTOR 3 WILL HAVE A HUGE

4037
02:32:33,800 --> 02:32:35,440
DIFFERENCE IN THE GROWING

4038
02:32:35,440 --> 02:32:36,640
LYMPHATIC CAPILLARIES.

4039
02:32:36,640 --> 02:32:37,720
>> OKAY.

4040
02:32:37,720 --> 02:32:39,520
THANK YOU VERY MUCH.

4041
02:32:39,520 --> 02:32:46,400
AND THERE IS A QUESTION FROM --

4042
02:32:46,400 --> 02:32:48,120
THERE'S A COMMENT -- THERE'S

4043
02:32:48,120 --> 02:32:51,200
SUGGESTIONS TO OLIVER FROM

4044
02:32:51,200 --> 02:32:51,560
SATHISH.

4045
02:32:51,560 --> 02:32:52,040
HI, OLIVER.

4046
02:32:52,040 --> 02:32:52,920
JUST A SUGGESTION HERE.

4047
02:32:52,920 --> 02:32:56,280
I BELIEVE THAT THE PROX1 FLOX

4048
02:32:56,280 --> 02:32:58,160
LINE YOU HAVE USED IN YOUR PAPER

4049
02:32:58,160 --> 02:33:01,120
WILL EXPRESS GFP UPON

4050
02:33:01,120 --> 02:33:02,320
CRE-MEDIATED DELETION.

4051
02:33:02,320 --> 02:33:04,400
HAVE YOU DONE GFP EXPRESSION

4052
02:33:04,400 --> 02:33:09,160
ANALYSIS AFTER TEK-CRE OR

4053
02:33:09,160 --> 02:33:09,760
PAX3-CRE DELETION?

4054
02:33:09,760 --> 02:33:11,560
>> WE ACTUALLY DON'T HAVE
THE

4055
02:33:11,560 --> 02:33:13,720
PROX1 ALLELE THAT EXPRESSES GFP

4056
02:33:13,720 --> 02:33:15,680
AFTER CRE RECOMBINATION, SO NO,

4057
02:33:15,680 --> 02:33:20,400
WE HAVEN'T DONE THAT.

4058
02:33:20,400 --> 02:33:26,480
BUT IN TERMS OF THE REST OF THE

4059
02:33:26,480 --> 02:33:30,400
QUESTION, SO WE ARE -- WE HAVE

4060
02:33:30,400 --> 02:33:33,320
BEEN BUILDING MODELS TO BE ABLE

4061
02:33:33,320 --> 02:33:34,760
TO MORE SPECIFICALLY LABEL JUST

4062
02:33:34,760 --> 02:33:36,880
THE ENDOTHELIAL CELLS DERIVED

4063
02:33:36,880 --> 02:33:42,040
FROM PRO AXIAL MESODERM, WHICH

4064
02:33:42,040 --> 02:33:43,320
WILL DEFINITELY MAKE IT MUCH

4065
02:33:43,320 --> 02:33:46,520
EASIER TO ACTUALLY ANALYZE WITH

4066
02:33:46,520 --> 02:33:47,880
IMAGING.

4067
02:33:47,880 --> 02:33:49,280
THANK YOU.

4068
02:33:49,280 --> 02:33:50,280
>> THANKS, OLI.

4069
02:33:50,280 --> 02:33:54,040
AND THERE'S A QUESTION FROM OUR

4070
02:33:54,040 --> 02:33:55,160
ORGANIZER, FROM ANDREA.

4071
02:33:55,160 --> 02:33:56,880
DO YOU WANT TO ASK YOUR

4072
02:33:56,880 --> 02:33:57,160
QUESTION?

4073
02:33:57,160 --> 02:33:57,640
>> THANKS.

4074
02:33:57,640 --> 02:33:59,040
GREAT JOB, EVERYONE.

4075
02:33:59,040 --> 02:34:01,640
SO MY QUESTION IS FOR ZORINA.

4076
02:34:01,640 --> 02:34:03,120
IT'S KIND OF A SELF-INTERESTED

4077
02:34:03,120 --> 02:34:04,400
QUESTION BECAUSE IT'S GETTING

4078
02:34:04,400 --> 02:34:06,640
MORE PEOPLE INVOLVED IN HUB MED.

4079
02:34:06,640 --> 02:34:08,840
SO IF YOU COULD PERHAPS SPEAK TO

4080
02:34:08,840 --> 02:34:10,480
IF THEY'RE INTERESTED IN JOINING

4081
02:34:10,480 --> 02:34:13,120
HUBMAP OR TO PARTICIPATING IN

4082
02:34:13,120 --> 02:34:15,520
HUBMAP, HOW THEY MIGHT GET

4083
02:34:15,520 --> 02:34:15,800
INVOLVED.

4084
02:34:15,800 --> 02:34:23,120
THANK YOU.

4085
02:34:23,120 --> 02:34:29,240
>> I THINK WE HAVE A
QUESTION

4086
02:34:29,240 --> 02:34:31,400
FROM XIAOLEI.

4087
02:34:31,400 --> 02:34:33,560
>> I BELIEVE YOU HAVE
IDENTIFIED

4088
02:34:33,560 --> 02:34:36,000
THE NOTCH SIGNALING HAS BEEN

4089
02:34:36,000 --> 02:34:37,040
AFFECTED IN YOUR SYSTEM.

4090
02:34:37,040 --> 02:34:39,440
I WONDER WHETHER YOU HAVE

4091
02:34:39,440 --> 02:34:41,600
CHECKED VEGF C IN YOUR SMOOT

4092
02:34:41,600 --> 02:34:42,000
MUSCLE CELLS?

4093
02:34:42,000 --> 02:34:45,240
>> THAT'S A GREAT
QUESTION.

4094
02:34:45,240 --> 02:34:46,680
WE'VE IDENTIFIED NOTCH 3 I THINK

4095
02:34:46,680 --> 02:34:47,320
TWO WEEKS AGO.

4096
02:34:47,320 --> 02:34:49,440
WE ARE STILL ANALYZING ALL THE

4097
02:34:49,440 --> 02:34:52,120
MICE, BUT FOR VEGF C, WE

4098
02:34:52,120 --> 02:34:54,400
PERSONALLY HAVE NOT LOOKED BUT

4099
02:34:54,400 --> 02:34:57,160
WE HAVE -- AT THE STAGES WHEN

4100
02:34:57,160 --> 02:34:58,560
THE MUSCLE IS DIFFERENTIATED.

4101
02:34:58,560 --> 02:34:59,720
HOWEVER, WE HAVE LOOKED MUCH

4102
02:34:59,720 --> 02:35:00,240
EARLIER.

4103
02:35:00,240 --> 02:35:01,240
I KNOW YOU'RE PASSIONATE ABOUT

4104
02:35:01,240 --> 02:35:02,760
THE EARLY EMBRYONIC DEVELOPMENT

4105
02:35:02,760 --> 02:35:04,400
AND WE ALWAYS LOOK MUCH EARLY.

4106
02:35:04,400 --> 02:35:09,080
AND SO -- AND WE SEE THAT VEGF C

4107
02:35:09,080 --> 02:35:10,880
EXPRESSION BOTH -- ACTUALLY AT

4108
02:35:10,880 --> 02:35:12,120
THE LEVEL OF RNA IS

4109
02:35:12,120 --> 02:35:15,240
SIGNIFICANTLY REDUCED IN THE

4110
02:35:15,240 --> 02:35:17,400
PITX2 HYPOMORPHIN INTESTINES.

4111
02:35:17,400 --> 02:35:19,080
SO WE'RE EXCITED ABOUT NOT JUST

4112
02:35:19,080 --> 02:35:20,280
THE POSSIBILITY THAT IT

4113
02:35:20,280 --> 02:35:22,480
REGULATES CONTRACTILITY, SO WE

4114
02:35:22,480 --> 02:35:23,840
SHOWED IT REGULATES ROSS BUT

4115
02:35:23,840 --> 02:35:25,800
ALSO WE THINK THAT MAYBE IT

4116
02:35:25,800 --> 02:35:28,400
COULD BE REGULATING VEGF C

4117
02:35:28,400 --> 02:35:29,920
EXPRESSION SO REDUCTION IN THAT

4118
02:35:29,920 --> 02:35:31,160
COULD POTENTIALLY BE INVOLVED IN

4119
02:35:31,160 --> 02:35:34,520
WHY THESE MUSCLES DON'T LINE UP

4120
02:35:34,520 --> 02:35:36,640
PROPERLY WITH THE ADJACENT

4121
02:35:36,640 --> 02:35:36,920
LACTEALS.

4122
02:35:36,920 --> 02:35:37,480
>> THAT WOULD BE AWESOME.

4123
02:35:37,480 --> 02:35:37,880
THANK YOU.

4124
02:35:37,880 --> 02:35:39,200
>> THANK YOU.

4125
02:35:39,200 --> 02:35:40,720
AND THEN WE HAVE A QUESTION FROM

4126
02:35:40,720 --> 02:35:41,480
RACHEL.

4127
02:35:41,480 --> 02:35:44,960
GO AHEAD, RACHEL.

4128
02:35:44,960 --> 02:35:45,520
>> HI.

4129
02:35:45,520 --> 02:35:47,000
I ALSO HAD A QUESTION FOR YOU.

4130
02:35:47,000 --> 02:35:48,600
YOUR TALK WAS REALLY LOVELY.

4131
02:35:48,600 --> 02:35:49,840
I'M WONDERING IF YOU WERE ABLE

4132
02:35:49,840 --> 02:35:52,440
TO CAPTURE SUFFICIENT NUMBERS OF

4133
02:35:52,440 --> 02:35:53,280
LYMPHATIC ENDOTHELIAL CELLS IN

4134
02:35:53,280 --> 02:35:55,400
YOUR SINGLE CELL RNA SEQ TO THEN

4135
02:35:55,400 --> 02:35:57,120
LOOK AT OTHER RECEPTORS AND

4136
02:35:57,120 --> 02:36:00,280
LIGANDS THAT MAY BE ACTING IN

4137
02:36:00,280 --> 02:36:02,600
CONCERT AND ALSO HOW FAR

4138
02:36:02,600 --> 02:36:03,600
POSTNATALLY YOU TOOK THIS.

4139
02:36:03,600 --> 02:36:05,560
I KNOW THAT PARTICULARLY IN THE

4140
02:36:05,560 --> 02:36:06,960
INTESTINE, A LOT OF THE

4141
02:36:06,960 --> 02:36:07,960
DEVELOPMENT, PARTICULARLY THE

4142
02:36:07,960 --> 02:36:09,400
STEM CELL COMPARTMENT

4143
02:36:09,400 --> 02:36:11,440
DEVELOPMENT, HAVE BEEN

4144
02:36:11,440 --> 02:36:12,800
POSTNATALLY, SO I'M CURIOUS

4145
02:36:12,800 --> 02:36:14,120
ABOUT SIGNALING NETWORKS THAT

4146
02:36:14,120 --> 02:36:15,440
MAY BE ACTIVE DURING THOSE

4147
02:36:15,440 --> 02:36:15,640
TIMES.

4148
02:36:15,640 --> 02:36:18,440
>> RACHEL, THANKS SO MUCH.

4149
02:36:18,440 --> 02:36:19,880
SO THE DATA I PRESENTED WAS ON

4150
02:36:19,880 --> 02:36:23,480
THE MUSE KAU LAYERS BUT WE ARE

4151
02:36:23,480 --> 02:36:24,360
VERY, VERY INTERESTED.

4152
02:36:24,360 --> 02:36:26,920
ONE IS TO UNDERSTAND ET ROW JE

4153
02:36:26,920 --> 02:36:28,240
NATE IN THE INTESTINE, AS YOU

4154
02:36:28,240 --> 02:36:28,480
KNOW.

4155
02:36:28,480 --> 02:36:29,560
I DON'T KNOW WHETHER THIS WOULD

4156
02:36:29,560 --> 02:36:33,240
BE ENOUGH, BUT WE ACTUALLY

4157
02:36:33,240 --> 02:36:35,120
GOT -- THE ENDOTHELIAL CELLS

4158
02:36:35,120 --> 02:36:36,640
WERE ACTUALLY CLUSTERING QUITE

4159
02:36:36,640 --> 02:36:38,200
NICELY AND WE WERE ABLE TO

4160
02:36:38,200 --> 02:36:40,400
IDENTIFY ARTERIAL ENT THEED YELL

4161
02:36:40,400 --> 02:36:42,280
CELLS, ARTERIAL PROGENITOR

4162
02:36:42,280 --> 02:36:44,640
CELLS, VEINS, LYMPHATIC

4163
02:36:44,640 --> 02:36:46,600
ENDOTHELIAL CELLS, BUT OUR

4164
02:36:46,600 --> 02:36:47,960
CURRENT ANALYSIS STOP AT

4165
02:36:47,960 --> 02:36:50,000
POSTNATAL DAY 1.5, BUT WE JUST

4166
02:36:50,000 --> 02:36:53,920
ADDED POST DAY TALL DAY 9 AND

4167
02:36:53,920 --> 02:36:54,880
POSTNATAL DAY 21.

4168
02:36:54,880 --> 02:36:56,160
ONE OF THE REASONS WHY I'M

4169
02:36:56,160 --> 02:36:57,160
EXCITED ABOUT YOUR TALK IS

4170
02:36:57,160 --> 02:37:00,200
BECAUSE WE ALSO WANT TO ADD THE

4171
02:37:00,200 --> 02:37:01,320
SPATIAL TRANSCRIPTOMICS FOR SOME

4172
02:37:01,320 --> 02:37:02,720
OF THE EARLIER TIME POINTS,

4173
02:37:02,720 --> 02:37:04,440
BECAUSE WE THINK THAT THE

4174
02:37:04,440 --> 02:37:06,120
SPATIAL QUEUES ARE JUST GOING TO

4175
02:37:06,120 --> 02:37:09,640
BE ABSOLUTELY CRITICAL.

4176
02:37:09,640 --> 02:37:10,720
THE GENES COULD BE THE SAME BUT

4177
02:37:10,720 --> 02:37:12,240
THE SPATIALLY DIFFERENTIAL

4178
02:37:12,240 --> 02:37:13,120
MECHANISMS ARE GOING TO BE

4179
02:37:13,120 --> 02:37:17,400
LIKELY TO BE VERY DIFFERENT.

4180
02:37:17,400 --> 02:37:18,400
>> IT WOULD BE FUN TO TALK
ABOUT

4181
02:37:18,400 --> 02:37:18,880
THAT SOME DAY.

4182
02:37:18,880 --> 02:37:21,080
>> ABSOLUTELY.

4183
02:37:21,080 --> 02:37:22,880
AND CAPILLARIES.

4184
02:37:22,880 --> 02:37:27,040
WE HAVE A LOT OF BLOT

4185
02:37:27,040 --> 02:37:28,280
CAPILLARIES WE'VE IDENTIFIED IN

4186
02:37:28,280 --> 02:37:30,680
THE INTESTINE.

4187
02:37:30,680 --> 02:37:36,720
WE HAVE A QUESTION FROM PATRICIA

4188
02:37:36,720 --> 02:37:37,000
GREENWEL.

4189
02:37:37,000 --> 02:37:39,120
>> I'M SORRY I JUST HAVE
BEEN

4190
02:37:39,120 --> 02:37:42,720
UNMUTED SO ITIOUS     SHOULD ACY

4191
02:37:42,720 --> 02:37:46,880
ANSWER THE QUESTION THAT WAS

4192
02:37:46,880 --> 02:37:48,120
MADE FOR ME EARLIER.

4193
02:37:48,120 --> 02:37:49,920
SO AS I WROTE, EVERYBODY IS

4194
02:37:49,920 --> 02:37:51,000
WELCOME TO PARTICIPATE IN

4195
02:37:51,000 --> 02:37:51,880
HUBMAP.

4196
02:37:51,880 --> 02:37:55,120
THERE IS A LOT OF DATA THAT IS

4197
02:37:55,120 --> 02:37:56,360
OPEN TO EVERYONE.

4198
02:37:56,360 --> 02:37:59,440
WE HAVE NOW SPECIFIC EFFORTS

4199
02:37:59,440 --> 02:38:01,040
THAT I'VE INDICATED TO LYMPHATIC

4200
02:38:01,040 --> 02:38:05,480
VAT CLA TOUR AND DR. SINGHALL IS

4201
02:38:05,480 --> 02:38:06,280
ONLINE.

4202
02:38:06,280 --> 02:38:08,400
YOU CAN ALSO BECOME AN ASSOCIATE

4203
02:38:08,400 --> 02:38:12,680
MEMBER AND ONE THING THAT I'M

4204
02:38:12,680 --> 02:38:14,320
JUST -- I WAS JUST TEXTING TO

4205
02:38:14,320 --> 02:38:16,760
SOME OF THE PEOPLE INVOLVED IN

4206
02:38:16,760 --> 02:38:18,120
HUBMAP IS THIS MEETING CAN HELP

4207
02:38:18,120 --> 02:38:21,160
US FURTHER DEFINE SPECIFIC

4208
02:38:21,160 --> 02:38:24,200
MARKERS FOR THE VASCULAR

4209
02:38:24,200 --> 02:38:24,840
ENDOTHELIAL CELLS WHICH HAVE

4210
02:38:24,840 --> 02:38:26,480
BEEN MY PASSION EVER SINCE GOD

4211
02:38:26,480 --> 02:38:28,120
KNOWS WHEN, I'M NOT GOING TO

4212
02:38:28,120 --> 02:38:30,400
DISCLOSE MY AGE.

4213
02:38:30,400 --> 02:38:31,680
BUT THAT'S VERY IMPORTANT

4214
02:38:31,680 --> 02:38:32,640
INFORMATION THAT WE SHOULD BE

4215
02:38:32,640 --> 02:38:34,960
ABLE TO CAPTURE ALSO IN HUBMAP

4216
02:38:34,960 --> 02:38:37,000
FOR THE BENEFIT OF EVERYONE.

4217
02:38:37,000 --> 02:38:39,400
SO HAPPY TO TALK ABOUT THAT

4218
02:38:39,400 --> 02:38:41,040
ANOTHER TIME, WHEN WE HAVE MORE

4219
02:38:41,040 --> 02:38:42,480
TIME.

4220
02:38:42,480 --> 02:38:42,720
THANKS.

4221
02:38:42,720 --> 02:38:48,880
>> SEE   ZORINA, THANK YOU
SO M.

4222
02:38:48,880 --> 02:38:49,160
PATRICIA.

4223
02:38:49,160 --> 02:38:49,720
>> THANK YOU.

4224
02:38:49,720 --> 02:38:50,960
THIS IS A QUESTION FOR RACHEL.

4225
02:38:50,960 --> 02:38:56,640
IT BEEN DEMONSTRATED THAT --

4226
02:38:56,640 --> 02:38:59,920
POSITIVE PELO CYTES ARE KEY

4227
02:38:59,920 --> 02:39:02,160
FACTORS IN -- THESE ARE ALSO IN

4228
02:39:02,160 --> 02:39:03,480
CLOSE PROXIMITY TO LYMPHATICS SO

4229
02:39:03,480 --> 02:39:04,640
MY QUESTION IS, DO YOU THINK

4230
02:39:04,640 --> 02:39:10,000
LYMPHATICS ALSO PLAY A ROLE IN

4231
02:39:10,000 --> 02:39:12,280
MAINTAINING TELOCYTES?

4232
02:39:12,280 --> 02:39:14,080
>> THAT'S A REALLY
INTERESTING

4233
02:39:14,080 --> 02:39:14,320
QUESTION.

4234
02:39:14,320 --> 02:39:15,440
I THINK THE OTHER TWO PAPERS

4235
02:39:15,440 --> 02:39:17,160
THAT CAME OUT NEARLY AT THE SAME

4236
02:39:17,160 --> 02:39:18,040
TIME ADDRESSED THIS MORE

4237
02:39:18,040 --> 02:39:19,320
SPECIFICALLY.

4238
02:39:19,320 --> 02:39:23,040
IT SEEMS RSPONDIN BEING

4239
02:39:23,040 --> 02:39:24,480
EXPRESSED IS ACTING ON MULTIPLE

4240
02:39:24,480 --> 02:39:25,440
CELL TYPES IN THE NICHE.

4241
02:39:25,440 --> 02:39:28,200
I THINK THE OTHER NICHE FACTORS,

4242
02:39:28,200 --> 02:39:29,600
CANONICAL NICHE FACTORS BEING

4243
02:39:29,600 --> 02:39:30,840
PRODUCED BY LYMPHATICS IN THE

4244
02:39:30,840 --> 02:39:33,880
NICHE LIKELY HAVE PLURIPOTENT

4245
02:39:33,880 --> 02:39:35,240
ROLES AND I ANTICIPATE THEY'RE

4246
02:39:35,240 --> 02:39:38,360
ACTING NOT ONLY ON THE STEM

4247
02:39:38,360 --> 02:39:42,520
CELLS BUT ALSO IN OUR DATA IT

4248
02:39:42,520 --> 02:39:48,520
SUGGESTS THERE'S A ROLE FOR --

4249
02:39:48,520 --> 02:39:52,320
CELLS, OTHER -- EVEN IMMUNE

4250
02:39:52,320 --> 02:39:52,800
CELLS.

4251
02:39:52,800 --> 02:39:54,200
I'M EXCITED TO SORT THAT OUT

4252
02:39:54,200 --> 02:39:54,400
NEXT.

4253
02:39:54,400 --> 02:39:55,880
>> THANK YOU.

4254
02:39:55,880 --> 02:39:58,640
>> JOHN, DO WE HAVE TIME
FOR ONE

4255
02:39:58,640 --> 02:40:04,880
LAST QUESTION TO MIKE DAVIS?

4256
02:40:04,880 --> 02:40:06,200
I WILL ASK.

4257
02:40:06,200 --> 02:40:08,160
SO DR. DAVIS, INTERESTING WORK.

4258
02:40:08,160 --> 02:40:10,520
YOU MENTIONED THE CONTRIBUTION

4259
02:40:10,520 --> 02:40:13,240
OF THE TWO TYPES OF PUMPS THAT

4260
02:40:13,240 --> 02:40:13,800
PROPEL LYMPH FLOW.

4261
02:40:13,800 --> 02:40:15,680
DO YOU KNOW IF THE DATA ARE THE

4262
02:40:15,680 --> 02:40:16,880
SAME ACROSS ALL LYMPHATIC

4263
02:40:16,880 --> 02:40:21,320
NETWORK IN THE BODY?

4264
02:40:21,320 --> 02:40:24,560
>> WELL, IT DEPENDS ON
WHAT BODY

4265
02:40:24,560 --> 02:40:25,320
YOU'RE TALKING ABOUT.

4266
02:40:25,320 --> 02:40:26,880
IF IT'S THE MOUSE BODY, NO,

4267
02:40:26,880 --> 02:40:28,760
THEY'RE NOT THE SAME.

4268
02:40:28,760 --> 02:40:32,520
AS I MENTIONED, ALL THE

4269
02:40:32,520 --> 02:40:36,320
LYMPHATICS IN THE MOUSE VISCERAL

4270
02:40:36,320 --> 02:40:40,840
AND THORACIC CAVITIES DON'T

4271
02:40:40,840 --> 02:40:41,840
ACTIVELY PUMP AND THAT SEEMS TO

4272
02:40:41,840 --> 02:40:43,840
BE UNIQUE AMONG OTHER SPECIES.

4273
02:40:43,840 --> 02:40:45,640
SO IT'S NOT REPRESENTATIVE OF

4274
02:40:45,640 --> 02:40:48,160
HUMAN VESSELS CERTAINLY.

4275
02:40:48,160 --> 02:40:50,200
THERE ARE REGIONAL DIFFERENCES

4276
02:40:50,200 --> 02:40:52,200
IN THE STRENGTH OF PUMPING.

4277
02:40:52,200 --> 02:40:54,960
AND SO THE VESSELS IN THE LOWER

4278
02:40:54,960 --> 02:40:58,280
EXTREMITIES TEND TO BE STRONGER

4279
02:40:58,280 --> 02:40:59,800
PUMPS, IF STUDIES UNDER

4280
02:40:59,800 --> 02:41:00,880
IDENTICAL CONDITIONS.

4281
02:41:00,880 --> 02:41:04,480
WE HAD A 2018 PAPER THAT

4282
02:41:04,480 --> 02:41:11,720
DEMONSTRATED THAT AT LEAST.

4283
02:41:11,720 --> 02:41:14,080
>> OKAY, THIS IS GREAT.

4284
02:41:14,080 --> 02:41:16,120
SO I THINK WE'RE OUT OF TIME.

4285
02:41:16,120 --> 02:41:18,760
OOO, THERE IS ONE LAST QUESTION.

4286
02:41:18,760 --> 02:41:21,400
GO AHEAD.

4287
02:41:21,400 --> 02:41:27,400
FROM NADA.

4288
02:41:27,400 --> 02:41:28,200
>> FORGET IT.

4289
02:41:28,200 --> 02:41:38,560
I HAVE A PROBLEM HERE.

4290
02:41:39,560 --> 02:41:43,000
>> NADA, DID WE LOSE YOU?

4291
02:41:43,000 --> 02:41:44,200
HAD

4292
02:41:44,200 --> 02:41:45,480
>> LATER.

4293
02:41:45,480 --> 02:41:46,720
I'LL ASK MY QUESTION LATER.

4294
02:41:46,720 --> 02:41:48,040
I HAVE TO FIGURE OUT MY

4295
02:41:48,040 --> 02:41:49,360
COMPUTER.

4296
02:41:49,360 --> 02:41:50,840
>> OKAY, NADA, THAT'S NO

4297
02:41:50,840 --> 02:41:51,160
PROBLEM.

4298
02:41:51,160 --> 02:41:53,240
YOU CAN ALWAYS USE THE Q & A

4299
02:41:53,240 --> 02:41:54,280
LITTLE CHAT ROOM.

4300
02:41:54,280 --> 02:41:54,480
OKAY.

4301
02:41:54,480 --> 02:41:56,080
SO ONCE AGAIN, I WANT TO THANK

4302
02:41:56,080 --> 02:41:59,120
ALL THE SPEAKERS, ALL THE

4303
02:41:59,120 --> 02:42:01,160
PARTICIPANTS FOR JUST REALLY

4304
02:42:01,160 --> 02:42:01,720
LIVELY DISCUSSIONS.

4305
02:42:01,720 --> 02:42:03,280
I INVITE YOU TO TAKE A SHORT

4306
02:42:03,280 --> 02:42:03,800
BREAK.

4307
02:42:03,800 --> 02:42:05,440
I BELIEVE THAT WE WOULD LIKE TO

4308
02:42:05,440 --> 02:42:08,720
HAVE EVERYBODY COME BACK FOR

4309
02:42:08,720 --> 02:42:09,560
11:15 FOR OUR SESSION NUMBER

4310
02:42:09,560 --> 02:42:13,000
THREE.

4311
02:42:13,000 --> 02:42:15,040
>> SO WE ARE READY NOW TO
START

4312
02:42:15,040 --> 02:42:19,240
SESSION NUMBER THREE, LYMPHATICS

4313
02:42:19,240 --> 02:42:21,280
IN INFLAMMATION AND DISEASES OF

4314
02:42:21,280 --> 02:42:22,600
THE GASTROINTESTINAL SYSTEM.

4315
02:42:22,600 --> 02:42:28,280
THE MODERATOR IS DR. YASUKO

4316
02:42:28,280 --> 02:42:30,840
IWAKIRI.

4317
02:42:30,840 --> 02:42:31,600
YALE SCHOOL OF MEDICINE.

4318
02:42:31,600 --> 02:42:32,600
>> THANK YOU, PATRICIA.

4319
02:42:32,600 --> 02:42:36,560
I'D LIKE TO THANK YOU FOR THE

4320
02:42:36,560 --> 02:42:37,800
OPPORTUNITY TO MODERATE THIS

4321
02:42:37,800 --> 02:42:38,680
EXCITING SESSION.

4322
02:42:38,680 --> 02:42:40,120
IT'S MY PLEASURE TO INTRODUCE

4323
02:42:40,120 --> 02:42:42,960
OUR FIRST SPEAKER, DR. RAFAEL

4324
02:42:42,960 --> 02:42:43,520
CZEPIELEWSKI.

4325
02:42:43,520 --> 02:42:44,920
WASHINGTON UNIVERSITY SCHOOL OF

4326
02:42:44,920 --> 02:42:45,880
MEDICINE IN ST. LOUIS.

4327
02:42:45,880 --> 02:42:49,280
HIS TALK ENTITLED ROLES OF

4328
02:42:49,280 --> 02:42:50,360
INTESTINAL LYMPHATIC DRAINAGE

4329
02:42:50,360 --> 02:42:52,280
AND REMODELING IN HEALTH AND

4330
02:42:52,280 --> 02:42:54,280
INFLAMMATORY BOWEL DISEASE.

4331
02:42:54,280 --> 02:43:01,720
RAFAEL, TAKE IT AWAY.

4332
02:43:01,720 --> 02:43:03,560
>> THANK YOU, EVERYONE.

4333
02:43:03,560 --> 02:43:05,840
I'M THRILLED TO BE INVITED TO

4334
02:43:05,840 --> 02:43:08,360
THIS OUTSTANDING SEMINAR.

4335
02:43:08,360 --> 02:43:11,080
AND TO BE TALKING TO YOU ABOUT

4336
02:43:11,080 --> 02:43:13,760
OUR RECENT DISCOVERIES ON THE

4337
02:43:13,760 --> 02:43:17,400
TOPIC OF LYMPHATIC DRAIN    DRAE

4338
02:43:17,400 --> 02:43:18,920
REMODELING IN HEALTH AND

4339
02:43:18,920 --> 02:43:20,880
INFLAMMATORY BOWEL DISEASE.

4340
02:43:20,880 --> 02:43:21,800
THROUGHOUT MY TALK I'LL BE

4341
02:43:21,800 --> 02:43:24,080
SHOWING YOU THESE QR CODES,

4342
02:43:24,080 --> 02:43:25,160
LINKS FOR RELEVANT PUBLICATIONS

4343
02:43:25,160 --> 02:43:28,240
THAT WE HAVE AND SOMEONE ELSE

4344
02:43:28,240 --> 02:43:29,960
DID ON THE SUBJECT, AND YOU CAN

4345
02:43:29,960 --> 02:43:32,320
FOLLOW UP AND FIND IT PRETTY

4346
02:43:32,320 --> 02:43:34,000
FAST THROUGHOUT MY TALK.

4347
02:43:34,000 --> 02:43:36,160
SO AS OTHER PANELISTS MENTIONED,

4348
02:43:36,160 --> 02:43:43,800
THE INTESTINAL LYMPHATICS IS

4349
02:43:43,800 --> 02:43:45,160
SURVEYED BY -- ESPECIALLY IN THE

4350
02:43:45,160 --> 02:43:48,400
SMALL INTESTINE, THERE'S THIS

4351
02:43:48,400 --> 02:43:49,800
SPECIAL LYMPHATIC CAPILLARIES

4352
02:43:49,800 --> 02:43:51,040
CALLED LACTEALS PRESENT IN EACH

4353
02:43:51,040 --> 02:43:55,400
VILLI OF THE IF YOU     GUT.

4354
02:43:55,400 --> 02:43:58,120
THIS SPECIAL CAPILLARIES,

4355
02:43:58,120 --> 02:44:00,760
LACTEALS, ARE IMPORTANT FOR

4356
02:44:00,760 --> 02:44:03,040
INTERSTITIAL FLUID DRAINAGE AND

4357
02:44:03,040 --> 02:44:05,440
TO FACILITATE IMMUNE CELL

4358
02:44:05,440 --> 02:44:07,600
MIGRATION BUT SPECIFIC TO THE

4359
02:44:07,600 --> 02:44:09,720
SMALL INTESTINE, THEY ARE KEY TO

4360
02:44:09,720 --> 02:44:12,200
MODULATE AND ALLOW DIETARY LIPID

4361
02:44:12,200 --> 02:44:16,160
UPTAKE AND TRANSPORT TO STEM

4362
02:44:16,160 --> 02:44:17,120
CIRCULATION AND KEY FOR THE

4363
02:44:17,120 --> 02:44:21,160
DEVELOPMENT OF ORAL TOLERANCE.

4364
02:44:21,160 --> 02:44:22,640
THESE FUNCTIONS ARE CONTROLLED

4365
02:44:22,640 --> 02:44:25,200
BY WHAT HAVE BEEN MENTIONED FROM

4366
02:44:25,200 --> 02:44:29,840
PREVIOUS PANELISTS WITH ITS

4367
02:44:29,840 --> 02:44:30,960
BUTTONS AND ZIPPER JUNCTIONS

4368
02:44:30,960 --> 02:44:33,720
BEING THE MODULATORS OF THE

4369
02:44:33,720 --> 02:44:34,600
ENTRANCE OF THE LYMPHATIC

4370
02:44:34,600 --> 02:44:39,400
SYSTEM.

4371
02:44:39,400 --> 02:44:43,880
SO WHERE IT STARTS IN EACH

4372
02:44:43,880 --> 02:44:47,040
VILLI, YOU HAVE AS YOU CAN SEE

4373
02:44:47,040 --> 02:44:50,560
HERE IN THIS VIDEO THE

4374
02:44:50,560 --> 02:44:53,720
SUBMUCOSAL LYMPHATICS IS FUELED

4375
02:44:53,720 --> 02:44:54,880
BY THE LYMPH DRAINING IN THIS

4376
02:44:54,880 --> 02:45:00,520
REGION OF THE GUT, AND THAT

4377
02:45:00,520 --> 02:45:01,640
DRAINS INTO LARGE LYMPHATIC

4378
02:45:01,640 --> 02:45:03,240
VESSELS THAT POSSESS VALVES THAT

4379
02:45:03,240 --> 02:45:04,600
CAN ENTER INTO DRAINING LYMPH

4380
02:45:04,600 --> 02:45:07,200
NODES, IN THIS CASE, THE

4381
02:45:07,200 --> 02:45:08,480
MESENTERY, AND THEY CAN GO

4382
02:45:08,480 --> 02:45:10,320
FORWARD TOWARDS THE THORACIC

4383
02:45:10,320 --> 02:45:11,400
DUCT AND SYSTEMIC CIRCLE

4384
02:45:11,400 --> 02:45:12,720
VAITION.

4385
02:45:12,720 --> 02:45:23,480
ESPECIALLY FOR INS TESSAL   INTL

4386
02:45:23,480 --> 02:45:24,880
LYMPHATICS, THERE'S VAST ADIPOSE

4387
02:45:24,880 --> 02:45:26,400
TISSUE THAT LITERALLY CONNECTS

4388
02:45:26,400 --> 02:45:32,880
THE GUT TO THE REST OF THE BODY.

4389
02:45:32,880 --> 02:45:36,640
AND SEGMENTS OF THE INTESTINE.

4390
02:45:36,640 --> 02:45:37,720
TODAY I'M GOING TO BE TALKING

4391
02:45:37,720 --> 02:45:39,160
ABOUT WHAT HAPPENS DURING

4392
02:45:39,160 --> 02:45:40,120
INFLAMMATORY BOWEL DISEASE.

4393
02:45:40,120 --> 02:45:41,800
WHICH ARE CHRONIC INFLAMMATIONS

4394
02:45:41,800 --> 02:45:42,760
OF THE SMALL AND LARGE

4395
02:45:42,760 --> 02:45:43,280
INTESTINE.

4396
02:45:43,280 --> 02:45:48,480
I'M GOING TO BE FOCUSED ON

4397
02:45:48,480 --> 02:45:49,120
CROHN'S DISEASE BECAUSE CROHN'S

4398
02:45:49,120 --> 02:45:50,880
DISEASE ALSO POSSESSES ONE

4399
02:45:50,880 --> 02:45:52,160
PHENOTYPE WHICH IS AN ALTERATION

4400
02:45:52,160 --> 02:45:55,120
AND A PROLIFERATION OF THE

4401
02:45:55,120 --> 02:45:56,000
MESENTERIC FAT.

4402
02:45:56,000 --> 02:45:58,960
AND THE DISEASE IS MORE

4403
02:45:58,960 --> 02:46:07,320
PROMINENT TO THE -- HISTORICAL

4404
02:46:07,320 --> 02:46:08,320
FINDINGS -- LYMPHATIC

4405
02:46:08,320 --> 02:46:09,200
INVOLVEMENT DURING -- ONLY IN

4406
02:46:09,200 --> 02:46:11,400
THE REGIONS ASSOCIATED WITH THE

4407
02:46:11,400 --> 02:46:13,040
DISEASE, AND OTHERS AT THE SAME

4408
02:46:13,040 --> 02:46:20,560
TIME WOULD CHARACTERIZE THE

4409
02:46:20,560 --> 02:46:21,440
DISEASE SUGGESTING THERE MIGHT

4410
02:46:21,440 --> 02:46:25,040
BE AN OBSTRUCTION OF THE

4411
02:46:25,040 --> 02:46:25,680
MESENTERIC LYMPHATICS.

4412
02:46:25,680 --> 02:46:26,720
THINKING ABOUT THAT, WE DECIDED

4413
02:46:26,720 --> 02:46:32,000
TO STUDY MESENTERIC FACT FROM

4414
02:46:32,000 --> 02:46:32,920
CROHN'S DISEASE PATIENTS AND

4415
02:46:32,920 --> 02:46:34,240
CONTROL PATIENTS AND WHAT WE

4416
02:46:34,240 --> 02:46:40,640
FOUND IS OBSTRUCTION BY TERTIARY

4417
02:46:40,640 --> 02:46:42,200
LYMPHOID ORGANS, THEY'RE

4418
02:46:42,200 --> 02:46:45,480
POSITIONED AROUND OR WITHIN

4419
02:46:45,480 --> 02:46:47,960
THESE LARGE COLLECTING VESSELS

4420
02:46:47,960 --> 02:46:49,200
COLLECTING THE INTESTINE TO THE

4421
02:46:49,200 --> 02:46:49,840
DRAINING LYMPH NODES.

4422
02:46:49,840 --> 02:46:52,360
SO THAT LED US TO HYPOTHESIZE

4423
02:46:52,360 --> 02:46:56,960
THAT MAYBE THE FORMATION OF THIS

4424
02:46:56,960 --> 02:46:58,600
LINK OF ORGANS ASSOCIATED WITH

4425
02:46:58,600 --> 02:47:00,160
THIS ALTERATION THE MESENTERY

4426
02:47:00,160 --> 02:47:03,080
ONLY TO THE REGIONS OF CHRONIC

4427
02:47:03,080 --> 02:47:04,200
INFLAMMATION COULD BE ASSOCIATED

4428
02:47:04,200 --> 02:47:05,960
WITH OVERALL PATHOLOGY OF

4429
02:47:05,960 --> 02:47:07,000
CROHN'S DISEASE.

4430
02:47:07,000 --> 02:47:10,320
AND ALSO THAT WHEN YOU HAVE A

4431
02:47:10,320 --> 02:47:12,920
DISRUPTION IN THE COLLECTING

4432
02:47:12,920 --> 02:47:16,000
VESSEL -- THAT COULD LEAD INTO

4433
02:47:16,000 --> 02:47:17,960
OTHER PROBLEMS SUCH AS

4434
02:47:17,960 --> 02:47:19,280
ALTERATION OF TRAFFIC AND

4435
02:47:19,280 --> 02:47:22,520
MOLECULAR TRANSIT.

4436
02:47:22,520 --> 02:47:26,040
SO WE DECIDED TO USE A MOUSE

4437
02:47:26,040 --> 02:47:32,040
MODEL OF TERMINAL ILIUM

4438
02:47:32,040 --> 02:47:37,000
INFLAMMATION.

4439
02:47:37,000 --> 02:47:39,160
THIS IS A SURPLUS OF PRODUCTION

4440
02:47:39,160 --> 02:47:40,280
OF THE TNF CYTOKINE.

4441
02:47:40,280 --> 02:47:44,040
THIS MODEL WAS GENERATED BY

4442
02:47:44,040 --> 02:47:46,360
GEORGE KOLLIAS WHERE YOU HAVE

4443
02:47:46,360 --> 02:47:49,200
INFLAMMATION OF THE TERMINAL

4444
02:47:49,200 --> 02:47:51,800
ILIUM, ENCIRCLES THE TNF AND

4445
02:47:51,800 --> 02:47:53,600
DESCRIPTION OF ORGAN --

4446
02:47:53,600 --> 02:47:54,720
FORMATION IN THE GUT TOO, AND WE

4447
02:47:54,720 --> 02:47:59,320
OBTAINED THIS MODEL -- WHAT WE

4448
02:47:59,320 --> 02:48:05,560
DID IS WE TOOK THIS TNF IBD

4449
02:48:05,560 --> 02:48:07,320
MOUSE MODEL AND CROSSED WITH A

4450
02:48:07,320 --> 02:48:10,040
LYMPHATIC REPORTER.

4451
02:48:10,040 --> 02:48:12,760
UNDER THE CONTROL OF PROX1 GENE.

4452
02:48:12,760 --> 02:48:16,040
WHAT YOU SEE HERE IS THE IMAGING

4453
02:48:16,040 --> 02:48:17,560
OF THIS MESENTERY WHICH IS

4454
02:48:17,560 --> 02:48:18,800
CONNECT BEING THE TERMINAL ILIUM

4455
02:48:18,800 --> 02:48:20,560
TO THE MESENTERY, WE CAN SEE

4456
02:48:20,560 --> 02:48:22,960
THIS FINE RED LINE GOING THROUGH

4457
02:48:22,960 --> 02:48:25,040
THE MESENTERY.

4458
02:48:25,040 --> 02:48:29,720
AND THIS IS A -- MADE CONTROL.

4459
02:48:29,720 --> 02:48:31,040
HOWEVER YOU HAVE THIS ROUND

4460
02:48:31,040 --> 02:48:34,520
STRUCTURE THAT FORMS AND ALSO

4461
02:48:34,520 --> 02:48:36,360
HAS THE PRESENCE OF LYMPHATICS

4462
02:48:36,360 --> 02:48:36,800
AROUND IT.

4463
02:48:36,800 --> 02:48:40,200
UPON CLOSER LOOK, ORGANS ARE

4464
02:48:40,200 --> 02:48:41,520
HIGHLY ASSOCIATED ONLY TO

4465
02:48:41,520 --> 02:48:43,040
COLLECTING LYMPHATIC VESSELS AND

4466
02:48:43,040 --> 02:48:46,680
YOU CAN APPRECIATE -- ON ITS

4467
02:48:46,680 --> 02:48:48,200
FORMATION, WE SAW THE LYMPHATIC

4468
02:48:48,200 --> 02:48:53,440
VALVE REGION WAS UNDERGOING

4469
02:48:53,440 --> 02:48:55,000
LYMPH ANGIOGENESIS, CREATING

4470
02:48:55,000 --> 02:48:58,040
SPROUTS OUT OF THE COLLECTING

4471
02:48:58,040 --> 02:49:00,160
VESSEL WHICH IS QUITE UNIQUE FOR

4472
02:49:00,160 --> 02:49:06,960
THIS MODEL.

4473
02:49:06,960 --> 02:49:08,360
COULD ALTER FUNCTIONS OF THE

4474
02:49:08,360 --> 02:49:09,280
LYMPHATIC DRAINAGE.

4475
02:49:09,280 --> 02:49:13,400
THEN WE CROSSED THE TNF IBD

4476
02:49:13,400 --> 02:49:14,560
MODEL WITH PHOTO CONVERTIBLE

4477
02:49:14,560 --> 02:49:14,960
MOUSE.

4478
02:49:14,960 --> 02:49:22,880
THIS MOUSE HAS ALL ITS CELLS --

4479
02:49:22,880 --> 02:49:25,960
IN GREEN AND YOU CAN USE FLEE

4480
02:49:25,960 --> 02:49:27,160
CYTOMETRY TO CHECK FOR THE

4481
02:49:27,160 --> 02:49:27,840
LABELED CELLS.

4482
02:49:27,840 --> 02:49:29,200
SO WE TESTED DURING THE

4483
02:49:29,200 --> 02:49:30,360
MIGRATION OF CELLS GOING OUT OF

4484
02:49:30,360 --> 02:49:33,600
THE INTESTINE TO THE MESENTERY

4485
02:49:33,600 --> 02:49:34,680
LYMPH NODE AND ELSEWHERE COULD

4486
02:49:34,680 --> 02:49:38,520
BE COLLECTED BY THIS -- WE

4487
02:49:38,520 --> 02:49:39,720
LABELED THE TERMINAL -- WE DON'T

4488
02:49:39,720 --> 02:49:41,440
KNOW WHERE THE DISEASE IS --

4489
02:49:41,440 --> 02:49:44,840
WITH LIGHT AND THEN WE CHECK THE

4490
02:49:44,840 --> 02:49:46,560
DRAINAGE OF THESE MIGRATED CELLS

4491
02:49:46,560 --> 02:49:47,360
24 HOURS LATER.

4492
02:49:47,360 --> 02:49:49,320
WHAT WE CAN FIND IS THAT INSTEAD

4493
02:49:49,320 --> 02:49:53,440
OF GOING INTO THE SYSTEMIC

4494
02:49:53,440 --> 02:49:54,560
CIRCULATION, MOST OF THE CELLS

4495
02:49:54,560 --> 02:49:56,400
ARE NOW ARRESTED IN THE

4496
02:49:56,400 --> 02:49:57,200
MESENTERY.

4497
02:49:57,200 --> 02:49:59,560
AND THOSE ARE IMMUNE CELLS.

4498
02:49:59,560 --> 02:50:02,400
AND THIS IS TRUE FOR T-CELLS, B

4499
02:50:02,400 --> 02:50:04,840
CELLS, ESPECIALLY FOR DENDRITIC

4500
02:50:04,840 --> 02:50:05,680
CELLS.

4501
02:50:05,680 --> 02:50:08,720
YOU CAN FIND THESE RED LABELED

4502
02:50:08,720 --> 02:50:09,840
CELLS INSIDE THE COLLECTING

4503
02:50:09,840 --> 02:50:11,800
VESSELS COMING FROM THE REGION

4504
02:50:11,800 --> 02:50:15,160
OF THE INTESTINE.

4505
02:50:15,160 --> 02:50:16,720
NEXT WE COLLABORATED WITH

4506
02:50:16,720 --> 02:50:17,480
DR. MICHAEL DAVIS FROM

4507
02:50:17,480 --> 02:50:19,360
UNIVERSITY OF MISSOURI TO DO

4508
02:50:19,360 --> 02:50:21,960
COLLECTING VESSEL CANNULATION

4509
02:50:21,960 --> 02:50:25,440
AND CHECK THE LYMPHATIC DRAINAGE

4510
02:50:25,440 --> 02:50:26,120
FUNCTION FOR LYMPHATICS AND

4511
02:50:26,120 --> 02:50:27,560
OTHER MOLECULAR CARGO.

4512
02:50:27,560 --> 02:50:29,200
WHAT YOU CAN SEE IN THIS VIDEO,

4513
02:50:29,200 --> 02:50:31,560
THE CANNULATION WAS DONE CLOSE

4514
02:50:31,560 --> 02:50:34,640
TO THE GUT WALL AND THEN THE

4515
02:50:34,640 --> 02:50:35,880
DRAINAGE IS GOING TO THE LEFT

4516
02:50:35,880 --> 02:50:39,200
SIDE OF THE SCREEN WHERE THE

4517
02:50:39,200 --> 02:50:41,840
MESENTERIC LYMPH NODE IS.

4518
02:50:41,840 --> 02:50:44,800
THIS GOES SMOOTHLY WITHIN FIVE

4519
02:50:44,800 --> 02:50:47,920
MINUTE, THE TRASER WHICH IS OF

4520
02:50:47,920 --> 02:50:50,360
HIGH MOLECULAR WEIGHT CAN ARRIVE

4521
02:50:50,360 --> 02:50:52,320
TO THE MESENTERY -- HOWEVER THE

4522
02:50:52,320 --> 02:50:55,000
SAME IS NOT TRUE FOR A MOUSE

4523
02:50:55,000 --> 02:50:56,440
WITH CHRONIC INFLAMMATION AND IN

4524
02:50:56,440 --> 02:50:59,080
THE PRESENCE OF -- WHERE IT

4525
02:50:59,080 --> 02:51:00,280
STARTED GOING LEFT, SIDE, NOW

4526
02:51:00,280 --> 02:51:02,400
THE DRAINAGE IS ALSO GOING TO

4527
02:51:02,400 --> 02:51:03,560
THE RIGHT SIDE OF YOUR SCREEN,

4528
02:51:03,560 --> 02:51:05,480
GOING ALL THE WAY BACK TO A

4529
02:51:05,480 --> 02:51:08,440
DIFFERENT PART OF THE INTESTINE.

4530
02:51:08,440 --> 02:51:12,680
WE CAN ALSO APPRECIATE THERE IS

4531
02:51:12,680 --> 02:51:14,240
LEAKAGE AND BLOCKAGE.

4532
02:51:14,240 --> 02:51:16,640
SO WITH PHYSIOLOGICAL INPUT

4533
02:51:16,640 --> 02:51:17,920
PRESSURE, WE CANNOT SEE THE

4534
02:51:17,920 --> 02:51:19,720
DRAINAGE ALL THE WAY TO THE

4535
02:51:19,720 --> 02:51:20,200
MESENTERY.

4536
02:51:20,200 --> 02:51:25,480
WHAT YOU SEE IS PILLAGE AT

4537
02:51:25,480 --> 02:51:29,160
THE -- LEADING TO LYMPHATICS AND

4538
02:51:29,160 --> 02:51:30,720
ALSO YOU SEE THE DRAINAGE GOING

4539
02:51:30,720 --> 02:51:32,240
BACKWARDS ALL THE WAY TO THE

4540
02:51:32,240 --> 02:51:33,440
GUT, WHICH DEMONSTRATE THAT ALL

4541
02:51:33,440 --> 02:51:38,680
THE SEGMENT, IT HAS COMPLETELY

4542
02:51:38,680 --> 02:51:39,480
DEFECTIVE BOWELS.

4543
02:51:39,480 --> 02:51:41,440
SO NEXT WE DEVELOP ANOTHER

4544
02:51:41,440 --> 02:51:48,760
APPROACH USING AN INTRAVITAL

4545
02:51:48,760 --> 02:51:51,520
STEREO SCOPE SYSTEM TO USE AND

4546
02:51:51,520 --> 02:51:54,480
CHECK FOR INTESTINAL LYMPHATIC

4547
02:51:54,480 --> 02:51:58,360
DRAINAGE TOWARDS THE MESENTERY.

4548
02:51:58,360 --> 02:52:03,160
SO AFTER THE INJECTION, MICRO

4549
02:52:03,160 --> 02:52:05,680
INJECTION, WE CAN FOLLOW UP TO

4550
02:52:05,680 --> 02:52:08,040
AN HOUR THE DRAINAGE ALL THE WAY

4551
02:52:08,040 --> 02:52:10,240
TO THE MESENTERY.

4552
02:52:10,240 --> 02:52:12,240
IN THE LITTER MATE MOUSE, WE CAN

4553
02:52:12,240 --> 02:52:13,440
VISUALIZE THIS HAPPENS QUITE

4554
02:52:13,440 --> 02:52:14,400
FAST, WITHIN FIVE MINUTE WE

4555
02:52:14,400 --> 02:52:16,000
ALREADY SEE THE TRASER GOING ALL

4556
02:52:16,000 --> 02:52:18,680
THE WAY TO THE DRAIN LYMPH NODE.

4557
02:52:18,680 --> 02:52:21,480
HOWEVER, THE SAME IS NOT TRUE IN

4558
02:52:21,480 --> 02:52:25,960
THE IBD SETTING WHERE THEY'RE

4559
02:52:25,960 --> 02:52:26,520
PRESENT IN THE MESENTERY.

4560
02:52:26,520 --> 02:52:28,560
WHAT YOU SEE HERE IS THOSE ROUND

4561
02:52:28,560 --> 02:52:30,320
STRUCTURES NOW LIGHT UP IN

4562
02:52:30,320 --> 02:52:32,320
GREEN, WHICH PROVES THAT THE

4563
02:52:32,320 --> 02:52:34,480
ASSOCIATION OF THE LYMPHATICS

4564
02:52:34,480 --> 02:52:35,960
AND THE INTERSTITIAL ORGAN WITH

4565
02:52:35,960 --> 02:52:38,000
YOU      BUT

4566
02:52:38,000 --> 02:52:40,040
YOU CAN ALSO SEE A LEAKAGE.

4567
02:52:40,040 --> 02:52:41,600
EVEN IF WE RECORD THIS VIDEO FOR

4568
02:52:41,600 --> 02:52:46,680
UP TO AN HOUR, WE DON'T SEE THE

4569
02:52:46,680 --> 02:52:47,960
DRAINAGE OF THE CARGO GOING ALL

4570
02:52:47,960 --> 02:52:49,880
THE WAY TO THE MESENTERIC LYMPH

4571
02:52:49,880 --> 02:52:50,640
NODE.

4572
02:52:50,640 --> 02:52:56,080
DEMONSTRATING THAT WE HAVE ORGAN

4573
02:52:56,080 --> 02:52:56,880
BLOCKAGE OF THE LYMPHATIC

4574
02:52:56,880 --> 02:52:57,320
SYSTEM.

4575
02:52:57,320 --> 02:52:59,720
SO WE CAN MEASURE THE LENGTH OF

4576
02:52:59,720 --> 02:53:01,560
TIME THAT IT TAKES TO GO FROM

4577
02:53:01,560 --> 02:53:04,800
INJECTION SITE TO THE MESENTERIC

4578
02:53:04,800 --> 02:53:06,160
LYMPH NODE AND WE CAN APPRECIATE

4579
02:53:06,160 --> 02:53:08,680
THAT THROUGH THE AGE OF THE

4580
02:53:08,680 --> 02:53:09,760
MOUSE, THIS PHENOTYPE OF

4581
02:53:09,760 --> 02:53:13,280
BLOCKAGE INCREASES, AND IF WE

4582
02:53:13,280 --> 02:53:19,640
TREAT THE MICE WITH ANTI-TNF,

4583
02:53:19,640 --> 02:53:21,680
STANDARD THERAPY FOR CROHN'S

4584
02:53:21,680 --> 02:53:25,280
DISEASE A AT AN AGE WHERE TLOs

4585
02:53:25,280 --> 02:53:30,680
ARE JUST FORMING WE CAN BLOCK -T

4586
02:53:30,680 --> 02:53:36,560
LED US TO ALSO THINK THAT MAYBE

4587
02:53:36,560 --> 02:53:39,080
TNF ITSELF MIGHT BE IMPACTING

4588
02:53:39,080 --> 02:53:40,080
ENDOTHELIAL CELLS.

4589
02:53:40,080 --> 02:53:42,800
SO WE DECIDED TO TEST TO PERFORM

4590
02:53:42,800 --> 02:53:45,880
AN IN VITRO STUDY USING HUMAN

4591
02:53:45,880 --> 02:53:48,040
ENDOTHELIAL CELLS TO CHECK

4592
02:53:48,040 --> 02:53:51,320
WHETHER TNF CYTOKINE CAN ALTER

4593
02:53:51,320 --> 02:53:53,920
HUMAN LYMPHATIC ENDOTHELIAL

4594
02:53:53,920 --> 02:53:54,120
CELLS.

4595
02:53:54,120 --> 02:53:57,240
AS MENTIONED BY PREVIOUS

4596
02:53:57,240 --> 02:53:59,760
PANELISTS, WE CULTURE THE CELLS

4597
02:53:59,760 --> 02:54:03,120
UNDER DIFFERENT CONDITIONS TO

4598
02:54:03,120 --> 02:54:05,520
TEST WHETHER THE LYMPHATIC

4599
02:54:05,520 --> 02:54:06,720
OSCILLATORY FLOW AND STATIC

4600
02:54:06,720 --> 02:54:07,880
CONDITIONS COULD BE ALTERED BY

4601
02:54:07,880 --> 02:54:10,320
THE PRESENCE OR ABSENCE OF T.V.

4602
02:54:10,320 --> 02:54:15,400
SO AS      TNF.

4603
02:54:15,400 --> 02:54:18,600
A KEY FACTOR UPREGULATED UNDER

4604
02:54:18,600 --> 02:54:19,640
OSCILLATORY FLOW CONDITIONS, AND

4605
02:54:19,640 --> 02:54:23,920
THEY CONTROL THE ECK PRETION   F

4606
02:54:23,920 --> 02:54:26,360
OTHER PROTEINS ESSENTIAL FOR

4607
02:54:26,360 --> 02:54:28,880
BOWEL MAINTENANCE.

4608
02:54:28,880 --> 02:54:32,480
SO WE USED THESE DIFFERENT

4609
02:54:32,480 --> 02:54:33,240
STATIC -- TO MIMIC THE

4610
02:54:33,240 --> 02:54:36,280
ENVIRONMENT OF A VALVE -- THE

4611
02:54:36,280 --> 02:54:37,800
ONES WE SEE IN MICE THAT ARE

4612
02:54:37,800 --> 02:54:40,680
BEING DEFECTIVE.

4613
02:54:40,680 --> 02:54:42,720
SO IN COLLABORATION WITH

4614
02:54:42,720 --> 02:54:44,520
DR. YING YANG AND DR. JOSH

4615
02:54:44,520 --> 02:54:47,200
SCALLAN, WE PERFORMED THE SAME

4616
02:54:47,200 --> 02:54:48,560
STUDIES WITH AND WITHOUT TNF.

4617
02:54:48,560 --> 02:54:51,480
WHAT WE FIND IS THE

4618
02:54:51,480 --> 02:54:52,120
OVEREXPRESSION OR UPREGULATION

4619
02:54:52,120 --> 02:54:55,760
OF GATA2 AND EXPRESSION OF PROX1

4620
02:54:55,760 --> 02:54:56,600
IS DOWNREGULATED IN FLOW

4621
02:54:56,600 --> 02:54:58,920
CONDITIONS WITH THE PRESENCE OF

4622
02:54:58,920 --> 02:55:05,680
TNF, AND ALTHOUGH FOX C IT2 DOET

4623
02:55:05,680 --> 02:55:07,680
GET ALTERED, ITS EXPRESSION IS

4624
02:55:07,680 --> 02:55:10,440
ALSO ALTERED BY BEING STATIC

4625
02:55:10,440 --> 02:55:12,600
WITH TNF, SHOWING THAT TNF

4626
02:55:12,600 --> 02:55:15,440
ITSELF CAN MODULATE THESE KEY

4627
02:55:15,440 --> 02:55:21,360
TRANSCRIPTION FACTORS THAT

4628
02:55:21,360 --> 02:55:24,520
CONTROL -- WE CAN SEE USING QPR

4629
02:55:24,520 --> 02:55:27,920
THAT KEY GENES ARE EXTREMELY

4630
02:55:27,920 --> 02:55:29,360
DOWNREGULATED IN THE PRESENCE OF

4631
02:55:29,360 --> 02:55:33,840
TNF.

4632
02:55:33,840 --> 02:55:34,600
DEMONSTRATING THE DEFECTS WE'RE

4633
02:55:34,600 --> 02:55:37,520
SEEING MIGHT BE DERIVED FROM A

4634
02:55:37,520 --> 02:55:40,480
DIRECT IMPACT OF TNF CYTOKINE

4635
02:55:40,480 --> 02:55:41,680
INTO LYMPHATIC ENDOTHELIAL

4636
02:55:41,680 --> 02:55:45,640
CELLS.

4637
02:55:45,640 --> 02:55:47,480
SO WITH THAT, I HOPE THAT YOU

4638
02:55:47,480 --> 02:55:49,120
COULD APPRECIATE THAT THE

4639
02:55:49,120 --> 02:55:50,000
LYMPHATIC SYSTEM IN THE

4640
02:55:50,000 --> 02:55:52,080
INTESTINE IS QUITE IMPORTANT FOR

4641
02:55:52,080 --> 02:55:53,720
LEUKOCYTE TRAFFICKING AND THE

4642
02:55:53,720 --> 02:55:58,760
DRAINAGE OF MOLECULAR SOLUTE,

4643
02:55:58,760 --> 02:56:01,200
AND DURING INFLAMMATION AND

4644
02:56:01,200 --> 02:56:02,400
ALTERATION NOT ONLY AT THE GUT

4645
02:56:02,400 --> 02:56:04,880
WALL BUT ALSO IN ITS DRAINING

4646
02:56:04,880 --> 02:56:09,920
MESENTERY, CAN INDUCE THE

4647
02:56:09,920 --> 02:56:12,440
FORMATION OF -- ANGIOGENESIS AT

4648
02:56:12,440 --> 02:56:16,040
THE COLLECTING VALVES THAT LEADS

4649
02:56:16,040 --> 02:56:17,720
TO -- AND -- DEFECTIVE CAN LEAD

4650
02:56:17,720 --> 02:56:21,000
TO RETROGRADE FLOW, LIPID REACH

4651
02:56:21,000 --> 02:56:25,920
WITH CARGO AND POTENTIALLY HAS

4652
02:56:25,920 --> 02:56:27,200
BACTERIA WHICH CAN ENHANCE

4653
02:56:27,200 --> 02:56:29,200
INFLAMMATION AT THE SITE AND THE

4654
02:56:29,200 --> 02:56:32,360
TLOs CAN BLOCK AND OBSTRUCT

4655
02:56:32,360 --> 02:56:35,000
THE NORMAL LYMPHATIC FLOW OF

4656
02:56:35,000 --> 02:56:35,880
CELLS IN CARGO.

4657
02:56:35,880 --> 02:56:39,840
AND WE COULD EXPLAIN THAT BY

4658
02:56:39,840 --> 02:56:42,320
VERIFYING TNF ITSELF CAN

4659
02:56:42,320 --> 02:56:43,760
DOWNREGULATE PROX1 AND OTHER KEY

4660
02:56:43,760 --> 02:56:45,720
TRANSCRIPTION FACTORS THAT CAN

4661
02:56:45,720 --> 02:56:49,880
MODULATE LYMPHATIC VALVE

4662
02:56:49,880 --> 02:56:50,520
MAINTENANCE.

4663
02:56:50,520 --> 02:56:51,760
IN TERMS OF OPPORTUNITIES OF OUR

4664
02:56:51,760 --> 02:56:54,600
WORK, I BELIEVE THAT THE

4665
02:56:54,600 --> 02:57:00,080
MECHANISM GOVERNING THIS LYMPH

4666
02:57:00,080 --> 02:57:00,960
ANGIOGENESIS AT THE VALVE SITE

4667
02:57:00,960 --> 02:57:04,160
AND COLLECTING VESSEL -- AM I

4668
02:57:04,160 --> 02:57:07,560
OUT?

4669
02:57:07,560 --> 02:57:13,000
>> YOU'RE OKAY.

4670
02:57:13,000 --> 02:57:14,640
>> AND COLLECTING VESSELS
IS

4671
02:57:14,640 --> 02:57:18,040
VERY IMPORTANT TO STUDY FURTHER,

4672
02:57:18,040 --> 02:57:21,760
AND UNDERSTANDING THE MECHANISM

4673
02:57:21,760 --> 02:57:24,920
OF HOW TNF IS MODULATED IS DOWN

4674
02:57:24,920 --> 02:57:27,120
REGS LAEVE -- THAT WILL BE QUITE

4675
02:57:27,120 --> 02:57:29,200
ESSENTIAL TO STUDY THE EFFECTS

4676
02:57:29,200 --> 02:57:31,400
OF INFLAMMATION INTO THE

4677
02:57:31,400 --> 02:57:32,240
LYMPHATIC BEDS.

4678
02:57:32,240 --> 02:57:33,920
ALSO IT'S IMPORTANT TO HIGHLIGHT

4679
02:57:33,920 --> 02:57:37,600
THAT THERE MIGHT BE UNEXPLORED

4680
02:57:37,600 --> 02:57:40,160
ROLES OF LYMPHATICS IN

4681
02:57:40,160 --> 02:57:42,880
INTESTINAL PATHOLOGIES, AND THE

4682
02:57:42,880 --> 02:57:44,240
SMALL ADD LARNLGD INTESTINE,

4683
02:57:44,240 --> 02:57:45,640
IMPORTANT TO HIGHLIGHT THE

4684
02:57:45,640 --> 02:57:46,600
DIFFERENCE BETWEEN CROHN'S

4685
02:57:46,600 --> 02:57:49,240
DISEASE AND ULCERATIVE COLITIS,

4686
02:57:49,240 --> 02:57:50,960
AND IN TERMS OF GENERAL GAPS, IT

4687
02:57:50,960 --> 02:57:52,280
WILL BE INTERESTING TO EXPLORE

4688
02:57:52,280 --> 02:57:55,160
ARE THERE RELATIONSHIPS BETWEEN

4689
02:57:55,160 --> 02:57:59,160
INTESTINAL LYMPHATICS AND OTHER

4690
02:57:59,160 --> 02:58:01,560
LYMPHATIC -- AND OTHER CELLS

4691
02:58:01,560 --> 02:58:04,880
AROUND IT, THAT SURROUND IT.

4692
02:58:04,880 --> 02:58:07,760
LACTEALS AND OTHER LYMPHATICS,

4693
02:58:07,760 --> 02:58:10,680
AND I THINK IMPORTANT TO

4694
02:58:10,680 --> 02:58:12,000
HIGHLIGHT, HOW THEY CAN SENSE

4695
02:58:12,000 --> 02:58:16,320
AND RESPOND TO THESE TISSUE

4696
02:58:16,320 --> 02:58:18,680
ALTERATIONS, MICROBIOME, IMMUNE

4697
02:58:18,680 --> 02:58:20,760
CELL QUEUES AND HOW CHRONIC

4698
02:58:20,760 --> 02:58:22,040
INFLAMMATION WOULD IMPACT THAT

4699
02:58:22,040 --> 02:58:25,280
AND HOW AGING CAN BE IMPACTING

4700
02:58:25,280 --> 02:58:26,560
ALSO THESE RELATIONSHIPS.

4701
02:58:26,560 --> 02:58:29,400
WITH THAT, I'D LIKE TO THANK MY

4702
02:58:29,400 --> 02:58:32,040
WHOLE LABORATORY, MY MENTOR, GED

4703
02:58:32,040 --> 02:58:34,680
LIN RANDOLPH AND SEVERAL KEY

4704
02:58:34,680 --> 02:58:37,520
COLLABORATORS AT WASH U AND

4705
02:58:37,520 --> 02:58:39,360
DR. MICHAEL DAVIS, YING YANG AND

4706
02:58:39,360 --> 02:58:42,160
JOSH SCALLAN FOR HELPING WITH

4707
02:58:42,160 --> 02:58:43,200
THIS WORK.

4708
02:58:43,200 --> 02:58:43,800
OUR FUNDING SOURCES.

4709
02:58:43,800 --> 02:58:45,200
I WOULD LOVE TO ANSWER QUESTIONS

4710
02:58:45,200 --> 02:58:45,840
RELATED TO OUR WORK.

4711
02:58:45,840 --> 02:58:49,160
THANK YOU SO MUCH.

4712
02:58:49,160 --> 02:58:51,680
>> THANK YOU, RAFAEL, FOR
THIS

4713
02:58:51,680 --> 02:58:52,040
FANTASTIC TALK.

4714
02:58:52,040 --> 02:58:58,160
I WANT TO REMIND THE VIDEO

4715
02:58:58,160 --> 02:59:01,080
VIEWERS THAT YOU CAN ALSO SEND

4716
02:59:01,080 --> 02:59:02,400
QUESTIONS VIA THE LIVE FEEDBACK

4717
02:59:02,400 --> 02:59:03,960
BUTTON.

4718
02:59:03,960 --> 02:59:04,920
IT'S MY GREAT PLEASURE TO

4719
02:59:04,920 --> 02:59:08,680
INTRODUCE OUR SECOND SPEAKER,

4720
02:59:08,680 --> 02:59:10,480
DR. DARIA ESTERHAZY FROM THE

4721
02:59:10,480 --> 02:59:11,720
UNIVERSITY OF CHICAGO.

4722
02:59:11,720 --> 02:59:16,520
HER TALK IS ENTITLED IMPACT OF

4723
02:59:16,520 --> 02:59:20,480
INTESTINAL HELMINTHS ON DUODENAL

4724
02:59:20,480 --> 02:59:20,960
LYMPHATIC FUNCTION.

4725
02:59:20,960 --> 02:59:31,280
>> THANK YOU A LOT.

4726
02:59:39,840 --> 02:59:41,560
MY SYSTEM IS NOT ALLOWING ME TO

4727
02:59:41,560 --> 02:59:42,680
DO THIS.

4728
02:59:42,680 --> 02:59:44,400
DO YOU HAVE A WAY TO SHARE IT?

4729
02:59:44,400 --> 02:59:46,120
>> THERE SHOULD BE A SHARE

4730
02:59:46,120 --> 02:59:48,160
BUTTON AT THE BOTTOM OF YOUR

4731
02:59:48,160 --> 02:59:48,520
SCREEN.

4732
02:59:48,520 --> 02:59:49,960
DO YOU HAVE YOUR SLIDES OPEN

4733
02:59:49,960 --> 02:59:50,160
ALREADY?

4734
02:59:50,160 --> 02:59:53,800
>> I DO.

4735
02:59:53,800 --> 02:59:58,240
IT SAYS MY SOFT     MICROSOFT PS

4736
02:59:58,240 --> 02:59:59,120
UNKNOWN.

4737
02:59:59,120 --> 03:00:09,440
I'M REALLY SORRY.

4738
03:00:21,080 --> 03:00:26,360
>> DARIA, ARE YOU ABLE TO
SHARE

4739
03:00:26,360 --> 03:00:26,960
YOUR SLIDES WITH US?

4740
03:00:26,960 --> 03:00:33,120
>> MY COMPUTER WAS
SWITCHED FROM

4741
03:00:33,120 --> 03:00:33,880
MY INSTITUTION.

4742
03:00:33,880 --> 03:00:37,480
>> MAYBE WE CAN SWITCH TO
THE

4743
03:00:37,480 --> 03:00:39,000
NEXT SPEAKER AND I CAN HELP YOU.

4744
03:00:39,000 --> 03:00:39,680
>> NO PROBLEM.

4745
03:00:39,680 --> 03:00:47,920
SO THE NEXT SPEAKER IS ACTUALLY

4746
03:00:47,920 --> 03:00:52,160
MYSELF.

4747
03:00:52,160 --> 03:00:53,480
TALKING ABOUT LYMPHATIC SYSTEM

4748
03:00:53,480 --> 03:00:55,000
IN CHRONIC LIVER DISEASE.

4749
03:00:55,000 --> 03:01:05,440
LET ME SHARE MY SCREEN.

4750
03:01:21,240 --> 03:01:31,560
CAN YOU SEE MY SCREEN?

4751
03:01:40,840 --> 03:01:43,040
>> THE LIVER IS THE KEY
ORGAN OF

4752
03:01:43,040 --> 03:01:46,520
LYMPH PRODUCTION, WITH 25 TO 50%

4753
03:01:46,520 --> 03:01:48,080
OF LYMPH PASSING THROUGH THE

4754
03:01:48,080 --> 03:01:49,280
THORACIC DUCT ORIGINATING IN THE

4755
03:01:49,280 --> 03:01:50,080
LIVER.

4756
03:01:50,080 --> 03:01:53,000
IN CIRRHOTIC PATIENTS, THE LYMPH

4757
03:01:53,000 --> 03:01:53,880
PRODUCTION FROM THE LIVER

4758
03:01:53,880 --> 03:01:57,120
INCREASES TO SIX FOLD LEADING TO

4759
03:01:57,120 --> 03:01:58,240
THE SERIOUS COMPLICATION CALLED

4760
03:01:58,240 --> 03:01:59,760
ASCITES.

4761
03:01:59,760 --> 03:02:01,160
COMPARED TO OTHER ORGAN, THE

4762
03:02:01,160 --> 03:02:03,160
LYMPHATIC SYSTEM IN THE LIVER IS

4763
03:02:03,160 --> 03:02:03,480
UNDERSTUDIED.

4764
03:02:03,480 --> 03:02:05,120
THAT IS BECAUSE OF THE LIMITED

4765
03:02:05,120 --> 03:02:07,080
NUMBER OF LYMPHATIC ENDOTHELIAL

4766
03:02:07,080 --> 03:02:07,640
CELL MARKERS.

4767
03:02:07,640 --> 03:02:10,480
THE TYPICAL LYMPHATIC

4768
03:02:10,480 --> 03:02:13,640
ENDOTHELIAL CELL MARKERS SUCH AS

4769
03:02:13,640 --> 03:02:24,200
PROX1, LYVE-1, FIT4 -- WHICH IS

4770
03:02:30,320 --> 03:02:33,240
A MAJOR CELL TYPE, MAJOR

4771
03:02:33,240 --> 03:02:34,000
ENDOTHELIAL CELL TYPE IN THE

4772
03:02:34,000 --> 03:02:37,600
LIVER.

4773
03:02:37,600 --> 03:02:41,600
ANOTHER REASON WOULD BE THE

4774
03:02:41,600 --> 03:02:43,320
COMPLEX STRUCTURE OF THE

4775
03:02:43,320 --> 03:02:45,400
VASCULATURE IN THE LIVER.

4776
03:02:45,400 --> 03:02:52,960
HERE  THERE ARE OTHER VESSELS IE

4777
03:02:52,960 --> 03:02:54,280
AREA AS WELL.

4778
03:02:54,280 --> 03:02:55,800
SO IN THIS DIAGRAM, I WOULD LIKE

4779
03:02:55,800 --> 03:03:05,320
TO SHOW YOU THE -- OF THE LIVER.

4780
03:03:05,320 --> 03:03:07,360
MOST OF THE LYMPHATIC VESSELS

4781
03:03:07,360 --> 03:03:10,240
ARE INDICATED IN THE PORTAL

4782
03:03:10,240 --> 03:03:15,040
TRACT LIVER WHICH CONSIST OF

4783
03:03:15,040 --> 03:03:18,560
PORTAL VEIN -- ARTERY, BILE

4784
03:03:18,560 --> 03:03:18,760
DUCT.

4785
03:03:18,760 --> 03:03:22,760
TRANSPORT TO THE DUODENUM FOR

4786
03:03:22,760 --> 03:03:23,720
ABSORPTION.

4787
03:03:23,720 --> 03:03:25,840
THE BLOOD COMING FROM THE PORTAL

4788
03:03:25,840 --> 03:03:27,480
VEIN AND HEPATIC ARTERIES ARE

4789
03:03:27,480 --> 03:03:31,640
MIXED WITHIN THE CIRCULATION.

4790
03:03:31,640 --> 03:03:33,720
THE HYDROSTATIC PRESSURE IN THE

4791
03:03:33,720 --> 03:03:35,320
CIRCULATION ALLOWS THE PLASMA

4792
03:03:35,320 --> 03:03:37,160
COMPONENT OF THE BLOOD FILTER

4793
03:03:37,160 --> 03:03:39,920
INTO THE SPACE OF -- WHICH IS

4794
03:03:39,920 --> 03:03:46,600
LOCATED BETWEEN THE HEPATOCYTE

4795
03:03:46,600 --> 03:03:49,120
AND THE SIGN SOY DAL AND

4796
03:03:49,120 --> 03:03:50,520
ENDOTHELIAL CELLS.

4797
03:03:50,520 --> 03:03:51,640
LIVER CIRRHOSIS SITUATION,

4798
03:03:51,640 --> 03:03:53,440
THERE'S INCREASING HYDROSTATIC

4799
03:03:53,440 --> 03:03:55,040
PRESSURE DUE TO THE MASSIVE

4800
03:03:55,040 --> 03:03:56,320
ACCUMULATION OF SCAR TISSUE

4801
03:03:56,320 --> 03:03:58,640
FORMATION OR FIBROSIS THAT

4802
03:03:58,640 --> 03:04:03,240
INCREASES THE PRODUCTION DCH.

4803
03:04:03,240 --> 03:04:07,280
NOT ONLY THE -- BUT ALSO

4804
03:04:07,280 --> 03:04:10,440
INFILTRATED IN CELLS --

4805
03:04:10,440 --> 03:04:11,760
PARTICULARLY IN THE PORTAL TRACT

4806
03:04:11,760 --> 03:04:12,960
AREA.

4807
03:04:12,960 --> 03:04:13,960
THEREFORE, THE LYMPHATIC SYSTEM

4808
03:04:13,960 --> 03:04:16,680
IN THE LIVER IS ALSO NOT ONLY

4809
03:04:16,680 --> 03:04:19,120
IMPORTANT FOR THE HOMEOSTASIS

4810
03:04:19,120 --> 03:04:23,000
BUT ALSO IMPORTANT FOR THE

4811
03:04:23,000 --> 03:04:23,920
DECREASING THE LOCAL

4812
03:04:23,920 --> 03:04:26,400
INFLAMMATION WITHIN THE LIVER.

4813
03:04:26,400 --> 03:04:27,760
APPROXIMATELY 80% OF THE LYMPH

4814
03:04:27,760 --> 03:04:29,840
PRODUCED WITHIN THE LIVER ARE

4815
03:04:29,840 --> 03:04:31,640
ACCOMMODATED BY THE PORTAL --

4816
03:04:31,640 --> 03:04:34,760
LYMPHATIC VESSEL IN -- AREA.

4817
03:04:34,760 --> 03:04:37,080
THIS DIAGRAM SHOWS THE THREE

4818
03:04:37,080 --> 03:04:40,680
DIMENSIONAL IMAGE OF LYMPHATIC

4819
03:04:40,680 --> 03:04:42,040
VESSELS WRAPPING AROUND THE

4820
03:04:42,040 --> 03:04:43,720
PORTAL VEIN AND HEPATIC

4821
03:04:43,720 --> 03:04:45,480
ARTERIES, AND BILE DUCT.

4822
03:04:45,480 --> 03:04:46,680
BECAUSE OF THE CLOSE VICINITY TO

4823
03:04:46,680 --> 03:04:49,200
THE BILE DUCT, LYMPHATIC VESSEL

4824
03:04:49,200 --> 03:04:57,840
ALSO SERVES AS THE SITE --

4825
03:04:57,840 --> 03:05:02,360
PARTICULARLY THE BILE DUCT.

4826
03:05:02,360 --> 03:05:08,200
THE  THEY'RE TRANSFERRED OUTSIDF

4827
03:05:08,200 --> 03:05:09,680
THE LIVER AND THEN FILTER

4828
03:05:09,680 --> 03:05:13,320
THROUGH THE REGIONAL -- HEPATIC

4829
03:05:13,320 --> 03:05:15,160
REGIONAL LYMPH NODE THEN MOVE TO

4830
03:05:15,160 --> 03:05:17,480
THE SYSTEM -- AND CONNECT TO THE

4831
03:05:17,480 --> 03:05:19,680
THORACIC DUCTS AND RETURN TO THE

4832
03:05:19,680 --> 03:05:22,960
SYSTEMIC CIRCULATION EVENTUALLY.

4833
03:05:22,960 --> 03:05:24,720
THERE ARE MULTIPLE STUDIES THAT

4834
03:05:24,720 --> 03:05:26,400
HAVE SHOWN THAT INCREASED

4835
03:05:26,400 --> 03:05:36,040
LYMPHATIC VESSEL NUMBERS OR LIM-

4836
03:05:36,040 --> 03:05:37,480
ASCITES, HYPERTENSION, SERIOUS

4837
03:05:37,480 --> 03:05:42,240
COMPLICATION OF CIRRHOSIS,

4838
03:05:42,240 --> 03:05:43,560
CANCERS, LIVER FIBROSIS WHICH

4839
03:05:43,560 --> 03:05:47,520
I'M GOING TO TALK LATER ON, AND

4840
03:05:47,520 --> 03:05:52,080
ISCHEMIA FACTORS OF INJURY,

4841
03:05:52,080 --> 03:05:53,760
HEPATIC ENCEPHALOPATHY, WHICH IS

4842
03:05:53,760 --> 03:05:54,800
THE SERIOUS COMPLICATION OF

4843
03:05:54,800 --> 03:05:58,640
LIVER DISEASES.

4844
03:05:58,640 --> 03:06:01,480
NOT ONLY TO INCREASE

4845
03:06:01,480 --> 03:06:02,360
ANGIOGENESIS BUT ALSO SEVERAL

4846
03:06:02,360 --> 03:06:07,960
STUDIES HAVE REPORTED THE

4847
03:06:07,960 --> 03:06:10,040
DECREASED -- IDENTITY AND

4848
03:06:10,040 --> 03:06:14,520
REDUCED LYMPH TRANSPORT IN --

4849
03:06:14,520 --> 03:06:16,160
OBSERVED IN THE PATHWAY TO

4850
03:06:16,160 --> 03:06:21,400
DISEASE, SHOWN VERY NICELY FROM

4851
03:06:21,400 --> 03:06:21,960
THE UNIVERSITY OF COLORADO.

4852
03:06:21,960 --> 03:06:24,760
THERE ARE A LOT TO BE ANSWERED

4853
03:06:24,760 --> 03:06:28,440
IN THE LIVER FIELD, FOR EXAMPLE,

4854
03:06:28,440 --> 03:06:29,440
WHAT ARE THE MOLECULAR

4855
03:06:29,440 --> 03:06:35,120
MECHANISMS OF INCREASED LYMPH

4856
03:06:35,120 --> 03:06:36,120
ANGIOGENESIS, WHAT ARE THE

4857
03:06:36,120 --> 03:06:37,360
FUNCTIONAL ROLES OF HEPATIC

4858
03:06:37,360 --> 03:06:40,240
LYMPHATIC VESSELS IN DIFFERENT

4859
03:06:40,240 --> 03:06:41,600
ETIOLOGIES OF LIVER DISEASES,

4860
03:06:41,600 --> 03:06:44,240
WHETHER INCREASED LYMPH

4861
03:06:44,240 --> 03:06:45,960
ANGIOGENESIS IS BENEFICIAL OR

4862
03:06:45,960 --> 03:06:47,920
HAS INCREASED CONSEQUENCES.

4863
03:06:47,920 --> 03:06:49,800
I'D LIKE TO SHOW YOU A PROJECT

4864
03:06:49,800 --> 03:06:52,880
WHICH SHOWS THE EFFECT OF --

4865
03:06:52,880 --> 03:06:55,320
HEPATIC VESSELS IN LIVER

4866
03:06:55,320 --> 03:06:56,080
FIBROSIS.

4867
03:06:56,080 --> 03:06:58,240
THIS PROJECT WAS MOSTLY DONE BY

4868
03:06:58,240 --> 03:07:00,640
A VERY TALENTED AND HARD WORKING

4869
03:07:00,640 --> 03:07:04,680
POSTDOC, JAIN JEONG.

4870
03:07:04,680 --> 03:07:06,680
INFLAMMATION DRIVES LIVER

4871
03:07:06,680 --> 03:07:09,840
FIBROSIS, CHRONIC INFLAMMATION

4872
03:07:09,840 --> 03:07:18,360
FROM CHRONIC ALCOHOL

4873
03:07:18,360 --> 03:07:20,680
CONSUMPTION, HCV OR HBV, DRUGS

4874
03:07:20,680 --> 03:07:25,720
AND DIETS, CAUSING CIRRHOSIS,

4875
03:07:25,720 --> 03:07:26,720
CARCINOGENESIS AND PORTAL

4876
03:07:26,720 --> 03:07:27,440
HYPERTENSION.

4877
03:07:27,440 --> 03:07:29,000
BECAUSE THE LYMPHATIC SYSTEM IS

4878
03:07:29,000 --> 03:07:31,560
IMPORTANT FOR REDUCING THE LOCAL

4879
03:07:31,560 --> 03:07:33,160
INFLAMMATORY RESPONSES, WE

4880
03:07:33,160 --> 03:07:35,760
THOUGHT THAT PERHAPS LYMPHATIC

4881
03:07:35,760 --> 03:07:39,520
SYSTEM PLAYS A ROLE FOR REDUCING

4882
03:07:39,520 --> 03:07:40,080
LIVER FIBROSIS.

4883
03:07:40,080 --> 03:07:43,360
TO STUDY THIS, WE USED TWO TYPES

4884
03:07:43,360 --> 03:07:45,080
OF EXPERIMENTAL MODEL OF LIVER

4885
03:07:45,080 --> 03:07:46,080
FIBROSUS.

4886
03:07:46,080 --> 03:07:47,960
ONE IS BILE DUCT LIGATION MODELS

4887
03:07:47,960 --> 03:07:53,520
AND THE OTHER IS THE CARBON

4888
03:07:53,520 --> 03:07:54,720
TETRACHLORIDE INHALATION MODEL.

4889
03:07:54,720 --> 03:07:56,280
BECAUSE OF THE TIME LIMIT I'M

4890
03:07:56,280 --> 03:07:59,120
GOING TO SHOW YOU SOME OF THE

4891
03:07:59,120 --> 03:08:00,560
DATA RELATED TO THE BILE DUCT

4892
03:08:00,560 --> 03:08:01,720
LIGATION OR BDL.

4893
03:08:01,720 --> 03:08:05,000
SO IN THIS MODEL WE LIGATE THE

4894
03:08:05,000 --> 03:08:09,320
BILE DUCT WHICH CAUSES THE --

4895
03:08:09,320 --> 03:08:11,960
INDUCES MASSIVE INFLAMMATION AND

4896
03:08:11,960 --> 03:08:14,000
LEADING TO INJURY AND FIBROSIS.

4897
03:08:14,000 --> 03:08:21,480
FIRST WE DETERMINE THE EVOLUTION

4898
03:08:21,480 --> 03:08:22,240
OF -- BDL.

4899
03:08:22,240 --> 03:08:25,080
AS YOU CAN SEE HERE, THE SERUM

4900
03:08:25,080 --> 03:08:26,760
ALT WHICH IS USED AS THE

4901
03:08:26,760 --> 03:08:28,960
INDICATOR OF LIVER FIBROSIS WAS

4902
03:08:28,960 --> 03:08:33,680
INCREASED UP TO TWO WEEKS AND IT

4903
03:08:33,680 --> 03:08:34,680
STAYS FOUR WEEKS AFTER.

4904
03:08:34,680 --> 03:08:37,320
ACTUALLY BY TWO WEEKS BILE DUCT

4905
03:08:37,320 --> 03:08:38,720
LIGATION, THOSE ANIMALS BECOME

4906
03:08:38,720 --> 03:08:39,520
VERY, VERY SICK.

4907
03:08:39,520 --> 03:08:42,440
IN THE LIVER FIBROSIS, YOU CAN

4908
03:08:42,440 --> 03:08:44,200
SEE HERE THERE'S INCREASE IN THE

4909
03:08:44,200 --> 03:08:45,520
FIBROSIS BY FOUR WEEKS AFTER THE

4910
03:08:45,520 --> 03:08:47,600
BILE DUCT LIGATION IN A

4911
03:08:47,600 --> 03:08:52,800
TIME-DEPENDENT MODEL.

4912
03:08:52,800 --> 03:08:54,000
LYMPHATIC VESSELS, SO HERE LEFT

4913
03:08:54,000 --> 03:08:57,680
SIDE SHOWS THE LYMPHATIC VESSELS

4914
03:08:57,680 --> 03:09:00,000
AROUND THE -- AREA OF THE SHAM

4915
03:09:00,000 --> 03:09:01,480
ANIMALS AND THE RIGHT SIDE SHOWS

4916
03:09:01,480 --> 03:09:03,000
THE BILE DUCT LIGATED ANIMALS.

4917
03:09:03,000 --> 03:09:05,560
RED SHOWS THE HEPATIC VESSELS.

4918
03:09:05,560 --> 03:09:08,040
AS YOU CAN SEE HERE IN BILE DUCT

4919
03:09:08,040 --> 03:09:09,320
LIGATION MODEL, THERE'S

4920
03:09:09,320 --> 03:09:11,200
SIGNIFICANT INDUCTION OF

4921
03:09:11,200 --> 03:09:12,680
LYMPHATIC VESSELS AROUND THE

4922
03:09:12,680 --> 03:09:14,160
PORTAL TRACT AREA AND THEY ARE

4923
03:09:14,160 --> 03:09:15,720
MAXIMALLY DILATED AS WELL TOO.

4924
03:09:15,720 --> 03:09:18,600
ALTHOUGH YOU CAN SEE THERE'S SO

4925
03:09:18,600 --> 03:09:19,600
MANY LYMPHATIC VESSELS GROWING

4926
03:09:19,600 --> 03:09:20,880
AROUND THE PORTAL TRACT AREA,

4927
03:09:20,880 --> 03:09:23,600
BUT THEY ARE NOT REALLY

4928
03:09:23,600 --> 03:09:24,560
RECOGNIZED, WHAT YOU CAN NOTICE

4929
03:09:24,560 --> 03:09:27,920
IN THE LIVER FIELD, BECAUSE

4930
03:09:27,920 --> 03:09:31,280
UNLESS YOU STAY WITH THE LYMPH

4931
03:09:31,280 --> 03:09:34,040
ENDOTHELIUM MARKER YOU CANNOT

4932
03:09:34,040 --> 03:09:35,280
ORGANIZE BECAUSE THEY ARE A VERY

4933
03:09:35,280 --> 03:09:36,240
THIN LAYER OF THE VESSELS.

4934
03:09:36,240 --> 03:09:40,320
WE THEN LOOKED AT THE LYMPHATIC

4935
03:09:40,320 --> 03:09:42,800
VESSEL NUMBERS IN THE DIFFERENT

4936
03:09:42,800 --> 03:09:44,560
STAGE OF FIBROSIS.

4937
03:09:44,560 --> 03:09:48,560
ALONG WITH THE BILE DUCT

4938
03:09:48,560 --> 03:09:51,360
PROLIFERATION.

4939
03:09:51,360 --> 03:09:52,800
PERFORATION.

4940
03:09:52,800 --> 03:09:55,880
SO WE NO IT'S INCREASING BECAUSE

4941
03:09:55,880 --> 03:09:58,040
OF -- BILE DUCT SHOWN IN GREEN,

4942
03:09:58,040 --> 03:09:59,840
LYMPHATIC VESSEL SHOWN IN RED.

4943
03:09:59,840 --> 03:10:02,880
BILE DUCT INCREASES ITS

4944
03:10:02,880 --> 03:10:04,000
PROLIFERATION EVEN AT FOUR WEEKS

4945
03:10:04,000 --> 03:10:08,800
AFTER THE BILE DUCT LIGATION.

4946
03:10:08,800 --> 03:10:11,680
HOWEVER, THE LYMPH VESSEL ALSO

4947
03:10:11,680 --> 03:10:12,760
BEGIN MAXIMUM ABOUT TWO WEEKS

4948
03:10:12,760 --> 03:10:15,400
AFTER THE BILE DUCT LIGATION,

4949
03:10:15,400 --> 03:10:16,520
HOWEVER, SIGNIFICANTLY DROPPED

4950
03:10:16,520 --> 03:10:17,640
BY FOUR WEEKS AFTER THE BILE

4951
03:10:17,640 --> 03:10:20,360
DUCT LIGATION, SO WE THOUGHT

4952
03:10:20,360 --> 03:10:23,840
THAT PERHAPS THIS SIGNIFICANT

4953
03:10:23,840 --> 03:10:26,160
DROP IN THE LYMPH VESSEL NUMBERS

4954
03:10:26,160 --> 03:10:28,120
ALLOW THE FIBROSIS TO PROGRESS

4955
03:10:28,120 --> 03:10:30,600
FARTHER TO CIRRHOSIS.

4956
03:10:30,600 --> 03:10:31,280
ALTHOUGH UNTIL TWO WEEKS AFTER

4957
03:10:31,280 --> 03:10:35,680
THE BILE DUCT LIGATION, THE

4958
03:10:35,680 --> 03:10:37,040
VESSEL TRIES TO PROTECT THE

4959
03:10:37,040 --> 03:10:37,880
LIVER FROM FIBROSIS.

4960
03:10:37,880 --> 03:10:42,200
SO TO TEST THIS, WE LOOKED AT

4961
03:10:42,200 --> 03:10:45,480
THE EFFECT OF LYMPH

4962
03:10:45,480 --> 03:10:46,800
ANGIOGENESIS -- EXPANSION OF

4963
03:10:46,800 --> 03:10:48,840
LIVER FIBROSIS.

4964
03:10:48,840 --> 03:10:57,600
FOR THAT, WE GAVE THE VEGF

4965
03:10:57,600 --> 03:10:58,720
3 RECEPTOR AND LOOKED AT THE

4966
03:10:58,720 --> 03:11:00,120
EFFECT ON LIVER FIBROSIS.

4967
03:11:00,120 --> 03:11:10,640
AS WE EXPECTED -- IN FIBROSIS

4968
03:11:10,640 --> 03:11:14,400
THERE'S SIGNIFICANT INDUCTION --

4969
03:11:14,400 --> 03:11:17,760
AS A RESULT OF BLOCKING LYMPH

4970
03:11:17,760 --> 03:11:18,200
ANGIOGENESIS.

4971
03:11:18,200 --> 03:11:21,280
AND LIVER INJURY SIGNIFICANTLY

4972
03:11:21,280 --> 03:11:23,920
INCREASED BY THE BLOCKING OF THE

4973
03:11:23,920 --> 03:11:26,560
VEGF RECEPTOR 3, AND DRAINAGE

4974
03:11:26,560 --> 03:11:29,720
FUNCTION ALSO DECREASED

4975
03:11:29,720 --> 03:11:34,200
SIGNIFICANTLY BY GIVING THE VEGF

4976
03:11:34,200 --> 03:11:35,760
3 INHIBITOR.

4977
03:11:35,760 --> 03:11:40,040
WHAT ABOUT VEGF C -- WHAT ABOUT

4978
03:11:40,040 --> 03:11:43,840
THE EFFECT OF VEGF3 EXPRESSION

4979
03:11:43,840 --> 03:11:45,920
BY FIBROSIS?

4980
03:11:45,920 --> 03:11:48,480
WE LOOKED AT THE EFFECT ON LIVER

4981
03:11:48,480 --> 03:11:48,720
FIBROSIS.

4982
03:11:48,720 --> 03:11:54,920
AS YOU CAN SEE HERE, BY

4983
03:11:54,920 --> 03:11:56,720
EXPRESSION, YOU SIGNIFICANTLY

4984
03:11:56,720 --> 03:11:58,120
DECREASED LIVER FIBROSIS AND

4985
03:11:58,120 --> 03:11:59,800
ALSO DECREASED THE LIVER INJURY,

4986
03:11:59,800 --> 03:12:03,960
INDICATING THAT THE VEGF-C

4987
03:12:03,960 --> 03:12:05,600
OVEREXPRESSION AND LYMPH

4988
03:12:05,600 --> 03:12:06,800
ANGIOGENESIS DECREASES LIVER

4989
03:12:06,800 --> 03:12:07,800
FIBROSIS AND INJURY.

4990
03:12:07,800 --> 03:12:10,080
WE ALSO LOOK AT WHAT IS THE

4991
03:12:10,080 --> 03:12:12,080
FUNCTIONAL CHANGES OF THE

4992
03:12:12,080 --> 03:12:13,520
HEPATIC ENDOTHELIAL CELLS IN

4993
03:12:13,520 --> 03:12:16,040
DIFFERENT STAGE OF A BILIARY

4994
03:12:16,040 --> 03:12:16,440
FIBROSIS?

4995
03:12:16,440 --> 03:12:20,240
SO WE ISOLATED ENDOTHELIAL CELLS

4996
03:12:20,240 --> 03:12:22,400
FROM THIS CHANNEL AND THEN

4997
03:12:22,400 --> 03:12:24,280
PERFORMED RNA SEQUENCING

4998
03:12:24,280 --> 03:12:25,120
ANALYSIS.

4999
03:12:25,120 --> 03:12:26,720
TO HIGHLIGHT THE MOST IMPORTANT

5000
03:12:26,720 --> 03:12:28,560
FINDING FROM THIS PATHWAY

5001
03:12:28,560 --> 03:12:29,520
ANALYSIS, IS THAT IN FOUR WEEKS

5002
03:12:29,520 --> 03:12:30,960
AFTER THE BILE DUCT LIGATION,

5003
03:12:30,960 --> 03:12:33,520
THERE WAS A SIGNIFICANT

5004
03:12:33,520 --> 03:12:36,120
INDUCTION OF THE COAGULATION OR

5005
03:12:36,120 --> 03:12:37,440
THROMBOTIC PATHWAY AND WE

5006
03:12:37,440 --> 03:12:42,680
CONFIRMED THIS BY STAINING THE

5007
03:12:42,680 --> 03:12:46,200
FIBRINOGEN IN THE LIVER, AS YOU

5008
03:12:46,200 --> 03:12:50,120
CAN SEE THERE'S -- FIBRIN SIN.

5009
03:12:50,120 --> 03:12:52,120
THIS INCREASED THROMBOTIC

5010
03:12:52,120 --> 03:12:55,720
RESPONSE MAY ACTUALLY BLOCK THE

5011
03:12:55,720 --> 03:13:00,960
HEPATIC DRAINAGE BY -- FOR THE

5012
03:13:00,960 --> 03:13:01,640
LIGATED ANIMALS.

5013
03:13:01,640 --> 03:13:09,320
JUST TO CONCLUDE, LYMPH

5014
03:13:09,320 --> 03:13:10,520
ANGIOGENESIS -- I WOULD LIKE TO

5015
03:13:10,520 --> 03:13:12,720
CONCLUDE WITH THE KNOWLEDGE GAP,

5016
03:13:12,720 --> 03:13:14,680
NEEDS AND OPPORTUNITIES FOR THE

5017
03:13:14,680 --> 03:13:17,080
STUDY OF DISEASES AND ITS

5018
03:13:17,080 --> 03:13:18,360
COMPLICATIONS.

5019
03:13:18,360 --> 03:13:20,040
FIRST IDENTIFICATION OF

5020
03:13:20,040 --> 03:13:21,800
ENDOTHELIAL MARKERS NOT

5021
03:13:21,800 --> 03:13:23,080
EXPRESSING OTHER LIVER CELL

5022
03:13:23,080 --> 03:13:25,080
TYPES IS URGENTLY NEEDED.

5023
03:13:25,080 --> 03:13:26,400
MECHANISMS OF LYMPH ANGIOGENESIS

5024
03:13:26,400 --> 03:13:27,840
IN THE LIVER ARE NOT FULLY

5025
03:13:27,840 --> 03:13:28,680
UNDERSTOOD.

5026
03:13:28,680 --> 03:13:30,360
ROLE OF LYMPHATIC SYSTEM IN

5027
03:13:30,360 --> 03:13:32,000
DIFFERENT ETIOLOGIES OF LIVER

5028
03:13:32,000 --> 03:13:32,960
DISEASES REMAIN TO BE

5029
03:13:32,960 --> 03:13:33,520
UNDERSTOOD.

5030
03:13:33,520 --> 03:13:36,200
FINALLY, MODULATION OF HEPATIC

5031
03:13:36,200 --> 03:13:37,400
LYMPHATIC SYSTEM COULD BE THE

5032
03:13:37,400 --> 03:13:38,480
NOVEL THERAPEUTIC STRATEGIES FOR

5033
03:13:38,480 --> 03:13:39,920
THE TREAT M OF LIVER DISEASES

5034
03:13:39,920 --> 03:13:41,000
AND ITS COMPLICATION.

5035
03:13:41,000 --> 03:13:43,120
I WOULD LIKE TO THANK ALL THE

5036
03:13:43,120 --> 03:13:45,720
PEOPLE WHO CONTRIBUTED TO THE

5037
03:13:45,720 --> 03:13:53,640
STUDY, PARTICULARLY JAIN AND

5038
03:13:53,640 --> 03:13:56,240
YILIN, AND NIH AND NIDDK FOR

5039
03:13:56,240 --> 03:13:56,760
SUPPORTING THIS PROJECT.

5040
03:13:56,760 --> 03:13:57,840
THANK YOU VERY MUCH FOR YOUR

5041
03:13:57,840 --> 03:14:00,120
ATTENTION.

5042
03:14:00,120 --> 03:14:01,640
I WOULD LIKE TO MOVE TO THE NEXT

5043
03:14:01,640 --> 03:14:05,000
SPEAKER.

5044
03:14:05,000 --> 03:14:07,440
DR. NADA ABUMRAD.

5045
03:14:07,440 --> 03:14:08,520
FROM WASHINGTON UNIVERSITY

5046
03:14:08,520 --> 03:14:10,160
SCHOOL OF MEDICINE.

5047
03:14:10,160 --> 03:14:12,880
HER TALK IS ENTITLED MAINTENANCE

5048
03:14:12,880 --> 03:14:16,560
OF LYMPHATIC VESSELS PREVENTS

5049
03:14:16,560 --> 03:14:18,400
LYMPH LEAKAGE AND OBESITY.

5050
03:14:18,400 --> 03:14:21,600
NADA, PLEASE GO AHEAD.

5051
03:14:21,600 --> 03:14:25,960
SO WHAT I'M GOING TO BE TALKING

5052
03:14:25,960 --> 03:14:27,720
ABOUT TODAY IS HOPEFULLY

5053
03:14:27,720 --> 03:14:29,200
RELEVANT TO SEVERAL OF THE TALKS

5054
03:14:29,200 --> 03:14:30,600
THAT I'VE LISTENED TO.

5055
03:14:30,600 --> 03:14:34,280
IT'S BEEN A GREAT MEETING SO

5056
03:14:34,280 --> 03:14:38,680
FAR, AND I THANK YOU FOR

5057
03:14:38,680 --> 03:14:40,120
INCLUDING ME IN THIS MEETING.

5058
03:14:40,120 --> 03:14:41,760
AND I HOPE THAT WE'LL BE ABLE TO

5059
03:14:41,760 --> 03:14:43,440
GET AN INTERESTING DISCUSSION AT

5060
03:14:43,440 --> 03:14:47,160
THE END OF THE SESSION.

5061
03:14:47,160 --> 03:14:50,440
THAT'S WHAT I HAD IN MIND WITH

5062
03:14:50,440 --> 03:14:51,200
THESE SLIDES.

5063
03:14:51,200 --> 03:14:55,160
SO WE'VE COVERED THE OLYMPICS,

5064
03:14:55,160 --> 03:14:56,520
WE'VE HAD SEVERAL INTRODUCTIONS

5065
03:14:56,520 --> 03:15:00,320
SO I AM NOT GOING TO COVER THEM.

5066
03:15:00,320 --> 03:15:01,360
EXCEPT TO MENTION THAT WE HAVE

5067
03:15:01,360 --> 03:15:03,920
TO REMEMBER THAT THEIR MAIN

5068
03:15:03,920 --> 03:15:10,960
FUNCTION IS BASICALLY TO PASS

5069
03:15:10,960 --> 03:15:12,840
THE LIPIDS, THESE GO TO TISSUES

5070
03:15:12,840 --> 03:15:14,440
WHERE THEY ARE BROKEN DOWN TO

5071
03:15:14,440 --> 03:15:18,600
FATTY ACIDS THAT ARE TAKEN UP BY

5072
03:15:18,600 --> 03:15:24,240
THE TISSUES AND METABOLIZED AND

5073
03:15:24,240 --> 03:15:25,440
USED FOR MAINTAINING HEALTH OF

5074
03:15:25,440 --> 03:15:29,080
THE TISSUE AND ITS RENEWAL.

5075
03:15:29,080 --> 03:15:33,960
HOWEVER, THEY ALSO CAN BECOME

5076
03:15:33,960 --> 03:15:36,600
TOXIC IF THEY ARE IN GREAT

5077
03:15:36,600 --> 03:15:42,240
CONCENTRATION AND NOT PROPERLY

5078
03:15:42,240 --> 03:15:42,560
USED.

5079
03:15:42,560 --> 03:15:44,200
SO I WILL SKIP THIS, ACTUALLY

5080
03:15:44,200 --> 03:15:45,400
I'LL MENTION IT BRIEFLY.

5081
03:15:45,400 --> 03:15:51,120
IT'S THAT WHAT WE KNOW ABOUT HOW

5082
03:15:51,120 --> 03:15:52,440
ABSORPTION IS REGULATED BY THE

5083
03:15:52,440 --> 03:15:56,920
LYMPHATICS IS THAT IF YOU IMPAIR

5084
03:15:56,920 --> 03:16:00,720
THE LACTEALS BY DIFFERENT

5085
03:16:00,720 --> 03:16:02,200
DEVELOPMENTAL MANIPULATION GENES

5086
03:16:02,200 --> 03:16:04,160
THAT ARE -- MANIPULATING GENES

5087
03:16:04,160 --> 03:16:05,360
THAT ARE INVOLVED IN

5088
03:16:05,360 --> 03:16:09,120
DEVELOPMENT, YOU CAN BLOCK LIPID

5089
03:16:09,120 --> 03:16:11,320
UPTAKE, AND THIS IS

5090
03:16:11,320 --> 03:16:15,040
METABOLICALLY PROTECTED.

5091
03:16:15,040 --> 03:16:20,440
THE SAME IS IF YOU ZIPPER THE

5092
03:16:20,440 --> 03:16:21,040
LACTEAL, THE JUNCTION THAT JOSH

5093
03:16:21,040 --> 03:16:23,640
WAS TALKING ABOUT, THE BUTTONS,

5094
03:16:23,640 --> 03:16:32,600
IF YOU ZIPPER THEM, THIS IS

5095
03:16:32,600 --> 03:16:35,000
WORK -- HOWEVER IF YOU EMBED THE

5096
03:16:35,000 --> 03:16:36,520
TRANSPORT BY -- YOU IMPAIR THE

5097
03:16:36,520 --> 03:16:41,680
TRANSPORT BY CREATING

5098
03:16:41,680 --> 03:16:47,400
DYSFUNCTION IN THE FUNCTION OF

5099
03:16:47,400 --> 03:16:48,560
THESE -- ESPECIALLY IF YOU HAVE

5100
03:16:48,560 --> 03:16:49,240
THE JUNCTIONS BETWEEN THE CELLS

5101
03:16:49,240 --> 03:16:54,440
AND YOU HAVE LEAKAGE, THIS

5102
03:16:54,440 --> 03:16:55,840
CREATES A RISK OF OBESITY

5103
03:16:55,840 --> 03:16:57,280
BECAUSE IT CAN CONTRIBUTE TO

5104
03:16:57,280 --> 03:16:58,960
VISCERAL OBESITY AND RISK OF

5105
03:16:58,960 --> 03:17:03,880
TYPE 2 DIABETES.

5106
03:17:03,880 --> 03:17:05,360
SO THE PROTEIN I'M GOING TO TALK

5107
03:17:05,360 --> 03:17:08,040
ABOUT IS CD36, WHICH IS A FATTY

5108
03:17:08,040 --> 03:17:10,440
ACID TRANSPORTER, IT DOESN'T

5109
03:17:10,440 --> 03:17:14,040
ONLY TRANSFER FATTY ACID BUT IT

5110
03:17:14,040 --> 03:17:15,640
ALSO TRANSPORTS SOME

5111
03:17:15,640 --> 03:17:18,600
LIPOPROTEINS AND VARIETY OF

5112
03:17:18,600 --> 03:17:19,000
NON-LIPID LIGANDS.

5113
03:17:19,000 --> 03:17:20,120
THE IMPORTANT THING ABOUT THIS

5114
03:17:20,120 --> 03:17:23,840
PROTEIN IS THAT IT SIGNALS, IT

5115
03:17:23,840 --> 03:17:30,320
ASSOCIATES WITH MULTIPLE KINASES

5116
03:17:30,320 --> 03:17:33,080
BUT BECAUSE SITE ASSOCIATION --

5117
03:17:33,080 --> 03:17:36,360
RPS THROUGH ITS CYTOPLASMIC

5118
03:17:36,360 --> 03:17:43,080
DOMAIN, AND THE STRUCTURE      L

5119
03:17:43,080 --> 03:17:47,560
STRUCTURE WAS IDENTIFIED AND WE

5120
03:17:47,560 --> 03:17:49,200
HAVE IDENTIFIED IT AS A FATTY

5121
03:17:49,200 --> 03:17:50,760
ACID TRANSPORTER, AND THEY FOUND

5122
03:17:50,760 --> 03:17:55,120
THE FATTY ACID IN THIS INTERNAL

5123
03:17:55,120 --> 03:17:57,240
TUNNEL WITHIN THE PROTEIN.

5124
03:17:57,240 --> 03:18:02,200
THE FAMILY OF PROTEIN, THE CD36

5125
03:18:02,200 --> 03:18:10,720
FAMILY OF PROTEIN WHICH    ALL S

5126
03:18:10,720 --> 03:18:11,800
CHANNEL INSIDE THE PROTEIN FOR

5127
03:18:11,800 --> 03:18:15,200
TRANSPORTING THE LIPID TO THE

5128
03:18:15,200 --> 03:18:16,440
BILAYER.

5129
03:18:16,440 --> 03:18:17,840
ANOTHER THING THAT IS IMPORTANT

5130
03:18:17,840 --> 03:18:20,240
ABOUT THIS PROTEIN IS THAT IT

5131
03:18:20,240 --> 03:18:22,440
CONNECTS TO THE CYTOSKELETON, SO

5132
03:18:22,440 --> 03:18:27,520
IT CAN CREATE SIGNALING THAT AT

5133
03:18:27,520 --> 03:18:28,480
THE SAME TIME INFLUENCES

5134
03:18:28,480 --> 03:18:32,560
MORPHOLOGY OF THE CELL,

5135
03:18:32,560 --> 03:18:36,400
INFLUENCES MIGRATION OF CELLS,

5136
03:18:36,400 --> 03:18:39,160
AND SECRETION, ET CETERA.

5137
03:18:39,160 --> 03:18:41,120
SO IT DOESN'T ONLY TRANSFER

5138
03:18:41,120 --> 03:18:42,640
LIPIDS, IN PARTICULAR, FATTY

5139
03:18:42,640 --> 03:18:44,520
ACID, IT HAS A BUNCH OF

5140
03:18:44,520 --> 03:18:45,440
ACTIVITIES THAT MAKE IT

5141
03:18:45,440 --> 03:18:54,600
COMPLICATED, BUT INTERESTING.

5142
03:18:54,600 --> 03:18:55,920
SO THE THING THAT MOTIVATES ME

5143
03:18:55,920 --> 03:18:57,560
IN STICKING WITH THIS PROTEIN IS

5144
03:18:57,560 --> 03:19:01,560
THAT IT'S HIGHLY POLYMORPHIC.

5145
03:19:01,560 --> 03:19:05,640
THE DEFICIENCY OCCURS IN 3% OF

5146
03:19:05,640 --> 03:19:09,680
ASIANS OR AFRICAN AMERICANS, AND

5147
03:19:09,680 --> 03:19:10,800
HERE IS SHOWING YOU A PERSON WHO

5148
03:19:10,800 --> 03:19:13,000
IS DEFICIENT IN CD36 AND YOU

5149
03:19:13,000 --> 03:19:14,200
FIND THAT FATTY ACID UPTAKE,

5150
03:19:14,200 --> 03:19:20,560
WHICH IS HERE, IT'S ASSESSED BY

5151
03:19:20,560 --> 03:19:22,800
PET SCANNING, YOU FIND THAT IT

5152
03:19:22,800 --> 03:19:28,600
IS ABSENT IN THE HEART OF THIS

5153
03:19:28,600 --> 03:19:32,920
PERSON THAT IS VERY -- WE HAVE

5154
03:19:32,920 --> 03:19:41,240
SHOWN THIS IN MICE AND THEN IT

5155
03:19:41,240 --> 03:19:43,040
WAS -- THIS IS WORK OF A GROUP

5156
03:19:43,040 --> 03:19:45,840
IN JAPAN AND ANOTHER GROUP AT

5157
03:19:45,840 --> 03:19:47,400
THE MAYO CLINIC BASICALLY SHOWED

5158
03:19:47,400 --> 03:19:50,160
THAT IT DOES FUNCTION IN UPTAKE

5159
03:19:50,160 --> 03:19:51,720
AND ESPECIALLY IN THE HEART

5160
03:19:51,720 --> 03:19:53,240
MUSCLE AND ADIPOSE TISSUE BUT

5161
03:19:53,240 --> 03:19:58,640
ALSO IN IMMUNE CELLS, AND IT'S

5162
03:19:58,640 --> 03:19:59,400
RELEVANT TO -- I WILL SHOW YOU

5163
03:19:59,400 --> 03:20:03,360
THE LYMPHATICS.

5164
03:20:03,360 --> 03:20:04,800
SO WE MADE THE OBSERVATION A

5165
03:20:04,800 --> 03:20:08,760
WHILE BACK THAT WHEN WE HAD

5166
03:20:08,760 --> 03:20:13,360
CD36-DEFICIENT MICE IN

5167
03:20:13,360 --> 03:20:18,400
COLLABORATION WITH PATRICK TSO,

5168
03:20:18,400 --> 03:20:20,920
HE HAS DEVELOPED THE

5169
03:20:20,920 --> 03:20:24,520
METHODOLOGY, WHO CANNULATE THE

5170
03:20:24,520 --> 03:20:25,200
MISS ENTERIC LYMPHATIC DUCTS AND

5171
03:20:25,200 --> 03:20:27,200
THE DISTRICT IS TO CANNULATE IT

5172
03:20:27,200 --> 03:20:28,080
OPPOSITE TO THE FLOW OF THE

5173
03:20:28,080 --> 03:20:29,160
LYMPH SO YOU CAN COLLECT THE

5174
03:20:29,160 --> 03:20:36,280
LYMPH AS YOU ARE -- SO WHAT WE

5175
03:20:36,280 --> 03:20:38,720
LEARNED IS THE CD36 DEFICIENT

5176
03:20:38,720 --> 03:20:40,680
MICE DO NOT PASS THE LIPID WELL

5177
03:20:40,680 --> 03:20:42,560
INTO THE LYMPH, BECAUSE THE

5178
03:20:42,560 --> 03:20:48,160
LYMPH HE WAS COLLECTING WAS LOW

5179
03:20:48,160 --> 03:20:50,040
IN TRIGLYCERIDE AND LOW IN

5180
03:20:50,040 --> 03:20:50,880
CHOLESTEROL.

5181
03:20:50,880 --> 03:20:52,280
INTERESTINGLY, IF WE FOLLOW THE

5182
03:20:52,280 --> 03:20:56,040
ABSORPTION OF LIPID IN THE

5183
03:20:56,040 --> 03:20:59,320
BLOOD, YOU SEE THAT THE

5184
03:20:59,320 --> 03:21:01,360
CD36-DEFICIENT MOUSE HAS THE

5185
03:21:01,360 --> 03:21:02,960
TRIGLYCERIDES APPEARING VERY

5186
03:21:02,960 --> 03:21:04,160
QUICKLY IN THE BLOOD, SO I KNOW

5187
03:21:04,160 --> 03:21:08,320
WE MENTIONED -- ONE OF THE

5188
03:21:08,320 --> 03:21:09,160
SPEAKERS MENTIONED EARLIER IS

5189
03:21:09,160 --> 03:21:13,480
THAT THERE ARE TWO WAYS FOR THE

5190
03:21:13,480 --> 03:21:14,600
LIPIDS TO GO INTO THE

5191
03:21:14,600 --> 03:21:15,560
CIRCULATION FROM THE GUT.

5192
03:21:15,560 --> 03:21:17,040
THEY EITHER GO VIA LIMB FA AT

5193
03:21:17,040 --> 03:21:19,760
THIS TIME            LYMPHATICSR

5194
03:21:19,760 --> 03:21:21,600
THEY CAN, UNDER CERTAIN

5195
03:21:21,600 --> 03:21:22,600
CIRCUMSTANCES, GO DIRECTLY TO

5196
03:21:22,600 --> 03:21:27,240
THE PORTAL VEIN, SO WE SEE IN

5197
03:21:27,240 --> 03:21:31,160
THE CD36 KO MOUSE, THE LIPIDS

5198
03:21:31,160 --> 03:21:33,360
ARE IMPAIRED AND INABILITY TO

5199
03:21:33,360 --> 03:21:35,120
ENTER THE LYMPH AND END UP

5200
03:21:35,120 --> 03:21:36,240
QUICKLY IN THE CIRCULATION.

5201
03:21:36,240 --> 03:21:43,680
NOW THESE LIPIDS ARE A LITTLE

5202
03:21:43,680 --> 03:21:44,800
DIFFERENT BECAUSE THERE IS A

5203
03:21:44,800 --> 03:21:47,880
DEFECT IN MAKING THEM, THEY ARE

5204
03:21:47,880 --> 03:21:49,480
SMALLER, AND WHAT WE SEE IS THAT

5205
03:21:49,480 --> 03:21:51,240
CLEARANCE IS ALSO A LITTLE BIT

5206
03:21:51,240 --> 03:21:53,840
DELAYED.

5207
03:21:53,840 --> 03:21:56,320
BUT THAT'S THE LYMPH -- THAT'S

5208
03:21:56,320 --> 03:21:59,080
THE LYMPH PHENOTYPE OF CD36

5209
03:21:59,080 --> 03:22:02,040
DEFICIENT MOUSE.

5210
03:22:02,040 --> 03:22:02,920
SO THAT OBSERVATION WE FORGOT

5211
03:22:02,920 --> 03:22:04,680
ABOUT IT FOR A WHILE UNTIL WE

5212
03:22:04,680 --> 03:22:08,600
GOT INTERESTED AGAIN IN THE

5213
03:22:08,600 --> 03:22:08,920
ENDOTHELIUM.

5214
03:22:08,920 --> 03:22:14,360
THERE WERE A LUNCH OF PAPERS   ,

5215
03:22:14,360 --> 03:22:16,040
I'M TALKING HERE ABOUT THE

5216
03:22:16,040 --> 03:22:20,520
VASCULAR ENDOTHELIUM, THE BLOOD

5217
03:22:20,520 --> 03:22:23,040
VESSELS, IS IMPORTANT FOR

5218
03:22:23,040 --> 03:22:25,960
REGULATING UPTAKE OF LIPIDS BY

5219
03:22:25,960 --> 03:22:27,200
TISSUES IE. SHOWING YOU HERE

5220
03:22:27,200 --> 03:22:28,360
THERE ARE TWO WAYS THAT LIPID

5221
03:22:28,360 --> 03:22:31,040
CAN GET INTO THE BLOOD BY

5222
03:22:31,040 --> 03:22:32,840
SECRETION OF FATTY ACID -- BY

5223
03:22:32,840 --> 03:22:37,440
FAT CELLS OR BY THE LYMPHATICS

5224
03:22:37,440 --> 03:22:41,720
EMPTYING INTO THE CIRCULATION.

5225
03:22:41,720 --> 03:22:43,280
THEN IN THE CASE OF THE

5226
03:22:43,280 --> 03:22:46,680
LYMPHATICS, THEY HAVE TO BE

5227
03:22:46,680 --> 03:22:50,720
PROCESSED BY LIPOPROTEIN -- TO

5228
03:22:50,720 --> 03:22:52,760
UNDERLYING TISSUES AND POSSIBLY

5229
03:22:52,760 --> 03:22:58,760
OTHER RECEPTORS.

5230
03:22:58,760 --> 03:23:02,040
SR-B1, IN COLLABORATION WITH

5231
03:23:02,040 --> 03:23:04,000
NYU, ACTUALLY THIS IS HIS WORK,

5232
03:23:04,000 --> 03:23:07,400
THE SRB1, WE JUST ARE

5233
03:23:07,400 --> 03:23:08,160
COLLABORATORS.

5234
03:23:08,160 --> 03:23:13,080
SO HE SHOWED THAT SRB-1 ACTUALLY

5235
03:23:13,080 --> 03:23:18,120
TAKES -- MICRONS.

5236
03:23:18,120 --> 03:23:18,320
SORRY?

5237
03:23:18,320 --> 03:23:19,920
>> TWO MINUTES REMAINING.

5238
03:23:19,920 --> 03:23:24,320
>> SO I SHOULD GO FAST.

5239
03:23:24,320 --> 03:23:27,200
WE KNOW A LOT ABOUT ENDOTHELIAL

5240
03:23:27,200 --> 03:23:32,360
CELLS, THAT THEY HAVE VERY --

5241
03:23:32,360 --> 03:23:34,560
ARE VERY HETEROGENEOUS AND CD36

5242
03:23:34,560 --> 03:23:36,200
MARKS THE MICRO VASCULATURE THAT

5243
03:23:36,200 --> 03:23:39,880
IS INVOLVED IN THE LIPIDS.

5244
03:23:39,880 --> 03:23:41,680
WHEN WE DELETED THE ENDOTHELIAL

5245
03:23:41,680 --> 03:23:44,960
CELL CD36, WHAT WE FOUND IS THAT

5246
03:23:44,960 --> 03:23:47,000
THERE WAS A DECREASE IN UPTAKE

5247
03:23:47,000 --> 03:23:48,840
OF FATTY ACID BY THE TISSUE, AND

5248
03:23:48,840 --> 03:23:53,240
THERE WAS AN INCREASE IN GLUCOSE

5249
03:23:53,240 --> 03:23:57,600
UPTAKE AT A COMPENSATORY

5250
03:23:57,600 --> 03:23:59,000
RESPONSE TO THE LACK OF FATTY

5251
03:23:59,000 --> 03:24:00,600
ACID UPTAKE.

5252
03:24:00,600 --> 03:24:02,800
SO THEN WE WANTED TO SEE WHAT

5253
03:24:02,800 --> 03:24:04,920
HAPPENS TO THE LACTEALS, AND

5254
03:24:04,920 --> 03:24:08,440
WHAT WE FOUND, AND THAT'S THE

5255
03:24:08,440 --> 03:24:13,240
WORK OF VINCENZ EA. CIFARELLI

5256
03:24:13,240 --> 03:24:15,720
WHO HAS HER OWN LAB AT ST. LOUIS

5257
03:24:15,720 --> 03:24:18,160
UNIVERSITY, WHAT WE FOUND IS

5258
03:24:18,160 --> 03:24:21,520
THAT THEY'RE HIGHLY FRAGMENTED.

5259
03:24:21,520 --> 03:24:24,520
IT WAS VERY INTERESTING TO NOTE

5260
03:24:24,520 --> 03:24:26,120
THAT ITS HIGHEST EXPRESSION WAS

5261
03:24:26,120 --> 03:24:32,080
IN THE COLLECTING VESSELS, YOU

5262
03:24:32,080 --> 03:24:33,000
SEE HERE FLUORESCENCE IN THE

5263
03:24:33,000 --> 03:24:34,320
COLLECTING VESSELS, ALTHOUGH IT

5264
03:24:34,320 --> 03:24:37,040
WAS ALSO EXPRESSED IN THE

5265
03:24:37,040 --> 03:24:41,640
LACTEALS.

5266
03:24:41,640 --> 03:24:43,080
WHAT THE PHENOTYPE OF THESE MICE

5267
03:24:43,080 --> 03:24:44,720
WAS, THEY HAD SHORTER LACTEALS

5268
03:24:44,720 --> 03:24:50,360
AND THEY HAD MORE OPENINGS.

5269
03:24:50,360 --> 03:24:55,080
SO THEN WE CREATED, IN

5270
03:24:55,080 --> 03:24:56,480
COLLABORATION WITH GWEN

5271
03:24:56,480 --> 03:25:00,360
RANDOLPH, WE CREATED A MOUSE

5272
03:25:00,360 --> 03:25:01,120
WITH CD36 DELETION IN THE

5273
03:25:01,120 --> 03:25:02,880
LACTEALS, AND WE FOUND THAT

5274
03:25:02,880 --> 03:25:05,800
THESE MICE ACCUMULATE VISCERAL

5275
03:25:05,800 --> 03:25:09,600
FAT, WITHOUT HIGH FAT DIET, THIS

5276
03:25:09,600 --> 03:25:16,040
IS JUST FED CHOW, THEY BECOME

5277
03:25:16,040 --> 03:25:22,080
RESISTANT AND HAVE INFLAMMATION

5278
03:25:22,080 --> 03:25:26,280
AND MACROPHAGE INFILTRATION.

5279
03:25:26,280 --> 03:25:27,800
SO THEY ARE -- WHAT WE FIGURED

5280
03:25:27,800 --> 03:25:31,840
OUT WAS THAT THEY ARE LEAKY,

5281
03:25:31,840 --> 03:25:34,760
THERE IS A LEAKAGE OF LYMPH BY

5282
03:25:34,760 --> 03:25:37,440
THE COLLECTING DUCT AND AB

5283
03:25:37,440 --> 03:25:41,000
SORGS,     

5284
03:25:41,000 --> 03:25:47,880
ABSORPTION, IT IS DELAYED, .  WT

5285
03:25:47,880 --> 03:25:49,560
WAS INTERESTING IS WE FOUND

5286
03:25:49,560 --> 03:25:50,520
METABOLISM IN THESE CELLS IS

5287
03:25:50,520 --> 03:25:50,960
DIFFERENT.

5288
03:25:50,960 --> 03:25:54,080
THEY HAVE A DECREASE IN CELL

5289
03:25:54,080 --> 03:25:55,400
RESPIRATION AND THEY DON'T

5290
03:25:55,400 --> 03:25:56,920
RESPOND TO VEGF BY INCREASING

5291
03:25:56,920 --> 03:26:00,360
THEIR CELLULAR RESPIRATION.

5292
03:26:00,360 --> 03:26:06,080
THEY ALSO HAVE INCREASED

5293
03:26:06,080 --> 03:26:07,720
GLYCOLYSIS, AGAIN, THEY DON'T

5294
03:26:07,720 --> 03:26:09,880
RESPOND TO VEGF.

5295
03:26:09,880 --> 03:26:15,640
THERE ARE DIFFERENCES ON VEGF

5296
03:26:15,640 --> 03:26:19,120
AND MIGRATION OF THE CELLS.

5297
03:26:19,120 --> 03:26:22,720
THESE CELLS DO NOT TIGHTEN UP

5298
03:26:22,720 --> 03:26:24,520
JUNCTIONS IN RESPONSE TO VEGF

5299
03:26:24,520 --> 03:26:26,920
WHEN THEY DON'T HAVE CD36 WHEN

5300
03:26:26,920 --> 03:26:30,440
IT'S DEPLETED.

5301
03:26:30,440 --> 03:26:33,600
SO IN SUMMARY, CD36 IS EXPRESSED

5302
03:26:33,600 --> 03:26:37,800
IN THE LACTEAL, BUT IT

5303
03:26:37,800 --> 03:26:39,680
PARTICULARLY HIGH IN THE

5304
03:26:39,680 --> 03:26:42,200
COLLECTING DUCTS.

5305
03:26:42,200 --> 03:26:46,720
ITS DELETION -- I WILL SHOW YOU,

5306
03:26:46,720 --> 03:26:50,120
INHIBITS VEGF R2 AND AKT

5307
03:26:50,120 --> 03:26:52,240
PHOSPHORYLATION, IT ENTERS

5308
03:26:52,240 --> 03:26:53,000
LYMPHATIC CELL INTEGRITY AND

5309
03:26:53,000 --> 03:26:58,360
RESULTS IN LEAKAGE.

5310
03:26:58,360 --> 03:27:00,240
SO THIS IS BASICALLY SHOWING YOU

5311
03:27:00,240 --> 03:27:03,480
THAT -- SO I'M GOING TO CLOSE ON

5312
03:27:03,480 --> 03:27:06,400
JUST MAKING A QUICK COMPARISON

5313
03:27:06,400 --> 03:27:08,600
BETWEEN THE LYMPHATIC

5314
03:27:08,600 --> 03:27:10,160
ENDOTHELIAL CELL AND BLOOD

5315
03:27:10,160 --> 03:27:11,280
ENDOTHELIAL CELLS.

5316
03:27:11,280 --> 03:27:14,760
WE SEE SOME DIMINUTION OF VEGF

5317
03:27:14,760 --> 03:27:17,400
R2 PHOSPHORYLATION, BUT WE SEE

5318
03:27:17,400 --> 03:27:19,840
REALLY ALMOST AN ABOLISHING OF

5319
03:27:19,840 --> 03:27:25,840
THE SIGNALING PHOSPHOAKT AND

5320
03:27:25,840 --> 03:27:27,480
THAT'S THE SAME WE SEE IN BLOOD

5321
03:27:27,480 --> 03:27:28,920
ENDOTHELIAL CELLS, SO WE ARE

5322
03:27:28,920 --> 03:27:29,720
FOCUSING ON THIS.

5323
03:27:29,720 --> 03:27:32,280
WE THINK THE CONNECTION TO FOS

5324
03:27:32,280 --> 03:27:38,600
COAKT AND ALSO FOX 01 IS ONE OF

5325
03:27:38,600 --> 03:27:40,320
THE FACTORS REGULATED BY CD36 IS

5326
03:27:40,320 --> 03:27:44,760
GOING TO HELP US UNDERSTAND HOW

5327
03:27:44,760 --> 03:27:46,840
CD36 REGULATE MAINTENANCE OF THE

5328
03:27:46,840 --> 03:27:49,040
JUNCTIONS IN BOTH, BECAUSE IT

5329
03:27:49,040 --> 03:27:50,920
ALSO CAUSES A LEAKAGE IN THE

5330
03:27:50,920 --> 03:27:59,520
BLOOD VESSELS.

5331
03:27:59,520 --> 03:28:00,640
I WILL SKIP THAT.

5332
03:28:00,640 --> 03:28:01,800
I WANT TO TELL YOU WHY WE ARE

5333
03:28:01,800 --> 03:28:04,760
FOCUSING ON THIS.

5334
03:28:04,760 --> 03:28:11,720
WE HAVE SHOWN ARE REGULATES AMPK

5335
03:28:11,720 --> 03:28:14,400
ACTIVITY, ALSO REGULATES FOX

5336
03:28:14,400 --> 03:28:16,520
01 DELIVERY OF FATTY ACIDS, SO

5337
03:28:16,520 --> 03:28:19,400
WE ARE GOING TO FIGURE OUT HOW

5338
03:28:19,400 --> 03:28:22,760
IT HELPS MAINTAIN HOMEOSTASIS OF

5339
03:28:22,760 --> 03:28:26,600
THE LYMPHATIC CELLS.

5340
03:28:26,600 --> 03:28:30,760
SO WHAT ARE THE KNOWLEDGE GAPS

5341
03:28:30,760 --> 03:28:32,080
TO MY PERSPECTIVE?

5342
03:28:32,080 --> 03:28:33,960
IT'S THE FACT WE DON'T KNOW A

5343
03:28:33,960 --> 03:28:36,720
LOT ABOUT HETEROGENEITY OF

5344
03:28:36,720 --> 03:28:37,400
LYMPHATIC ENDOTHELIAL CELLS IN

5345
03:28:37,400 --> 03:28:39,640
TERMS OF GENE EXPRESSION,

5346
03:28:39,640 --> 03:28:40,080
SIGNATURE, FUNCTION.

5347
03:28:40,080 --> 03:28:42,880
IN TERMS OF HOW THIS CHANGES

5348
03:28:42,880 --> 03:28:44,560
FROM, LET'S SAY, THE LACTEALS TO

5349
03:28:44,560 --> 03:28:46,520
THE COLLECTING TO THE

5350
03:28:46,520 --> 03:28:47,160
MESENTERIC, ET CETERA.

5351
03:28:47,160 --> 03:28:48,720
WE DON'T KNOW VERY MUCH ABOUT

5352
03:28:48,720 --> 03:28:52,360
THE MECHANISM THAT MAINTAINS

5353
03:28:52,360 --> 03:28:54,640
VESSEL HOMEOSTASIS AND OPTIMIZES

5354
03:28:54,640 --> 03:28:56,960
FUNCTION, AND WE ALSO DON'T KNOW

5355
03:28:56,960 --> 03:28:59,320
MUCH ABOUT THE METABOLIC FACTOR

5356
03:28:59,320 --> 03:29:02,040
THAT ALTERS THE LEC PHENOTYPE.

5357
03:29:02,040 --> 03:29:03,800
AND THE QUESTION I WAS GOING TO

5358
03:29:03,800 --> 03:29:05,840
ASK BEFORE IS THAT IF SOME OF

5359
03:29:05,840 --> 03:29:07,880
THE SPEAKERS ARE TALKING ABOUT

5360
03:29:07,880 --> 03:29:12,520
THE STEM CELLS AND REGULATION OF

5361
03:29:12,520 --> 03:29:15,880
DEVELOPMENTAL ASPECTS, HAVE

5362
03:29:15,880 --> 03:29:17,840
LOOKED AT FATTY ACID OXIDATION

5363
03:29:17,840 --> 03:29:21,520
AND THE METABOLIC ASPECTS OF THE

5364
03:29:21,520 --> 03:29:25,840
RELATIONSHIP.

5365
03:29:25,840 --> 03:29:26,760
SO I THINK I HAVE MENTIONED THE

5366
03:29:26,760 --> 03:29:29,600
PEOPLE WHO DID THE WORK I HAVE

5367
03:29:29,600 --> 03:29:30,600
SHOWN YOU.

5368
03:29:30,600 --> 03:29:36,400
THIS IS MY LAB MANAGER WHO IS A

5369
03:29:36,400 --> 03:29:38,360
WONDERFUL PARTNER IN THIS WORK.

5370
03:29:38,360 --> 03:29:43,840
BUT I WANT TO MENTION VINCENZA

5371
03:29:43,840 --> 03:29:48,120
IS PURSUING THE LYMPHATIC

5372
03:29:48,120 --> 03:29:49,320
SYSTEM, SHE IS DEVELOPING HER

5373
03:29:49,320 --> 03:29:50,920
LAB SO HOPEFULLY WE HEAR A LOT

5374
03:29:50,920 --> 03:29:51,920
FROM HER IN THE FUTURE.

5375
03:29:51,920 --> 03:29:53,680
SHE IS NOW AT ST. LOUIS

5376
03:29:53,680 --> 03:29:53,960
UNIVERSITY.

5377
03:29:53,960 --> 03:29:54,400
THANK YOU.

5378
03:29:54,400 --> 03:29:56,560
>> THANK YOU, NADA, FOR
THIS

5379
03:29:56,560 --> 03:29:57,200
FASCINATING WORK.

5380
03:29:57,200 --> 03:29:58,640
SO WE'RE GOING TO MOVE TO THE

5381
03:29:58,640 --> 03:30:01,120
NEXT SPEAKER, DR. DARIA

5382
03:30:01,120 --> 03:30:02,560
ESTERHAZY.

5383
03:30:02,560 --> 03:30:04,120
FROM THE UNIVERSITY OF CHICAGO.

5384
03:30:04,120 --> 03:30:09,040
HER TALK IS ENTITLED IMPACT OF

5385
03:30:09,040 --> 03:30:12,000
INTESTINAL HELMINTHS ON DUO DEAL

5386
03:30:12,000 --> 03:30:12,560
LYMPHATIC FUNCTION.

5387
03:30:12,560 --> 03:30:13,120
GO AHEAD.

5388
03:30:13,120 --> 03:30:15,440
>> YES, NOW I SHOULD BE
ABLE TO.

5389
03:30:15,440 --> 03:30:16,040
I REALLY APOLOGIZE.

5390
03:30:16,040 --> 03:30:17,680
THIS WAS A SYSTEM SETTING,

5391
03:30:17,680 --> 03:30:27,120
BELIEVE IT OR NOT.

5392
03:30:27,120 --> 03:30:31,080
OKAY.

5393
03:30:31,080 --> 03:30:31,760
SO MANY THANKS FOR THE

5394
03:30:31,760 --> 03:30:32,400
OPPORTUNITY.

5395
03:30:32,400 --> 03:30:35,000
SO I'LL TELL YOU ABOUT HOW WE

5396
03:30:35,000 --> 03:30:38,040
STUDIED THE INTESTINAL

5397
03:30:38,040 --> 03:30:42,720
LYMPHATICS OR HOW OW LAB     OUD

5398
03:30:42,720 --> 03:30:43,880
UP DOING SO.

5399
03:30:43,880 --> 03:30:44,680
I'LL GIVE YOU A BRIEF OVERVIEW

5400
03:30:44,680 --> 03:30:47,440
AS TO WHAT OUR WORK IS ABOUT IN

5401
03:30:47,440 --> 03:30:47,840
GENERAL.

5402
03:30:47,840 --> 03:30:51,040
WE LOOK AT THE LYMPHATICS FROM A

5403
03:30:51,040 --> 03:30:51,880
LYMPH NODE PERSPECTIVE, AND IT

5404
03:30:51,880 --> 03:30:53,240
STARTED OFF WITH THIS

5405
03:30:53,240 --> 03:30:55,440
UNDERSTANDING THAT THE LYMPH

5406
03:30:55,440 --> 03:30:59,080
NODES ALONG THE GASTROINTESTINAL

5407
03:30:59,080 --> 03:31:01,720
TRACT ARE ANATOMICALLY BUT ALSO

5408
03:31:01,720 --> 03:31:02,520
FUNCTIONALLY DISTINCT BECAUSE

5409
03:31:02,520 --> 03:31:03,320
YOU'RE EXPOSED TO DIFFERENT

5410
03:31:03,320 --> 03:31:05,400
THINGS ALONG THE INTESTINE AND

5411
03:31:05,400 --> 03:31:07,920
OBVIOUSLY EACH INTESTINAL

5412
03:31:07,920 --> 03:31:09,600
SEGMENT ALSO HAS DIFFERENT

5413
03:31:09,600 --> 03:31:10,360
PURPOSES.

5414
03:31:10,360 --> 03:31:12,400
AND WE OBSERVED THAT OVERALL,

5415
03:31:12,400 --> 03:31:14,480
THE UPPER SMALL INTESTINAL LYMPH

5416
03:31:14,480 --> 03:31:18,240
MODES MOUNT BY DEFAULT AN

5417
03:31:18,240 --> 03:31:18,840
IMMUNOIMPRESSIVE IMMUNE RESPONSE

5418
03:31:18,840 --> 03:31:24,040
AND FOR THE DOWN,        THE FUE

5419
03:31:24,040 --> 03:31:24,880
MORE INFLAMMATORY.

5420
03:31:24,880 --> 03:31:26,520
THAT BALL ABC SEEMS TO BE

5421
03:31:26,520 --> 03:31:27,840
HEALTHY BECAUSE ON THE FLIP SIDE

5422
03:31:27,840 --> 03:31:29,840
IF THAT BALANCE IS PERTURBED,

5423
03:31:29,840 --> 03:31:34,200
THAT CAN LEAD TO, AGAIN,

5424
03:31:34,200 --> 03:31:34,960
SEGMENT-SPECIFIC DISEASE IN THE

5425
03:31:34,960 --> 03:31:37,280
UPPER SMALL INTESTINE AND MORE

5426
03:31:37,280 --> 03:31:40,480
PROMINENT INFLAMMATORY BOWEL

5427
03:31:40,480 --> 03:31:42,200
DISEASES IN THE DISTAL INTESTINE

5428
03:31:42,200 --> 03:31:43,200
AND ALSO CANCER.

5429
03:31:43,200 --> 03:31:44,080
THE TWO PROJECT AREAS IN THE LAB

5430
03:31:44,080 --> 03:31:45,680
ARE ON THE ONE HAND

5431
03:31:45,680 --> 03:31:46,640
UNDERSTANDING THE CROSSTALK

5432
03:31:46,640 --> 03:31:48,760
BETWEEN THE GUT, PANCREAS AND

5433
03:31:48,760 --> 03:31:51,680
LIVER AND SO THAT IS AN

5434
03:31:51,680 --> 03:31:53,440
INTERESTING DISCUSSION, WE ALSO

5435
03:31:53,440 --> 03:31:54,040
LOOK AT LYMPHATICS.

5436
03:31:54,040 --> 03:31:55,400
THAT'S NOT THE AREA I WILL TALK

5437
03:31:55,400 --> 03:31:55,920
ABOUT TODAY.

5438
03:31:55,920 --> 03:31:57,800
I WILL TALK ABOUT THIS OTHER

5439
03:31:57,800 --> 03:32:02,040
AREA WE'VE ONLY RECENTLY STARTED

5440
03:32:02,040 --> 03:32:04,560
TO TALK ABOUT, DRIVING FORCES

5441
03:32:04,560 --> 03:32:07,680
AND CELLULAR SUBSTRATES OF

5442
03:32:07,680 --> 03:32:08,240
TISSUE-SPECIFIC LYMPH NODES.

5443
03:32:08,240 --> 03:32:09,760
WHAT I WILL FOCUS ON TODAY IS

5444
03:32:09,760 --> 03:32:12,040
THIS UPPER REGION, BECAUSE IT'S

5445
03:32:12,040 --> 03:32:14,600
INTERESTING IN THAT IT'S

5446
03:32:14,600 --> 03:32:15,960
IMMUNOSUPPRESSIVE OR TOLERANCE

5447
03:32:15,960 --> 03:32:17,360
PROMOTING AND HOW THAT THING CAN

5448
03:32:17,360 --> 03:32:20,760
BE PERTURBED BY LUMINAL EVENTS

5449
03:32:20,760 --> 03:32:25,840
SUCH AS HELMINTH INFECTIONS.

5450
03:32:25,840 --> 03:32:28,760
THE HELMINTH THAT STARTED US OFF

5451
03:32:28,760 --> 03:32:32,040
IS THIS ORIGINALLY RAT HELMINTH

5452
03:32:32,040 --> 03:32:42,400
CALLED STRONGYLOIDES

5453
03:32:42,400 --> 03:32:43,160
VENEZUELENSIS.

5454
03:32:43,160 --> 03:32:44,360
WE CAN LOOK AT IT FROM THE

5455
03:32:44,360 --> 03:32:46,560
IMMUNE CELL SIDE WITHOUT GOING

5456
03:32:46,560 --> 03:32:47,960
INTO ALL THE DETAILS OF THE

5457
03:32:47,960 --> 03:32:51,640
IMMUNE SYSTEM, UPON INFECTION,

5458
03:32:51,640 --> 03:32:56,440
REALLY ONLY IN THIS -- EACH OF

5459
03:32:56,440 --> 03:33:01,240
THESE LYMPH -- THEY ARE MARKED

5460
03:33:01,240 --> 03:33:05,080
BY BEING CD11B POSITIVE, AND OF

5461
03:33:05,080 --> 03:33:07,560
COURSE THEY ARE MIGRATORY BY

5462
03:33:07,560 --> 03:33:08,560
BEING POSITIVE OVER HERE.

5463
03:33:08,560 --> 03:33:10,560
AGAIN THAT'S A PHENOTYPE WE ONLY

5464
03:33:10,560 --> 03:33:14,320
SEE IN THE NICHE THAT DRAINS THE

5465
03:33:14,320 --> 03:33:18,360
INFLAMED GAP SEGMENT BEING THE

5466
03:33:18,360 --> 03:33:19,280
DUODENUM.

5467
03:33:19,280 --> 03:33:22,680
WE HAVE AN INCREASE OF TH2 CELLS

5468
03:33:22,680 --> 03:33:28,960
AND ONLY A LITTLE -- THE ONE --

5469
03:33:28,960 --> 03:33:29,920
LOCALIZATION, AND THIS ALSO

5470
03:33:29,920 --> 03:33:32,920
AFFECTS WHAT WE CALL HOW YOU

5471
03:33:32,920 --> 03:33:34,440
REACT TO YOUR FOOD, WHERE ALL OF

5472
03:33:34,440 --> 03:33:37,200
A SUDDEN IF YOU HAVE A WORM IN

5473
03:33:37,200 --> 03:33:38,600
YOUR DUODENUM, YOU ARE LESS ABLE

5474
03:33:38,600 --> 03:33:40,880
TO MOUNT THESE IMMUNE RESPONSES

5475
03:33:40,880 --> 03:33:44,360
AND THIS ACTUALLY LEADS TO FOOD

5476
03:33:44,360 --> 03:33:45,440
ALLERGY IN THE MOUSE MODEL.

5477
03:33:45,440 --> 03:33:47,800
NOW THE INTERESTING THING ABOUT

5478
03:33:47,800 --> 03:33:49,240
THE WORM IS OF COURSE EVERY

5479
03:33:49,240 --> 03:33:51,000
INFECTION LEADS TO SOME KIND OF

5480
03:33:51,000 --> 03:33:54,080
LYMPH NODE SWELLING BUT HONESTLY

5481
03:33:54,080 --> 03:33:56,280
WE DON'T EVER SEE IT AS EXTREME

5482
03:33:56,280 --> 03:34:00,400
AS UPON HELMINTH INFECTION.

5483
03:34:00,400 --> 03:34:02,640
THIS IS A LYMPH NODE JUST WITH

5484
03:34:02,640 --> 03:34:04,720
AN IPHONE LOOKS LIKE, JUST BY

5485
03:34:04,720 --> 03:34:06,840
VISUALIZING, WE CAN TELL THE

5486
03:34:06,840 --> 03:34:08,280
INFECTION -- IF YOU STAIN FOR

5487
03:34:08,280 --> 03:34:09,600
THIS, THIS REALLY GOES IN HAND

5488
03:34:09,600 --> 03:34:10,440
AND THAT'S WHERE IT'S DIFFERENT

5489
03:34:10,440 --> 03:34:12,080
FROM, SAY, TRANSIENT INFECTIONS

5490
03:34:12,080 --> 03:34:15,760
WITH VIRUSES, WITH ANGIOGENESIS

5491
03:34:15,760 --> 03:34:20,800
AND LYMPH ANG GENESIS.   ANGIOG.

5492
03:34:20,800 --> 03:34:23,640
BASICALLY ASKED THIS VERY

5493
03:34:23,640 --> 03:34:24,360
FUNDAMENTAL QUESTION OF WHERE

5494
03:34:24,360 --> 03:34:25,440
DOES THIS ALL START, IN OTHER

5495
03:34:25,440 --> 03:34:26,960
WORDS, WHAT ARE THE GUT TISSUE

5496
03:34:26,960 --> 03:34:29,040
EVENTS THAT GOVERN THIS

5497
03:34:29,040 --> 03:34:30,480
ADAPTATION TO HELMINTH INFECTION

5498
03:34:30,480 --> 03:34:31,560
AND I'LL SHOW YOU IN A MINUTE

5499
03:34:31,560 --> 03:34:33,320
WHY WE ACTUALLY STARTED ASKING

5500
03:34:33,320 --> 03:34:35,040
MORE SPECIFICALLY, ARE THE

5501
03:34:35,040 --> 03:34:36,040
TISSUE LYMPHATICS REALLY

5502
03:34:36,040 --> 03:34:37,080
AFFECTED BY THE HELMINTH

5503
03:34:37,080 --> 03:34:38,440
INFECTION AND IF SO, WHAT ARE

5504
03:34:38,440 --> 03:34:39,640
THE IMMEDIATE DOWNSTREAM

5505
03:34:39,640 --> 03:34:40,280
CONSEQUENCES?

5506
03:34:40,280 --> 03:34:41,720
AND I'LL NOT TALK ABOUT THE

5507
03:34:41,720 --> 03:34:42,920
UPSTREAM EVENTS THAT WE'RE

5508
03:34:42,920 --> 03:34:44,880
OBVIOUSLY ALSO STUDYING, AND

5509
03:34:44,880 --> 03:34:46,280
THEN FINALLY WHAT IT TAKES TO

5510
03:34:46,280 --> 03:34:46,960
RESOLVE THIS.

5511
03:34:46,960 --> 03:34:50,480
AND THEN WE ONLY OBSERVE THIS

5512
03:34:50,480 --> 03:34:51,120
WITH THIS ONE SO WE REALLY

5513
03:34:51,120 --> 03:34:52,280
WANTED TO KNOW IS THIS SOMETHING

5514
03:34:52,280 --> 03:34:55,280
THAT ALL HELMINTHS DO OR JUST --

5515
03:34:55,280 --> 03:34:57,760
AND HOW DOES THAT COMPARE

5516
03:34:57,760 --> 03:34:59,280
POTENTIALLY TO OTHER INSULTS IN

5517
03:34:59,280 --> 03:35:01,680
THE GUT INDUCED BY PATHOGENS,

5518
03:35:01,680 --> 03:35:04,160
AND IS IT SPECIFIC TO THIS

5519
03:35:04,160 --> 03:35:04,920
DUODENAL NICHE OR DOES IT GO

5520
03:35:04,920 --> 03:35:05,360
BEYOND THAT.

5521
03:35:05,360 --> 03:35:08,000
SO WHY STUDY THE LYMPHATICS?

5522
03:35:08,000 --> 03:35:09,840
THIS ACTUALLY LINKS QUITE NICELY

5523
03:35:09,840 --> 03:35:13,080
TO THE PREVIOUS TALK AND ITS

5524
03:35:13,080 --> 03:35:14,640
THEME, AND THAT IT DOES ALSO

5525
03:35:14,640 --> 03:35:15,920
AFFECT LIPID ABSORPTION.

5526
03:35:15,920 --> 03:35:17,120
SO ON THE ONE HAND WE COULD

5527
03:35:17,120 --> 03:35:18,600
TEASE OUT THAT PHENOTYPE BY

5528
03:35:18,600 --> 03:35:20,680
PUTTING MICE ON A HIGH FAT DIET

5529
03:35:20,680 --> 03:35:23,120
WHERE NORMALLY THEY GAIN WEIGHT,

5530
03:35:23,120 --> 03:35:24,120
BUT IF YOU INFECT WITH A WORM,

5531
03:35:24,120 --> 03:35:25,560
EIGHT DAYS POST INFECTION

5532
03:35:25,560 --> 03:35:26,640
INSTEAD OF CONTINUING TO GAIN

5533
03:35:26,640 --> 03:35:28,680
WEIGHT, THE MICE IF ANYTHING

5534
03:35:28,680 --> 03:35:30,200
LOSE WEIGHT.

5535
03:35:30,200 --> 03:35:33,520
INDICATING THEY HAVE SOME AT

5536
03:35:33,520 --> 03:35:35,240
LEAST MINIMAL METABOLIC DEFECT

5537
03:35:35,240 --> 03:35:36,880
AND WE DON'T THINK IT'S BECAUSE

5538
03:35:36,880 --> 03:35:37,680
THEY BURN MORE, BECAUSE ACTUALLY

5539
03:35:37,680 --> 03:35:44,760
WHEN YOU LOOK MORE CLOSELY, BY

5540
03:35:44,760 --> 03:35:46,360
GAVAGE AND MEASURING

5541
03:35:46,360 --> 03:35:48,560
TRIGLYCERIDES IN THE SERUM, THE

5542
03:35:48,560 --> 03:35:50,960
OIL WILL NOT HAVE REACHED MUCH

5543
03:35:50,960 --> 03:35:53,040
BEYOND THE DUODENUM IN A MOUSE,

5544
03:35:53,040 --> 03:35:55,720
THIS IS 8 DAYS POST INFECTION,

5545
03:35:55,720 --> 03:35:57,600
YOU HAVE A DECREASE IN UPTAKE

5546
03:35:57,600 --> 03:35:59,360
INTO THE SERUM.

5547
03:35:59,360 --> 03:36:02,320
THIS PERSISTS AT LEAST FIVE DAYS

5548
03:36:02,320 --> 03:36:04,080
AFTER THE WORM CLEARANCE, SO

5549
03:36:04,080 --> 03:36:06,000
AGAIN, SUGGESTING THAT THERE

5550
03:36:06,000 --> 03:36:07,480
MUST HAVE BEEN MASSIVE

5551
03:36:07,480 --> 03:36:10,280
RESTRUCTURING AND THEN IF YOU

5552
03:36:10,280 --> 03:36:11,920
LOOK OVER FOUR WEEKS OUT, IF

5553
03:36:11,920 --> 03:36:13,960
ANYTHING IT'S INCREASED BUT IT'S

5554
03:36:13,960 --> 03:36:14,920
CERTAINLY NOT DECREASED ANY

5555
03:36:14,920 --> 03:36:16,800
MORE, SO EVENTUALLY THAT ISSUE

5556
03:36:16,800 --> 03:36:17,120
RESOLVES.

5557
03:36:17,120 --> 03:36:18,320
THIS WAS ALL WORK I SHOULD SAY

5558
03:36:18,320 --> 03:36:24,720
ABOUT A PH.D. STUDENT WHO IS --

5559
03:36:24,720 --> 03:36:25,960
HAS BEEN WORKING VERY HARD ON

5560
03:36:25,960 --> 03:36:27,040
THIS FOR THREE YEARS.

5561
03:36:27,040 --> 03:36:30,320
SO WE KNOW THAT THE UPPER

5562
03:36:30,320 --> 03:36:31,600
INTESTINAL LYMPHATICS ARE

5563
03:36:31,600 --> 03:36:33,120
HEAVILY IMPLICATED IN LIPID

5564
03:36:33,120 --> 03:36:33,920
ABSORPTION.

5565
03:36:33,920 --> 03:36:34,920
AND BECAUSE WE HAVEN'T HAD THE

5566
03:36:34,920 --> 03:36:36,280
PICTURE UP YET, I WOULD JUST

5567
03:36:36,280 --> 03:36:37,600
LIKE TO MENTION THAT THE

5568
03:36:37,600 --> 03:36:41,400
LACTEALS ALONG THE INTESTINE

5569
03:36:41,400 --> 03:36:42,080
ACTUALLY DECREASE.

5570
03:36:42,080 --> 03:36:44,440
OF COURSE THE VILLUS LENGTH

5571
03:36:44,440 --> 03:36:47,000
DECREASES BUT ALSO THE DUODENAL

5572
03:36:47,000 --> 03:36:47,960
LYMPHATICS, AND WE'RE NOT THE

5573
03:36:47,960 --> 03:36:49,760
FIRST ONE TO OBSERVE THAT,

5574
03:36:49,760 --> 03:36:50,560
SOMETIMES EVEN HAVE TWO LACTEALS

5575
03:36:50,560 --> 03:36:53,840
IN ORDER TO ACCOMMODATE FOR THIS

5576
03:36:53,840 --> 03:36:55,360
INCREASED NEED FOR LIPID

5577
03:36:55,360 --> 03:36:56,120
TRANSPORT.

5578
03:36:56,120 --> 03:36:58,480
WE ALSO KNOW THAT MOST LIPIDS

5579
03:36:58,480 --> 03:37:02,640
ARE TAKEN UP IN THE DUODENUM

5580
03:37:02,640 --> 03:37:12,280
FOLLOWED BY THE JU KNEW NIM,   W

5581
03:37:12,280 --> 03:37:16,080
THAT YOU NEED TO BASICALLY

5582
03:37:16,080 --> 03:37:17,800
PACKAGE THIS INTO MICRONS

5583
03:37:17,800 --> 03:37:20,400
BECAUSE IF YOU HAD INHIBITOR TO

5584
03:37:20,400 --> 03:37:23,600
THE GAVAGE CALLED PL81, YOU'LL

5585
03:37:23,600 --> 03:37:31,720
ACCUMULATE THE FATS.

5586
03:37:31,720 --> 03:37:34,040
YOU SEE MOST LIPIDS IN THE

5587
03:37:34,040 --> 03:37:36,200
DUODENAL LYMPH NODES BUT IF YOU

5588
03:37:36,200 --> 03:37:37,720
PREVENT INFLAMMATION, THAT'S NO

5589
03:37:37,720 --> 03:37:38,560
LONGER TRUE.

5590
03:37:38,560 --> 03:37:40,200
AND SO ONE THING THAT WAS

5591
03:37:40,200 --> 03:37:42,320
ALREADY MENTIONED BUT MAYBE NOT

5592
03:37:42,320 --> 03:37:48,720
IN THAT DETAIL, IT FURNS OUT TUT

5593
03:37:48,720 --> 03:37:49,920
OBVIOUSLY ON THE LYMPHATIC SIDE

5594
03:37:49,920 --> 03:37:53,000
OF THINGS, NOT ONLY THE VASTNESS

5595
03:37:53,000 --> 03:37:55,160
OF THE VASCULATURE, HOW MANY

5596
03:37:55,160 --> 03:37:56,320
LIPIDS YOU CAN TAKE UP SO YOU

5597
03:37:56,320 --> 03:37:59,400
HAVE THESE MORE PER   PERMISSIVE

5598
03:37:59,400 --> 03:38:01,560
BUTTON-LIKE JUNCTIONS, THIS IS

5599
03:38:01,560 --> 03:38:03,520
HOW WE QUANTIFY THIS, BY

5600
03:38:03,520 --> 03:38:04,760
BASICALLY ITS IMAGE

5601
03:38:04,760 --> 03:38:06,800
QUANTIFICATION IS A LOT OF WORK

5602
03:38:06,800 --> 03:38:08,560
BUT THAT'S WHAT THE FIELD SEEMS

5603
03:38:08,560 --> 03:38:10,040
TO DO.

5604
03:38:10,040 --> 03:38:12,160
SO WHEN YOU QUANTIFY ALONG THE

5605
03:38:12,160 --> 03:38:14,120
INTESTINE, THIS SORT OF

5606
03:38:14,120 --> 03:38:14,960
CORRELATES ALONG WITH WHAT WE

5607
03:38:14,960 --> 03:38:18,160
THINK IS THE INVOLVEMENT OF THE

5608
03:38:18,160 --> 03:38:20,960
LIPID ABSORPTION, AS YOU GO

5609
03:38:20,960 --> 03:38:22,880
ALONG THE SMALL INTESTINE, THE

5610
03:38:22,880 --> 03:38:26,080
LACTEALS BECOME MORE

5611
03:38:26,080 --> 03:38:26,400
ZIPPER-LIKE.

5612
03:38:26,400 --> 03:38:34,720
NOW IF WE LOOK AT THAT FROM A

5613
03:38:34,720 --> 03:38:35,800
DISTENDED LYMPHATICS POINT OF

5614
03:38:35,800 --> 03:38:39,200
VIEW, THE LACTEALS ARE MUCH MORE

5615
03:38:39,200 --> 03:38:40,520
DISTENDED AND INTERESTINGLY THEY

5616
03:38:40,520 --> 03:38:43,120
BECOME MUCH MORE ZIPPER-LIKE SO

5617
03:38:43,120 --> 03:38:45,840
THAT WOULD CORRELATE WITH THIS

5618
03:38:45,840 --> 03:38:47,920
DECREASED FAT AND PHENOTYPE.

5619
03:38:47,920 --> 03:38:50,960
WE WANTED TO KNOW IF ONE

5620
03:38:50,960 --> 03:38:53,040
HELMINTH OR SEVERAL HELMINTHS DO

5621
03:38:53,040 --> 03:38:53,760
THIS.

5622
03:38:53,760 --> 03:38:55,440
IN SHORT -- DO THE SAME THING

5623
03:38:55,440 --> 03:38:57,200
WHERE YOU BECOME MORE

5624
03:38:57,200 --> 03:38:58,800
ZIPPER-LIKE UPON THE HELMINTH

5625
03:38:58,800 --> 03:38:59,920
INFECTION AND THE LACTEALS

5626
03:38:59,920 --> 03:39:00,880
BECOME MORE DISTENDED.

5627
03:39:00,880 --> 03:39:04,800
I SHOULD SAY WE DID NOT SEE THIS

5628
03:39:04,800 --> 03:39:06,760
UPON BACTERIA OR VIRUSES

5629
03:39:06,760 --> 03:39:08,720
SUGGESTING THIS IS A HELMINTH

5630
03:39:08,720 --> 03:39:10,120
INFECTION WHICH WE'RE NOW TRYING

5631
03:39:10,120 --> 03:39:10,480
TO WORK OUT.

5632
03:39:10,480 --> 03:39:11,760
THE FINAL THING THAT I WANTED TO

5633
03:39:11,760 --> 03:39:15,040
TOUCH ON IS HOW WE LOOKED AT NOT

5634
03:39:15,040 --> 03:39:18,080
ONLY FAT TRANSPORT BUT ALSO

5635
03:39:18,080 --> 03:39:19,680
IMMUNE CELL TRAFFICKING BUT WE

5636
03:39:19,680 --> 03:39:24,960
MADE THE INTESTINE GREAN    GREN

5637
03:39:24,960 --> 03:39:26,640
INDUCIBLE ROSA26 MOUSE AND THE

5638
03:39:26,640 --> 03:39:28,200
IDEA IS THAT BECAUSE YOU HAVE

5639
03:39:28,200 --> 03:39:32,240
INTESTINAL CELL TURNOVER, SOME

5640
03:39:32,240 --> 03:39:33,760
DENDRITIC CELLS WILL BECOME

5641
03:39:33,760 --> 03:39:36,600
GREEND MIGRATE TO         

5642
03:39:36,600 --> 03:39:38,480
GREEN AND MIGRATE TO THE LYMPH

5643
03:39:38,480 --> 03:39:39,040
NODES.

5644
03:39:39,040 --> 03:39:41,000
THREE DAYS AFTER INFECTION WITH

5645
03:39:41,000 --> 03:39:42,520
WORM, ANOTHER FIVE DAYS LATER,

5646
03:39:42,520 --> 03:39:44,160
WE CAN SEE THIS ACTUALLY ALSO

5647
03:39:44,160 --> 03:39:46,440
CORRELATES WITH A MASSIVE

5648
03:39:46,440 --> 03:39:47,280
MIGRATION DEFECT.

5649
03:39:47,280 --> 03:39:50,040
SUGGESTING THAT THE ZIPPER-LIKE

5650
03:39:50,040 --> 03:39:53,640
FUNCTION OF THE -- OR CLOSING OF

5651
03:39:53,640 --> 03:39:55,360
THE DUODENAL LYMPHATICS ALSO

5652
03:39:55,360 --> 03:39:57,360
AFFECT HOW IMMUNE CELLS TRAFFIC.

5653
03:39:57,360 --> 03:39:58,560
AND THAT'S ALL OF COURSE ONLY

5654
03:39:58,560 --> 03:40:01,360
THE TIP OF THE ICE   ICEBERG, SI

5655
03:40:01,360 --> 03:40:02,360
WOULD JUST LIKE TO FINISH WITH

5656
03:40:02,360 --> 03:40:04,560
THE GAPS AND NEEDS AND BIGGER

5657
03:40:04,560 --> 03:40:04,800
PICTURE.

5658
03:40:04,800 --> 03:40:05,920
WE HAVE NO IDEA WHAT THIS LOOKS

5659
03:40:05,920 --> 03:40:09,280
LIKE IN HUMANS BUT IT'S

5660
03:40:09,280 --> 03:40:11,440
INTRIGUING TO THINK THAT

5661
03:40:11,440 --> 03:40:12,880
HELMINTHS, IN MANY PARTS OF THE

5662
03:40:12,880 --> 03:40:14,760
WORLD, ARE STILL A DAILY BREAD

5663
03:40:14,760 --> 03:40:18,320
AND BUTTER AND CAN COINCIDE WITH

5664
03:40:18,320 --> 03:40:20,080
PHENOTYPES OF MALABSORPTION AND

5665
03:40:20,080 --> 03:40:23,480
VITAMIN E DEFICIENCY IN PARTS OF

5666
03:40:23,480 --> 03:40:23,720
THE WORLD.

5667
03:40:23,720 --> 03:40:25,520
I WOULD SAY IN THE BROADER

5668
03:40:25,520 --> 03:40:28,360
SENSE, SOME THINGS HAVE BEEN

5669
03:40:28,360 --> 03:40:29,880
TOUCHED ON BUT THIS REALLY

5670
03:40:29,880 --> 03:40:31,480
RELATES TO THIS SITE-SPECIFIC --

5671
03:40:31,480 --> 03:40:33,360
WE LACK THIS INFORMATION OF

5672
03:40:33,360 --> 03:40:37,840
SITE-SPECIFIC TRANS CRYPTOMIX IN

5673
03:40:37,840 --> 03:40:39,120
GUT LYMPHATICS, PARTICULARLY

5674
03:40:39,120 --> 03:40:41,200
HARD TO STUDY JUST BECAUSE OUR

5675
03:40:41,200 --> 03:40:43,080
RNA INTEGRITY IS SO MUCH MORE

5676
03:40:43,080 --> 03:40:44,160
COMPROMISED.

5677
03:40:44,160 --> 03:40:46,560
IDENTIFYING RELEVANT MOLECULES

5678
03:40:46,560 --> 03:40:48,520
AND CELLS WITH WHICH THEY

5679
03:40:48,520 --> 03:40:49,960
COMMUNICATE AND SORT OF REGULATE

5680
03:40:49,960 --> 03:40:50,600
THEIR DYNAMICS.

5681
03:40:50,600 --> 03:40:52,680
I DO THINK WE STILL LACK

5682
03:40:52,680 --> 03:40:53,720
FUNDAMENTAL UNDERSTANDING OF

5683
03:40:53,720 --> 03:40:58,120
WHAT THE GUT LYMPH COMPOSITION

5684
03:40:58,120 --> 03:41:01,080
IS ALONG THE INTESTINE.

5685
03:41:01,080 --> 03:41:02,720
SPATIAL TRANSCRIPTOMICS, SOME OF

5686
03:41:02,720 --> 03:41:03,760
THOSE ISSUES IN PART BECAUSE

5687
03:41:03,760 --> 03:41:06,280
THEY DON'T RELY ON LIVE TISSUE.

5688
03:41:06,280 --> 03:41:07,920
WITH THAT, I WOULD LIKE TO THANK

5689
03:41:07,920 --> 03:41:10,760
THE PEOPLE IN MY TEAM, MOST

5690
03:41:10,760 --> 03:41:13,400
NOTABLY JORDAN LANE, AND I'M

5691
03:41:13,400 --> 03:41:14,640
HAPPY TO TAKE QUESTIONS LATER

5692
03:41:14,640 --> 03:41:15,200
ON.

5693
03:41:15,200 --> 03:41:19,640
THANK YOU.

5694
03:41:19,640 --> 03:41:23,400
>> THANK YOU, DARE   
DARIA.

5695
03:41:23,400 --> 03:41:24,280
REALLY INTERESTING WORK.

5696
03:41:24,280 --> 03:41:29,720
SO I'D LIKE TO INTRODUCE OUR

5697
03:41:29,720 --> 03:41:32,440
LAST SPEAKER, DR. JORGE

5698
03:41:32,440 --> 03:41:34,000
CASTORENA-GONZALEZ FROM TULANE

5699
03:41:34,000 --> 03:41:34,920
UNIVERSITY SCHOOL OF MEDICINE.

5700
03:41:34,920 --> 03:41:37,720
HIS TALK ENTITLED MECHANISMS OF

5701
03:41:37,720 --> 03:41:39,000
IMPAIRED LYMPH TRANSPORT IN

5702
03:41:39,000 --> 03:41:44,720
OBESITY HAD BEEN     -INDUCED L.

5703
03:41:44,720 --> 03:41:46,680
>> THANK YOU FOR A NICE

5704
03:41:46,680 --> 03:41:47,600
INTRODUCTION.

5705
03:41:47,600 --> 03:41:49,520
I WOULD LIKE TO BEGIN MY

5706
03:41:49,520 --> 03:41:52,880
PRESENTATION BY THANKING THE

5707
03:41:52,880 --> 03:41:54,000
ORGANIZERS FOR ALLOWING US TO

5708
03:41:54,000 --> 03:41:54,760
PRESENT TODAY.

5709
03:41:54,760 --> 03:41:56,120
I ALSO WANT TO START MY

5710
03:41:56,120 --> 03:41:58,320
PRESENTATION BY ACKNOWLEDGING

5711
03:41:58,320 --> 03:42:00,200
THOSE -- THE MEMBERS OF MY LAB.

5712
03:42:00,200 --> 03:42:05,960
THE WORK CH VICTORIA AND KELLI

5713
03:42:05,960 --> 03:42:09,040
HAS BEEN ESSENTIAL FOR THE WORK

5714
03:42:09,040 --> 03:42:10,880
OF MY LAB SINCE WE STARTED TWO

5715
03:42:10,880 --> 03:42:11,160
YEARS AGO.

5716
03:42:11,160 --> 03:42:12,280
I ALSO WANT TO THANK MY

5717
03:42:12,280 --> 03:42:13,800
COLLABORATORS AND MY FORMER

5718
03:42:13,800 --> 03:42:15,640
MENTORS, ESPECIALLY DR. MICHAEL

5719
03:42:15,640 --> 03:42:16,360
DAVIS, AND OF COURSE I WANT TO

5720
03:42:16,360 --> 03:42:20,480
THANK THE NIH FOR THE FUNDING

5721
03:42:20,480 --> 03:42:21,480
THAT MAKES THIS RESEARCH

5722
03:42:21,480 --> 03:42:21,800
POSSIBLE.

5723
03:42:21,800 --> 03:42:24,440
SO I DON'T HAVE TO CONVINCE YOU

5724
03:42:24,440 --> 03:42:27,880
THAT OBESITY IS A MAJOR HEALTH

5725
03:42:27,880 --> 03:42:28,560
PROBLEM WORLDWIDE.

5726
03:42:28,560 --> 03:42:29,960
IN THE LAST REPORT BY THE WORLD

5727
03:42:29,960 --> 03:42:31,360
HEALTH ORGANIZATION, ABOUT

5728
03:42:31,360 --> 03:42:35,440
650 MILLION ADULTS ARE OBESE.

5729
03:42:35,440 --> 03:42:37,400
AND THERE IS A VERY CLEAR

5730
03:42:37,400 --> 03:42:39,360
CONNECTION BETWEEN OBESITY AND

5731
03:42:39,360 --> 03:42:40,480
LYMPHATICS DYSFUNCTION.

5732
03:42:40,480 --> 03:42:44,600
THIS IS EVEN MORE CLEAR IN

5733
03:42:44,600 --> 03:42:45,960
MORBIDLY OBESE PATIENTS, THOSE

5734
03:42:45,960 --> 03:42:48,960
PRESENT WITH A BMI OF OVER

5735
03:42:48,960 --> 03:42:53,680
40 KILOGRAMS PER METER SQUARED,

5736
03:42:53,680 --> 03:42:55,440
AT HIGHER RISK OF DEVELOPING

5737
03:42:55,440 --> 03:42:58,040
LOWER EXTREMITY LYMPHEDEMA.

5738
03:42:58,040 --> 03:43:00,840
SO THE CONNECTION BETWEEN

5739
03:43:00,840 --> 03:43:03,600
OBESITY AND LYMPHATIC

5740
03:43:03,600 --> 03:43:05,040
DYSFUNCTION IS REALLY A

5741
03:43:05,040 --> 03:43:06,520
DYSFUNCTION AND

5742
03:43:06,520 --> 03:43:07,280
DISEASE-PROMOTING FEEDBACK LOOP.

5743
03:43:07,280 --> 03:43:10,680
IN THIS RECENT STUDY BY

5744
03:43:10,680 --> 03:43:12,960
DR. KATARU AND THE GROUP BY

5745
03:43:12,960 --> 03:43:13,840
DR. BABAK MEHRARA.

5746
03:43:13,840 --> 03:43:15,800
SO IN MANY PLACES OF THE BODY,

5747
03:43:15,800 --> 03:43:18,200
WE KNOW THAT LYMPH HAS TO BE

5748
03:43:18,200 --> 03:43:20,080
TRANSPORTED AGAINST AN ADVERSE

5749
03:43:20,080 --> 03:43:21,360
PRESSURE DRIVEN AND THIS IS DUE

5750
03:43:21,360 --> 03:43:22,560
TO GRAVITATIONAL FORCES.

5751
03:43:22,560 --> 03:43:23,960
AT THE CLINIC, THE PHYSICIANS

5752
03:43:23,960 --> 03:43:28,240
ARE ABLE TO ASSESS DRAINAGE OR

5753
03:43:28,240 --> 03:43:29,680
TRANSPORT OF LYMPH BY ASSESSING

5754
03:43:29,680 --> 03:43:35,440
DRAINAGE INTO THE SPECIFIC LYMPH

5755
03:43:35,440 --> 03:43:35,640
NODES.

5756
03:43:35,640 --> 03:43:39,000
SO IN TERMS OF OBESITY INDUCED

5757
03:43:39,000 --> 03:43:40,440
LYMPHEDEMA, WHICH IS THE CENTRAL

5758
03:43:40,440 --> 03:43:44,240
TOPIC OF THIS TALK, IN PARALYMPH

5759
03:43:44,240 --> 03:43:46,120
DRPT OR DRAINAGE CAN RESULT FROM

5760
03:43:46,120 --> 03:43:50,800
NORMAL OR IMPAIRED UPPER TAKE OF

5761
03:43:50,800 --> 03:43:55,080
INTERSTITIAL FLUID AFTER

5762
03:43:55,080 --> 03:43:57,360
CAPILLARIES, VFL DEFICIENCIES,

5763
03:43:57,360 --> 03:44:00,240
INCREASED PERMEABILITY,

5764
03:44:00,240 --> 03:44:02,800
OBSTRUCTION OR DELAYED FLOW

5765
03:44:02,800 --> 03:44:03,480
AMONG OTHERS.

5766
03:44:03,480 --> 03:44:04,800
LYMPHEDEMA IS USUALLY ASSOCIATED

5767
03:44:04,800 --> 03:44:05,760
WITH A FEW OTHER CONDITIONS LIKE

5768
03:44:05,760 --> 03:44:07,760
THE ONES LISTED HERE.

5769
03:44:07,760 --> 03:44:09,840
SO IN MY LAB, ONE OF THE

5770
03:44:09,840 --> 03:44:13,080
TECHNIQUES WE USE IS THE STUDY

5771
03:44:13,080 --> 03:44:15,600
OF MICRO DISSECTED LYMPHATIC

5772
03:44:15,600 --> 03:44:17,320
VESSELS FROM DIFFERENT SPECIES.

5773
03:44:17,320 --> 03:44:20,520
IN OUR MOST RECENT PUBLICATION,

5774
03:44:20,520 --> 03:44:23,240
WE INCLUDED FULL VIDEO IN THE

5775
03:44:23,240 --> 03:44:23,920
SUPPLEMENTAL MATERIALS

5776
03:44:23,920 --> 03:44:25,880
EXPLAINING THIS PROCESS.

5777
03:44:25,880 --> 03:44:28,560
ONCE WE HAVE OUR DISSECTED

5778
03:44:28,560 --> 03:44:29,440
LYMPHATIC SEGMENT, WE TRANSFER

5779
03:44:29,440 --> 03:44:32,560
IT ON TO AN OBSERVATION CHAMBER,

5780
03:44:32,560 --> 03:44:34,160
AND BY USING TWO GLASS MICRO

5781
03:44:34,160 --> 03:44:36,440
PIPETTES, WE CAN STUDY THESE

5782
03:44:36,440 --> 03:44:37,360
LYMPHATIC SEGMENTS.

5783
03:44:37,360 --> 03:44:39,960
IN MY LAB, WE USE A MICRO

5784
03:44:39,960 --> 03:44:43,880
FLUIDICS FLOW CONTROLLER THROUGH

5785
03:44:43,880 --> 03:44:44,760
HAVING INDEPENDENT CONTROL OF

5786
03:44:44,760 --> 03:44:46,280
INPUT AND OUTPUT FLOW.

5787
03:44:46,280 --> 03:44:48,360
SO WE CAN STUDY ASPECTS OF

5788
03:44:48,360 --> 03:44:49,400
FUNCTION OF COLLECTING LYMPHATIC

5789
03:44:49,400 --> 03:44:52,520
DEVELOPS ELSE FROM          

5790
03:44:52,520 --> 03:44:54,520
VESSELS FROM DIFFERENT SPECIES.

5791
03:44:54,520 --> 03:44:56,280
INCLUDING HUMANS, WE CAN CONTROL

5792
03:44:56,280 --> 03:44:58,720
FOR DIFFERENT AND SPECIFIC AN

5793
03:44:58,720 --> 03:44:59,920
ANATOMICAL REGIONS, WE CAN

5794
03:44:59,920 --> 03:45:01,440
CONTROL TEMPERATURE, FLOW AND

5795
03:45:01,440 --> 03:45:02,760
PRESSURE KENTUCKYS AND EVALUATE

5796
03:45:02,760 --> 03:45:08,800
THE EEFNGHTS OF       EFFECTS OL

5797
03:45:08,800 --> 03:45:09,800
AGENTS.

5798
03:45:09,800 --> 03:45:15,120
WITH THESE TECH    TECHNIQUES WN

5799
03:45:15,120 --> 03:45:17,680
QUANTITATIVELY ASSESS THE

5800
03:45:17,680 --> 03:45:19,480
CONTRACTILE FUNCTION OF THESE

5801
03:45:19,480 --> 03:45:21,960
VESSELS, THEIR AMPLITUDE,

5802
03:45:21,960 --> 03:45:23,640
FREQUENCY, EJECTION FRACTION AND

5803
03:45:23,640 --> 03:45:24,520
SOME OTHER FACTORS.

5804
03:45:24,520 --> 03:45:28,560
A FEW YEARS AGO WE HAD A

5805
03:45:28,560 --> 03:45:29,160
COLLABORATION WITH A SURGEON.

5806
03:45:29,160 --> 03:45:33,160
AT THE TIME WE WERE -- PATIENTS

5807
03:45:33,160 --> 03:45:38,200
WHO HAD A BMI OF OVER 40 MG PER

5808
03:45:38,200 --> 03:45:39,400
METERS SQUARED.

5809
03:45:39,400 --> 03:45:40,800
HOW THE LYMPHATIC CONTRACTILITY

5810
03:45:40,800 --> 03:45:42,600
OF THESE HUMAN VESSELS COMPARED

5811
03:45:42,600 --> 03:45:46,440
TO THAT THAT WE NORMALLY OBSERVE

5812
03:45:46,440 --> 03:45:47,840
IN LEAN WILD TYPE MICE.

5813
03:45:47,840 --> 03:45:49,680
AS YOU CAN SEE, INITIALLY, WE

5814
03:45:49,680 --> 03:45:53,720
DID NOT SEE ANY SIGNIFICANT

5815
03:45:53,720 --> 03:45:54,840
DIFFERENCES WHEN WE COMPARE

5816
03:45:54,840 --> 03:45:57,280
HUMAN AND MOUSE DATA AS EVIDENT

5817
03:45:57,280 --> 03:46:00,240
BY THESE TWO PLOTS WHERE WE'RE

5818
03:46:00,240 --> 03:46:01,440
PRESENTING CONTRACTION FREQUENCY

5819
03:46:01,440 --> 03:46:02,520
AND EJECTION FRACTION AS A

5820
03:46:02,520 --> 03:46:03,960
FUNCTION OF INTRALUMINAL

5821
03:46:03,960 --> 03:46:06,760
PRESSURE.

5822
03:46:06,760 --> 03:46:10,280
HOWEVER, A RECENT STUDY

5823
03:46:10,280 --> 03:46:11,040
SHOWED -- BY DR. RAFAEL

5824
03:46:11,040 --> 03:46:12,480
CZEPIELEWSKI WHO PRESENTED

5825
03:46:12,480 --> 03:46:13,600
EARLIER TODAY IN COLLABORATION

5826
03:46:13,600 --> 03:46:16,080
WITH DR. MICHAEL DAVIS, THEY

5827
03:46:16,080 --> 03:46:17,760
RECENTLY MEASURED THE IN VIVO

5828
03:46:17,760 --> 03:46:19,600
PRESSURES IN THE MOUSE AND THEY

5829
03:46:19,600 --> 03:46:21,040
FOUND THAT THE PRESSURES THEY

5830
03:46:21,040 --> 03:46:23,200
WERE ABLE TO MEASURE WERE ALL

5831
03:46:23,200 --> 03:46:24,760
BELOW REALLY 5 CENTIMETERS OF

5832
03:46:24,760 --> 03:46:25,480
WATER.

5833
03:46:25,480 --> 03:46:27,480
SO THAT WILL PUT THE MOUSE

5834
03:46:27,480 --> 03:46:28,920
LYMPHATIC VESSELS IN THIS

5835
03:46:28,920 --> 03:46:32,520
REGION.

5836
03:46:32,520 --> 03:46:33,720
WHEN WE'RE TALKING ABOUT HUMAN

5837
03:46:33,720 --> 03:46:34,720
VESSELS, A COUPLE THINGS WE HAVE

5838
03:46:34,720 --> 03:46:38,680
TO CONSIDER IS FIRST ALTHOUGH WE

5839
03:46:38,680 --> 03:46:39,960
DIDN'T OBSERVE ANY CONTRACTILE

5840
03:46:39,960 --> 03:46:41,000
DEFECTS, WE HAVE TO CONSIDER

5841
03:46:41,000 --> 03:46:44,240
THAT WE TESTED THESE LYMPHATIC

5842
03:46:44,240 --> 03:46:45,320
VESSELS OUTSIDE THEIR NATIVE

5843
03:46:45,320 --> 03:46:47,080
ENVIRONMENT, WHICH IS LIKELY A

5844
03:46:47,080 --> 03:46:48,600
VERY PRO INFLAMMATORY

5845
03:46:48,600 --> 03:46:51,880
ENVIRONMENT, AND SECOND, IF

5846
03:46:51,880 --> 03:46:53,520
OBESITY RESULTS IN THE OVERLOAD

5847
03:46:53,520 --> 03:46:54,840
OF LYMPHATIC NETWORKS WITH FLUID

5848
03:46:54,840 --> 03:46:56,240
BACKING UP, LEADING TO A

5849
03:46:56,240 --> 03:46:58,480
SIGNIFICANT INCREASE OF

5850
03:46:58,480 --> 03:47:01,760
TRANSMURAL PRESSURE, THAT WOULD

5851
03:47:01,760 --> 03:47:03,440
PUT THE HUMAN LYMPHATIC ME SALS

5852
03:47:03,440 --> 03:47:05,080
IN OBESE PATIENTS IN THIS AREA

5853
03:47:05,080 --> 03:47:07,760
OF THE BLOOD, WHERE THE EJECTION

5854
03:47:07,760 --> 03:47:10,560
FRACK SHUPS ARE SO LOW, THAT

5855
03:47:10,560 --> 03:47:12,720
LIKELY HAVE A VERY, VERY

5856
03:47:12,720 --> 03:47:17,000
COMPROMISED PUMPING CAPABILITY.

5857
03:47:17,000 --> 03:47:19,400
SO WE KNOW IN ADDITION TO

5858
03:47:19,400 --> 03:47:20,280
CONTRACTIONS, LYMPHATIC VALVES

5859
03:47:20,280 --> 03:47:24,680
ARE CRITICAL FOR EFFICIENT LYMPH

5860
03:47:24,680 --> 03:47:25,320
TRANSPORTS.

5861
03:47:25,320 --> 03:47:26,240
SO THESE ARE THREE DIFFERENT

5862
03:47:26,240 --> 03:47:27,200
CONSTRUCTIONS THAT WE HAVE

5863
03:47:27,200 --> 03:47:30,680
GENERATED IN MY LAB FROM

5864
03:47:30,680 --> 03:47:32,520
COLLECTING LYMPHATIC VALVES.

5865
03:47:32,520 --> 03:47:34,880
AS YOU CAN SEE, THIS IS A

5866
03:47:34,880 --> 03:47:36,080
LYMPHATIC VALVE IN AN OPEN

5867
03:47:36,080 --> 03:47:38,720
POSITION, HOWEVER, WE KNOW THESE

5868
03:47:38,720 --> 03:47:43,320
VALVES CLOSE IN THE PRESENCE OF

5869
03:47:43,320 --> 03:47:45,720
DECREASED PRESH REMEMBER

5870
03:47:45,720 --> 03:47:49,200
GRADIENT, FORMING A VERY, VERY

5871
03:47:49,200 --> 03:47:51,880
TIGHT SEAL WHICH PREVENTS

5872
03:47:51,880 --> 03:47:52,640
BACKFLOW.

5873
03:47:52,640 --> 03:47:56,000
BUT LYMPHATIC VALVES ARE NOT

5874
03:47:56,000 --> 03:47:58,240
ONLY CRITICAL AT MINIMIZING RM

5875
03:47:58,240 --> 03:47:59,440
BLOOD FLOW.

5876
03:47:59,440 --> 03:48:01,920
THESE ARE ALSO CRITICAL FOR --

5877
03:48:01,920 --> 03:48:04,040
BECAUSE THEY ALLOW FOR THE

5878
03:48:04,040 --> 03:48:05,520
GENERATION OF PROPULSIVE

5879
03:48:05,520 --> 03:48:07,360
PRESSURE DURING THE CONTRACTION

5880
03:48:07,360 --> 03:48:07,760
CYCLE.

5881
03:48:07,760 --> 03:48:13,520
THIS IS DISPLAYED IN THIS VIDEO,

5882
03:48:13,520 --> 03:48:15,160
THIS LYMPHATIC VESSEL OF THE

5883
03:48:15,160 --> 03:48:16,160
MOUSE.

5884
03:48:16,160 --> 03:48:18,960
SO AS YOU WERE ABLE TO SEE IN

5885
03:48:18,960 --> 03:48:20,120
DR. MICHAEL DAVIS' PRESENTATION,

5886
03:48:20,120 --> 03:48:22,720
THE GOLD STANDARD TECHNIQUE FOR

5887
03:48:22,720 --> 03:48:24,280
ASSESSING LYMPHATIC VALVE

5888
03:48:24,280 --> 03:48:31,240
FUNCTIONING EX-VO VO --       -Y

5889
03:48:31,240 --> 03:48:32,840
COMPLEX, COMPLICATED SYSTEMS TO

5890
03:48:32,840 --> 03:48:34,160
USE AND VERY FEW ARE STILL IN

5891
03:48:34,160 --> 03:48:35,040
GOOD WORKING CONDITION AROUND

5892
03:48:35,040 --> 03:48:35,920
THE WORLD.

5893
03:48:35,920 --> 03:48:37,640
SO A FEW YEARS ARC WE DEVELOPED

5894
03:48:37,640 --> 03:48:39,960
A SIMPLIFIED METHOD FOR

5895
03:48:39,960 --> 03:48:42,080
QUANTITATIVE ASSESSMENT FOR

5896
03:48:42,080 --> 03:48:42,760
LYMPHATIC VALVE FUNCTION.

5897
03:48:42,760 --> 03:48:44,560
THIS ALLOWS US TO DETERMINE THE

5898
03:48:44,560 --> 03:48:49,720
AMOUNT OF PRESSURE ACROSS A

5899
03:48:49,720 --> 03:48:49,920
VALVE.

5900
03:48:49,920 --> 03:48:52,560
WE HAVE A SINGLE VALVE SYSTEM

5901
03:48:52,560 --> 03:48:53,880
AND INITIALLY WE START WITH THE

5902
03:48:53,880 --> 03:48:55,400
SAME PRESSURE IN THE INPUT AND

5903
03:48:55,400 --> 03:48:58,600
THE OUTPUT AND WE START

5904
03:48:58,600 --> 03:49:00,640
INCREASING THE OUTPUT PRESSURE,

5905
03:49:00,640 --> 03:49:01,760
CHALLENGING THIS VALVE.

5906
03:49:01,760 --> 03:49:03,720
SO THIS IS DISPLAYED IN THIS

5907
03:49:03,720 --> 03:49:04,400
VIDEO OVER HERE.

5908
03:49:04,400 --> 03:49:09,760
SO AS I WOULD     -- AS OUTPUT E

5909
03:49:09,760 --> 03:49:12,520
BEGINS TO INCREASE, THE LYMPH

5910
03:49:12,520 --> 03:49:14,560
VALVE INCREASES, AND PRESSURE

5911
03:49:14,560 --> 03:49:17,240
CONTINUES TO INCREASE, THIS

5912
03:49:17,240 --> 03:49:22,480
SECTION OF THE VESSEL TENDS TO

5913
03:49:22,480 --> 03:49:24,680
AFFECT THE REST OF THE LYMPHATIC

5914
03:49:24,680 --> 03:49:24,920
SYSTEM.

5915
03:49:24,920 --> 03:49:26,120
SOME OF THE WORK WE DID IN MY

5916
03:49:26,120 --> 03:49:28,600
LAB WAS THAT WE SUBJECTED MICE

5917
03:49:28,600 --> 03:49:30,040
FOR 14 WEEKS TO EITHER A CONTROL

5918
03:49:30,040 --> 03:49:33,800
OR A WESTERN DIET, AND TO INDUCE

5919
03:49:33,800 --> 03:49:34,360
OBESITY.

5920
03:49:34,360 --> 03:49:36,400
SO THESE MICE BECAME OBESE.

5921
03:49:36,400 --> 03:49:39,040
THEY ALSO DISPLAYED HIGH BLOOD

5922
03:49:39,040 --> 03:49:42,400
GLUCOSE AND HIGH CHOLESTEROL

5923
03:49:42,400 --> 03:49:43,640
LEVELS.

5924
03:49:43,640 --> 03:49:45,680
OH, THE COMPETENCE OF LYMPHATIC

5925
03:49:45,680 --> 03:49:47,560
VALVES FROM TWO DIFFERENT

5926
03:49:47,560 --> 03:49:48,240
ANATOMICAL REGIONS.

5927
03:49:48,240 --> 03:49:50,080
WE FIRST LOOK AT POPLITEAL AREA

5928
03:49:50,080 --> 03:49:52,480
AND TO OUR SURPRISE, WE DID NOT

5929
03:49:52,480 --> 03:49:55,000
SEE ANY LYMPHATIC VALVE

5930
03:49:55,000 --> 03:49:56,760
DEFICIENCIES AS EVIDENT BY THE

5931
03:49:56,760 --> 03:49:59,720
SIMILAR AND VERY LOW PRESSURE --

5932
03:49:59,720 --> 03:50:03,800
THAT WE OBSERVE HERE.

5933
03:50:03,800 --> 03:50:05,200
BACK LEAKS WE OBSERVED HERE.

5934
03:50:05,200 --> 03:50:07,720
THESE ANIMALS HAD SIGNIFICANT

5935
03:50:07,720 --> 03:50:08,600
PRESSURE BACK-LEAK.

5936
03:50:08,600 --> 03:50:11,240
SO THESE ARE WHAT WE REFER TO AS

5937
03:50:11,240 --> 03:50:11,880
LEAKY VALVES.

5938
03:50:11,880 --> 03:50:14,040
SO FURTHERMORE, IF WE GO BACK TO

5939
03:50:14,040 --> 03:50:15,800
THE VIDEO I JUST SHOWED YOU

5940
03:50:15,800 --> 03:50:17,120
BEFORE, THIS TIME THE VIDEO IS

5941
03:50:17,120 --> 03:50:19,120
GOING TO STOP WHEN THE VALVE

5942
03:50:19,120 --> 03:50:20,320
ENGAGES AND GOES INTO A CLOSED

5943
03:50:20,320 --> 03:50:21,960
POSITION.

5944
03:50:21,960 --> 03:50:26,240
SO IN THIS SPECIFIC CASE, WE CAN

5945
03:50:26,240 --> 03:50:28,440
SEE THAT FOR THIS PARTICULAR

5946
03:50:28,440 --> 03:50:30,640
VESSEL SEGMENT, IT REQUIRES

5947
03:50:30,640 --> 03:50:32,360
ABOUT 0.5 CENTIMETERS OF ADVERSE

5948
03:50:32,360 --> 03:50:34,920
PRESSURE GRADIENT TO DRIVE THIS

5949
03:50:34,920 --> 03:50:36,000
LYMPHATIC VALVE INTO THE CLOSED

5950
03:50:36,000 --> 03:50:36,360
POSITION.

5951
03:50:36,360 --> 03:50:41,920
THIS IS ACTUALLY A VERY -- FOR

5952
03:50:41,920 --> 03:50:42,880
HEALTHY CONTROL VALVES, BUT AS

5953
03:50:42,880 --> 03:50:46,160
YOU CAN SEE, WHEN WE COMPARED

5954
03:50:46,160 --> 03:50:48,120
CONTROL VERSUS WESTERN DIET, WE

5955
03:50:48,120 --> 03:50:49,840
FOUND THOSE LEAKY MESENTERIC

5956
03:50:49,840 --> 03:50:52,880
VALVES, THEY ALSO REQUIRE

5957
03:50:52,880 --> 03:50:56,760
SIGNIFICANTLY HIGHER LEVELS OF

5958
03:50:56,760 --> 03:50:58,000
ADVERSE PRESSURE TRYING TO DRIVE

5959
03:50:58,000 --> 03:50:59,120
THEM INTO THE CLOSED POSITION.

5960
03:50:59,120 --> 03:51:01,960
IF WE GO BACK TO THE STUDY I WAS

5961
03:51:01,960 --> 03:51:07,880
REFERRING TO EARLIER IT WAS

5962
03:51:07,880 --> 03:51:09,640
REPORTED PRESSURES IN THE MOUSE

5963
03:51:09,640 --> 03:51:11,400
ARE BELOW 5 CENTIMETERS OF

5964
03:51:11,400 --> 03:51:12,600
WATER, THAT WOULD MEAN IN OUR

5965
03:51:12,600 --> 03:51:14,240
DATA, ABOUT ONE-THIRD OF OUR

5966
03:51:14,240 --> 03:51:19,400
VALVES FROM OBESE LIFE ARE NEVER

5967
03:51:19,400 --> 03:51:22,040
LIKELY ABLE TO -- AS THEY ARE

5968
03:51:22,040 --> 03:51:22,720
REQUIRING MORE THAN

5969
03:51:22,720 --> 03:51:26,640
5 CENTIMETERS OF WATER TO CLOSE.

5970
03:51:26,640 --> 03:51:29,280
SO FOR THESE VALVES WE ACTUALLY

5971
03:51:29,280 --> 03:51:31,320
WERE NOT ABLE TO IDENTIFY ANY

5972
03:51:31,320 --> 03:51:32,840
STRUCTURAL OBVIOUS ABNORMALITIES

5973
03:51:32,840 --> 03:51:34,920
THAT COULD BE ASSOCIATED WITH

5974
03:51:34,920 --> 03:51:38,920
THIS LEAKINESS AND INCREASED

5975
03:51:38,920 --> 03:51:40,400
LEVELS OF ADVERSE PRESSURE

5976
03:51:40,400 --> 03:51:41,680
REQUIRED TO CLOSE THESE VALVES,

5977
03:51:41,680 --> 03:51:48,480
SO WHAT WE'RE HIGH POT      HYPS

5978
03:51:48,480 --> 03:51:51,000
IS A QUESTION FROM EARLIER

5979
03:51:51,000 --> 03:51:52,880
TODAY, WOULD WE BELIEVE THE

5980
03:51:52,880 --> 03:51:54,480
WORK -- THE WORKING HIGH

5981
03:51:54,480 --> 03:51:56,640
POTASSIUM THESE IS LYMPHATIC

5982
03:51:56,640 --> 03:51:59,320
VALVE STIFFENING MAY BE AN

5983
03:51:59,320 --> 03:52:01,520
IMPORTANT FACTOR IN OBESITY AND

5984
03:52:01,520 --> 03:52:03,040
OBESITY INDUCED LYMPHEDEMA.

5985
03:52:03,040 --> 03:52:04,360
ONE OF THE THINGS WE WERE ABLE

5986
03:52:04,360 --> 03:52:06,440
TO FIND IN THESE ANIMALS WAS

5987
03:52:06,440 --> 03:52:11,520
WHEN COLLECTING THESE LYMPH

5988
03:52:11,520 --> 03:52:14,360
VALVE FROM THE -- WAS

5989
03:52:14,360 --> 03:52:18,280
SIGNIFICANTLY INCREASED.

5990
03:52:18,280 --> 03:52:19,680
PAI-1 IS A MAJOR INHIBITOR OF

5991
03:52:19,680 --> 03:52:31,320
TISSUE AND UROKINASE      UROKI-

5992
03:52:36,480 --> 03:52:37,240
METABOLIC SYNDROME AND OTHERS.

5993
03:52:37,240 --> 03:52:41,280
SO WE SUBJECTED PAI-1 SUFFICIENT

5994
03:52:41,280 --> 03:52:42,960
MICE TO THE SAME DIET REGIMEN

5995
03:52:42,960 --> 03:52:44,560
AND WHAT WE WERE ABLE TO FIND IS

5996
03:52:44,560 --> 03:52:49,760
THAT BY ONE KNOCKOUT MICE FED A

5997
03:52:49,760 --> 03:52:52,600
WESTERN BUY ET WERE SUFFICIENTLY

5998
03:52:52,600 --> 03:52:59,160
PROTECTED AGAINST OBESITY

5999
03:52:59,160 --> 03:53:00,880
COMPARED TO -- PRODUCES NORMAL

6000
03:53:00,880 --> 03:53:02,640
BLOOD GLUCOSE AND CHOLESTEROL

6001
03:53:02,640 --> 03:53:02,840
LEVELS.

6002
03:53:02,840 --> 03:53:03,960
MORE IMPORTANTLY, WE BELIEVE THE

6003
03:53:03,960 --> 03:53:08,880
OVERALL IMPROVEMENT IN METABOLIC

6004
03:53:08,880 --> 03:53:13,400
FUNCTION AND THIS ALLOWED THESE

6005
03:53:13,400 --> 03:53:16,520
MICE TO PREVENT THE LYMPHATIC

6006
03:53:16,520 --> 03:53:24,120
FUNCTION THAT WAS OAR   OBSERVEN

6007
03:53:24,120 --> 03:53:25,240
KNOCKOUT MICE.

6008
03:53:25,240 --> 03:53:29,400
YOU CAN SEE THEY ARE LOW AS THE

6009
03:53:29,400 --> 03:53:31,400
CONTROL DIET AND ALL THE VALVES

6010
03:53:31,400 --> 03:53:35,080
ARE REQUIRING THE SAME ADVERSE

6011
03:53:35,080 --> 03:53:35,680
PRESSURE DURING THE CLOSING.

6012
03:53:35,680 --> 03:53:36,640
SO SOME OF THE CURRENT AND

6013
03:53:36,640 --> 03:53:38,040
FUTURE WORK WE'RE DOING IN MY

6014
03:53:38,040 --> 03:53:39,680
LAB IS, WE'RE TRYING TO

6015
03:53:39,680 --> 03:53:41,160
DETERMINE THEN OR ANSWER THE

6016
03:53:41,160 --> 03:53:43,080
QUESTION WHAT IS CHANGING IN THE

6017
03:53:43,080 --> 03:53:51,400
LYMPHATIC ENDOTHELIUM OF

6018
03:53:51,400 --> 03:53:53,160
COLLECTING LYMPH AND

6019
03:53:53,160 --> 03:53:55,560
UNDERSTANDING THE MECHANISMS

6020
03:53:55,560 --> 03:53:57,800
INVOLVED IN VALVE DYSFUNCTION IN

6021
03:53:57,800 --> 03:53:58,080
OBESITY.

6022
03:53:58,080 --> 03:54:00,320
WE ARE UTILIZING A TECHNIQUE

6023
03:54:00,320 --> 03:54:03,720
THAT WAS INITIALLY DEVELOPED BY

6024
03:54:03,720 --> 03:54:06,560
DR. STEVEN SEGAL AT UNIVERSITY

6025
03:54:06,560 --> 03:54:06,840
OF MISSOURI.

6026
03:54:06,840 --> 03:54:09,880
THIS WAS LATER ADOPTED BY YOURS

6027
03:54:09,880 --> 03:54:16,240
FOR LYMPHATICS, BASICALLY --

6028
03:54:16,240 --> 03:54:17,800
RECENTLY WE PUBLISHED THIS PAPER

6029
03:54:17,800 --> 03:54:20,320
WHERE WE'RE ABLE TO FURTHER

6030
03:54:20,320 --> 03:54:23,360
OPTIMIZE THIS TECHNIQUE TO APPLY

6031
03:54:23,360 --> 03:54:24,800
IT FOR DIFFERENT SPECIES

6032
03:54:24,800 --> 03:54:26,240
INCLUDING HUMANS AND SO NOW

6033
03:54:26,240 --> 03:54:28,080
WE'RE TRYING TO CHARACTERIZE

6034
03:54:28,080 --> 03:54:30,160
CHANGES IN THE INTACT

6035
03:54:30,160 --> 03:54:31,360
ENDOTHELIUM OF LYMPHATIC VESSELS

6036
03:54:31,360 --> 03:54:33,240
FROM DIFFERENT SPECIES AND

6037
03:54:33,240 --> 03:54:34,640
DIFFERENT ANATOMICAL REGIONS,

6038
03:54:34,640 --> 03:54:38,640
EITHER IN THE INTACT STATE OR BY

6039
03:54:38,640 --> 03:54:40,680
FURTHER CULTURING THESE

6040
03:54:40,680 --> 03:54:46,520
LYMPHATIC ENDOTHELIAL TUBES.

6041
03:54:46,520 --> 03:54:48,120
SO THIS IS BASICALLY WITH A

6042
03:54:48,120 --> 03:54:51,760
PURPOSE OF UNDERSTANDING AND

6043
03:54:51,760 --> 03:54:52,960
CHARACTERIZING CHANGES IN THE

6044
03:54:52,960 --> 03:54:54,120
LYMPHATIC ENDOTHELIUM OF

6045
03:54:54,120 --> 03:54:55,920
COLLECTING VESSELS FROM LEAN

6046
03:54:55,920 --> 03:54:59,120
CONTROLS AND DIET-INDUCED OBESE

6047
03:54:59,120 --> 03:55:01,560
WILD TYPE AND PAI-1-DEFICIENT

6048
03:55:01,560 --> 03:55:02,120
MICE.

6049
03:55:02,120 --> 03:55:03,080
WE'RE TRYING TO DO THESE AND

6050
03:55:03,080 --> 03:55:05,160
TRYING TO LOOK AT THINGS THAT

6051
03:55:05,160 --> 03:55:07,200
ARE KNOWN TO INTERACT WITH

6052
03:55:07,200 --> 03:55:07,760
PAI-1.

6053
03:55:07,760 --> 03:55:09,600
SO WITH THIS TECHNIQUE, WE'RE

6054
03:55:09,600 --> 03:55:12,640
ABLE TO UTILIZE THESE TYPE OF

6055
03:55:12,640 --> 03:55:14,120
TECHNIQUES AND WE START

6056
03:55:14,120 --> 03:55:16,520
BASICALLY WITH A MORE --

6057
03:55:16,520 --> 03:55:18,280
POPULATION SO WE DON'T HAVE TO

6058
03:55:18,280 --> 03:55:21,240
DEAL WITH TRYING TO CLEAN OUT OR

6059
03:55:21,240 --> 03:55:24,400
SELL A SAMPLE BASICALLY.

6060
03:55:24,400 --> 03:55:25,600
SO ONE OF THE OTHER THINGS THAT

6061
03:55:25,600 --> 03:55:27,560
WE'RE DOING IN MY LAB IS, AS

6062
03:55:27,560 --> 03:55:29,960
HIGHLIGHTED IN PREVIOUS

6063
03:55:29,960 --> 03:55:32,280
PRESENTATIONS, WE KNOW THAT A

6064
03:55:32,280 --> 03:55:33,040
MAJOR FUNCTION OF THE LYMPHATIC

6065
03:55:33,040 --> 03:55:34,480
SYSTEM IS THAT OF LIPID

6066
03:55:34,480 --> 03:55:35,000
ABSORPTION.

6067
03:55:35,000 --> 03:55:36,560
SO WE'RE ALSO INTERESTED IN

6068
03:55:36,560 --> 03:55:39,400
TRYING TO DETERMINE WHETHER

6069
03:55:39,400 --> 03:55:41,120
PAI-1 PLAYS A ROLE IN REGULATING

6070
03:55:41,120 --> 03:55:42,440
LACTEAL INTEGRITY AND FUNCTION

6071
03:55:42,440 --> 03:55:45,080
IN DIET-INDUCED OBESITY.

6072
03:55:45,080 --> 03:55:46,160
THESE ARE JUST SOME RECENT

6073
03:55:46,160 --> 03:55:49,040
PICTURES WE WERE EABL    ABLE TT

6074
03:55:49,040 --> 03:55:52,520
IN MY LAB.

6075
03:55:52,520 --> 03:55:54,280
I WANT TO THANK HER FOR SHARING

6076
03:55:54,280 --> 03:55:56,400
HER EXPERTISE.

6077
03:55:56,400 --> 03:55:57,600
SO TO CLOSE MY PRESENTATION,

6078
03:55:57,600 --> 03:55:59,320
SOME OF THE GAPS AND

6079
03:55:59,320 --> 03:56:00,440
OPPORTUNITIES, SOME OF THEM THAT

6080
03:56:00,440 --> 03:56:03,960
ARE SPECIFIC TO THE CURRENT

6081
03:56:03,960 --> 03:56:06,160
FOCUS OF THE RESEARCH PERFORMED

6082
03:56:06,160 --> 03:56:08,880
IN MY LAB IS TO DETERMINE THE

6083
03:56:08,880 --> 03:56:12,560
LYMPHATIC-SPECIFIC ROLE OF PAI-C

6084
03:56:12,560 --> 03:56:14,760
AND METABOLIC DYSFUNCTION IN

6085
03:56:14,760 --> 03:56:15,400
DIET-INDUCED OBESITY.

6086
03:56:15,400 --> 03:56:17,160
ASSESS THE POTENTIAL OF

6087
03:56:17,160 --> 03:56:19,720
PHARMACOLOGICAL PAI-1 INHIBITORS

6088
03:56:19,720 --> 03:56:21,080
AS A NOVEL THERAPEUTIC STRATEGY

6089
03:56:21,080 --> 03:56:24,880
IN OBESITY AND OBESITY-INDUCED

6090
03:56:24,880 --> 03:56:25,720
LYMPHATIC DYSFUNCTION.

6091
03:56:25,720 --> 03:56:27,480
OTHER FACTORS ARE LONG TERM AND

6092
03:56:27,480 --> 03:56:29,080
CLINICALLY RELEVANT FOR

6093
03:56:29,080 --> 03:56:30,480
SECONDARY LYMPHEDEMA PATIENTS,

6094
03:56:30,480 --> 03:56:33,720
DETERMINE THE EXTENT OF

6095
03:56:33,720 --> 03:56:35,400
LYMPHATIC VALVE DYSFUNCTION AND

6096
03:56:35,400 --> 03:56:37,320
STIFFENING OF COLLECTING

6097
03:56:37,320 --> 03:56:38,480
LYMPHATICS IN OBESE AND

6098
03:56:38,480 --> 03:56:40,120
NON-OBESE PATIENTS WITH

6099
03:56:40,120 --> 03:56:40,880
SECONDARY LYMPHEDEMA.

6100
03:56:40,880 --> 03:56:42,840
HOPEFULLY AT SOME POINT WE CAN

6101
03:56:42,840 --> 03:56:44,960
IDENTIFY THE UNDERLYING

6102
03:56:44,960 --> 03:56:46,680
MECHANISMS AND DEVELOP

6103
03:56:46,680 --> 03:56:47,800
PHARMACOLOGICAL TREATMENTS, BUT

6104
03:56:47,800 --> 03:56:49,640
EVEN THE SIZE OF THIS ENDEAVOR,

6105
03:56:49,640 --> 03:56:50,960
WE BELIEVE THAT THESE WOULD

6106
03:56:50,960 --> 03:56:53,800
REQUIRE THE DEVELOPMENT OF NOVEL

6107
03:56:53,800 --> 03:56:58,480
TECHNICAL AND   APPROACHES AND O

6108
03:56:58,480 --> 03:56:59,520
ANALYTICAL METHODOLOGIES, AS

6109
03:56:59,520 --> 03:57:02,480
WELL AS A MULTIDISCIPLINARY AND

6110
03:57:02,480 --> 03:57:03,280
MULTI-INSTITUTIONAL

6111
03:57:03,280 --> 03:57:06,440
COLLABORATIVE EFFORTS.

6112
03:57:06,440 --> 03:57:08,920
THANK YOU FOR YOUR ATTENTION.

6113
03:57:08,920 --> 03:57:11,160
>> THANK YOU VERY MUCH,
JORGE,

6114
03:57:11,160 --> 03:57:13,920
FOR THIS REALLY GREAT TALK.

6115
03:57:13,920 --> 03:57:15,360
SO NOW WE MOVE ON TO THE Q &
A

6116
03:57:15,360 --> 03:57:15,560
SESSION.

6117
03:57:15,560 --> 03:57:19,200
WE HAVE RECEIVED A LOT OF

6118
03:57:19,200 --> 03:57:20,920
QUESTIONS SO I WILL TRY TO

6119
03:57:20,920 --> 03:57:21,920
DISTRIBUTE TO EACH INDIVIDUAL AS

6120
03:57:21,920 --> 03:57:23,440
MUCH AS POSSIBLE.

6121
03:57:23,440 --> 03:57:28,200
SO THE FIRST QUESTION FOR

6122
03:57:28,200 --> 03:57:30,760
RAFAEL.

6123
03:57:30,760 --> 03:57:35,480
BUT FOR THOSE WHO RESEARCH

6124
03:57:35,480 --> 03:57:37,320
LYMPHATIC FUNCTION AND IBD, ARE

6125
03:57:37,320 --> 03:57:42,480
THERE ANY CONCERNS FOR TAKING

6126
03:57:42,480 --> 03:57:50,440
THE OMENTUM AS A LYMPH NODE

6127
03:57:50,440 --> 03:57:54,280
TRANSFER AND CAUSING IATROGENIC

6128
03:57:54,280 --> 03:57:55,960
ABDOMINAL LYMPH FLOW ISSUES?

6129
03:57:55,960 --> 03:57:58,800
>> I'M NOT SURE I
UNDERSTOOD THE

6130
03:57:58,800 --> 03:58:00,960
COMPLETE CONNECTION.

6131
03:58:00,960 --> 03:58:05,120
SO THE OMENTUM ITSELF, IT'S NOT

6132
03:58:05,120 --> 03:58:07,640
COMPLETELY DRAINING THE SAME

6133
03:58:07,640 --> 03:58:12,680
NETWORK THAT MESENTERY OR OTHER

6134
03:58:12,680 --> 03:58:16,720
PERITONEAL CALFITY     CAVITY TO

6135
03:58:16,720 --> 03:58:18,480
THE OMENTUM WILL END UP DRAINING

6136
03:58:18,480 --> 03:58:21,240
INTO THE ROOT OF THE NETWORK,

6137
03:58:21,240 --> 03:58:23,840
BUT USUALLY AT LEAST WE DON'T

6138
03:58:23,840 --> 03:58:25,480
SEE IT'S COMPLETELY WIRED THE

6139
03:58:25,480 --> 03:58:26,400
SAME WAY.

6140
03:58:26,400 --> 03:58:32,640
BUT I DID   DIDN'T UNDERSTAND TE

6141
03:58:32,640 --> 03:58:34,320
LYMPH NODE TRANSFER PART OF THE

6142
03:58:34,320 --> 03:58:36,320
QUESTION, SO IN TERMS OF IBD, I

6143
03:58:36,320 --> 03:58:41,800
DON'T THINK THAT THE FIELD HAS

6144
03:58:41,800 --> 03:58:42,880
THINGS THAT -- REMOVING THE

6145
03:58:42,880 --> 03:58:45,600
OMENTUM OR ITS LYMPHATICS WOULD

6146
03:58:45,600 --> 03:58:46,840
DIRECTLY IMPACT THE GUT.

6147
03:58:46,840 --> 03:58:47,720
>> OKAY.

6148
03:58:47,720 --> 03:58:48,480
THANK YOU.

6149
03:58:48,480 --> 03:58:51,320
THE NEXT QUESTION ALSO FOR

6150
03:58:51,320 --> 03:58:52,080
RAFAEL.

6151
03:58:52,080 --> 03:58:53,600
THIS IS FROM ANDREA.

6152
03:58:53,600 --> 03:58:56,160
WOULD YOU LIKE TO UNMUTE AND ASK

6153
03:58:56,160 --> 03:58:56,680
YOUR QUESTION?

6154
03:58:56,680 --> 03:59:01,200
AN ANDREA, IF YOU ARE STILL THE?

6155
03:59:01,200 --> 03:59:03,400
>> BEAUTIFUL TALK, ELEGANT
WORK,

6156
03:59:03,400 --> 03:59:06,000
LOVE YOUR USE OF MULTIPLE

6157
03:59:06,000 --> 03:59:06,280
MODALITIES.

6158
03:59:06,280 --> 03:59:07,760
QUESTION S WITH THE LYMPH

6159
03:59:07,760 --> 03:59:09,280
LEAKAGE, ARE YOU ABLE TO PARTNER

6160
03:59:09,280 --> 03:59:10,640
THAT WITH A REPORTER ANIMAL THAT

6161
03:59:10,640 --> 03:59:12,680
MAY ALLOW YOU TO TRACK

6162
03:59:12,680 --> 03:59:14,360
INFILTRATION OF DIFFERENT

6163
03:59:14,360 --> 03:59:16,200
MYELOID CELLS OR, YOU KNOW, I

6164
03:59:16,200 --> 03:59:18,520
MEAN, THE GUESS THE QUESTION

6165
03:59:18,520 --> 03:59:20,840
TECHNICALLY, HOW MANY CHANNELS,

6166
03:59:20,840 --> 03:59:21,800
HOW MANY THINGS CAN YOU LOOK AT

6167
03:59:21,800 --> 03:59:24,440
IN YOUR TWO-PHOTON IMAGING?

6168
03:59:24,440 --> 03:59:26,360
JUST REALLY LOVED IT.

6169
03:59:26,360 --> 03:59:28,800
>> YES, SO I HAVE MAJORLY

6170
03:59:28,800 --> 03:59:31,120
FOCUSED MY 15-MINUTE TALK INTO

6171
03:59:31,120 --> 03:59:33,640
MORE THE LYMPHATIC, WHICH WAS

6172
03:59:33,640 --> 03:59:34,840
THE OVERARCHING QUESTION THAT WE

6173
03:59:34,840 --> 03:59:36,800
WERE DISCUSSING, BUT I SAW SOME

6174
03:59:36,800 --> 03:59:40,040
OTHER QUESTIONS RELATED TO WHAT

6175
03:59:40,040 --> 03:59:40,800
DO IMMUNE CELLS LOOK LIKE IN

6176
03:59:40,800 --> 03:59:45,360
THIS SCENARIO, AND I'VE HAD

6177
03:59:45,360 --> 03:59:46,680
IMMUNOLOGIST TRAINING SO I'VE

6178
03:59:46,680 --> 03:59:47,880
CHECKED SEVERAL OF THESE IMMUNE

6179
03:59:47,880 --> 03:59:50,280
CELLS THAT ARE PRESENT IN THE

6180
03:59:50,280 --> 03:59:51,840
TELOS AND THE LYMPHATICS.

6181
03:59:51,840 --> 03:59:56,880
SO SO FAR, WE HAVE BEEN DOING --

6182
03:59:56,880 --> 03:59:59,760
IT'S STILL RESTRICTED TO A

6183
03:59:59,760 --> 04:00:00,840
COUPLE CALLERS.

6184
04:00:00,840 --> 04:00:02,800
WE ARE TRYING TO EXPAND THIS A

6185
04:00:02,800 --> 04:00:03,560
LITTLE BIT MORE TO SEE IF THE

6186
04:00:03,560 --> 04:00:05,720
IMMUNE CELLS CAN COME OUT INTO

6187
04:00:05,720 --> 04:00:10,680
THE PERITONEAL CALFITY AND     G

6188
04:00:10,680 --> 04:00:12,320
THESE PHOTO TAGGING TECHNIQUES

6189
04:00:12,320 --> 04:00:14,120
TO TRY TO TRACE THAT, BUT AS FAR

6190
04:00:14,120 --> 04:00:17,600
AS WE CAN SEE NOW, THERE'S ALSO

6191
04:00:17,600 --> 04:00:18,680
ACCUMULATION AND BLOCKAGE, IS

6192
04:00:18,680 --> 04:00:22,880
THAT WE CAN SEE SO FAR, BUT IF

6193
04:00:22,880 --> 04:00:24,640
YOU ALLOW THE MOUSE MODEL TO

6194
04:00:24,640 --> 04:00:26,800
PROGRESS IN TERMS OF DISEASE AND

6195
04:00:26,800 --> 04:00:32,280
AGE, THEN YOU END UP DEVELOPING

6196
04:00:32,280 --> 04:00:33,160
ASCITES, SO IN THAT PAPER, I

6197
04:00:33,160 --> 04:00:34,720
REPORT A PERCENTAGE OF THE MICE

6198
04:00:34,720 --> 04:00:37,200
WHEN THEY ARE REALLY OLD, THEY

6199
04:00:37,200 --> 04:00:39,720
DEVELOP ASCITES, WHICH IS AN

6200
04:00:39,720 --> 04:00:42,040
ACCUMULATION OF LYMPH IN THE

6201
04:00:42,040 --> 04:00:42,680
PERITONEAL CALFITY.

6202
04:00:42,680 --> 04:00:48,080
BUT       CAVITY.

6203
04:00:48,080 --> 04:00:49,280
BUT WE ARE TRAINED SO WE CAN ADD

6204
04:00:49,280 --> 04:00:54,520
MORE MARKERS, WE CAN DO

6205
04:00:54,520 --> 04:00:55,480
HOPEFULLY MORE.

6206
04:00:55,480 --> 04:00:55,840
>> THANK YOU.

6207
04:00:55,840 --> 04:01:00,480
WE HAVE A QUESTION FROM A

6208
04:01:00,480 --> 04:01:01,280
PANELIST, TIM.

6209
04:01:01,280 --> 04:01:02,600
PLEASE UNMUTE AND ASK QUESTION.

6210
04:01:02,600 --> 04:01:06,400
>> HI, RAPHA.

6211
04:01:06,400 --> 04:01:07,760
YOU MENTIONED DID YOU START

6212
04:01:07,760 --> 04:01:10,160
LOOKING AT THE CELL TYPES IN

6213
04:01:10,160 --> 04:01:10,680
THESE TLOs.

6214
04:01:10,680 --> 04:01:13,760
ARE THEY NAIVE, ACTIVATED,

6215
04:01:13,760 --> 04:01:14,600
RESPONDING TO SOMETHING IN

6216
04:01:14,600 --> 04:01:14,920
PARTICULAR?

6217
04:01:14,920 --> 04:01:17,000
>> YES.

6218
04:01:17,000 --> 04:01:21,440
SO THE ANSWER HAS TWOFOLD.

6219
04:01:21,440 --> 04:01:25,480
ONE IS IF WE THINK ABOUT THE

6220
04:01:25,480 --> 04:01:26,320
LEUKOCYTE CIRCULATION WITHIN

6221
04:01:26,320 --> 04:01:27,120
LYMPHATICS, MOST OF THE CELLS

6222
04:01:27,120 --> 04:01:30,880
THAT ARE CIRCLE     CIRCULATINGB

6223
04:01:30,880 --> 04:01:32,280
AND T-CELLS THAT KEEP

6224
04:01:32,280 --> 04:01:33,720
CIRCULATING THROUGH SEVERAL

6225
04:01:33,720 --> 04:01:34,680
TISSUES AND THEY JUST KEEP

6226
04:01:34,680 --> 04:01:35,760
GOING, ESPECIALLY AT THE GUT,

6227
04:01:35,760 --> 04:01:37,480
THEY JUST KEEP COMING AND GOING.

6228
04:01:37,480 --> 04:01:39,640
SO THERE IS A BUNCH OF NAIVE

6229
04:01:39,640 --> 04:01:40,080
T-CELLS.

6230
04:01:40,080 --> 04:01:42,160
THEY ARE AT THE END OF

6231
04:01:42,160 --> 04:01:43,160
ACCUMULATING DUE TO THIS EFFECT

6232
04:01:43,160 --> 04:01:45,160
BUT WE ALSO HAVE -- WHEN WE LOOK

6233
04:01:45,160 --> 04:01:48,840
FOR THE ACTIVATED CELLS, WE HAVE

6234
04:01:48,840 --> 04:01:50,720
MORE ACTIVATED T-CELLS

6235
04:01:50,720 --> 04:01:53,120
ESPECIALLY.

6236
04:01:53,120 --> 04:01:57,240
AND THE OTHER WORK STUDYING THE

6237
04:01:57,240 --> 04:02:00,520
B CELLS, ALTERATION IN THE B

6238
04:02:00,520 --> 04:02:01,760
CELL AND ANTIBODIES.

6239
04:02:01,760 --> 04:02:03,680
SO WE SEE A MORE ACTIVATED --

6240
04:02:03,680 --> 04:02:07,040
SINCE THIS MOUSE MODEL IS HIGHLY

6241
04:02:07,040 --> 04:02:11,920
INFLAMMATORY, BUT IF   IF YOU JT

6242
04:02:11,920 --> 04:02:12,960
COUNT BY THE NUMBER, BECAUSE YOU

6243
04:02:12,960 --> 04:02:14,400
HAVE THIS OBSTRUCTION, YOU END

6244
04:02:14,400 --> 04:02:15,760
UP ACCUMULATING THE CELLS THEY

6245
04:02:15,760 --> 04:02:17,720
MOVE THE MOST TO, SO WE END UP

6246
04:02:17,720 --> 04:02:20,000
HAVING A LOT OF NAIVE CELLS.

6247
04:02:20,000 --> 04:02:21,680
AND IT'S IMPORTANT TO MENTION

6248
04:02:21,680 --> 04:02:26,640
THAT THESE TELOS ARE ALSO,

6249
04:02:26,640 --> 04:02:28,640
BECAUSE THEY'RE -- WITH A

6250
04:02:28,640 --> 04:02:31,200
DIFFERENT WEIRD STRUCTURE, THEY

6251
04:02:31,200 --> 04:02:34,600
ALLOW CELLS GOING FROM THE BLOOD

6252
04:02:34,600 --> 04:02:36,000
CIRCULATION GOING INTO IT.

6253
04:02:36,000 --> 04:02:37,960
IN A SMALLER PACE.

6254
04:02:37,960 --> 04:02:43,360
>> AND IS THERE OUTFLOW
TRACT,

6255
04:02:43,360 --> 04:02:45,560
LIKE S1P DEPENDENT AND ALL THOSE

6256
04:02:45,560 --> 04:02:45,760
THINGS?

6257
04:02:45,760 --> 04:02:47,640
>> THAT IS THE PART THAT I
STILL

6258
04:02:47,640 --> 04:02:48,960
HAVEN'T FOLLOWED UP ON, AND WE

6259
04:02:48,960 --> 04:02:50,240
REALLY WANT TO UNDERSTAND THE

6260
04:02:50,240 --> 04:02:54,760
PART LIKE HOW -- BECAUSE AT SOME

6261
04:02:54,760 --> 04:02:56,400
LEVEL CELLS EXIT OTHERWISE YOU

6262
04:02:56,400 --> 04:02:59,240
WILL EXPLODE, SO WE ARE TRYING

6263
04:02:59,240 --> 04:03:00,880
TO UNDERSTAND HOW MUCH IS THE

6264
04:03:00,880 --> 04:03:02,800
EXIT, AND IF THERE ARE ANY OTHER

6265
04:03:02,800 --> 04:03:03,560
REROUTING OF THE LYMPHATIC

6266
04:03:03,560 --> 04:03:04,640
DRAINAGE THAT IS HAPPENING IN

6267
04:03:04,640 --> 04:03:10,680
THE GUT, IF IT'S MORE MALLABLE,

6268
04:03:10,680 --> 04:03:15,920
SO THERE IS A SIZE WE ARE

6269
04:03:15,920 --> 04:03:16,200
EXPLORING.

6270
04:03:16,200 --> 04:03:19,320
>> SELEN, WOULD YOU LIKE
TO

6271
04:03:19,320 --> 04:03:20,560
UNMUTE AND ANSWER THE QUESTION?

6272
04:03:20,560 --> 04:03:21,880
>> THANKS FOR ANSWERING MY

6273
04:03:21,880 --> 04:03:22,640
ORIGINAL QUESTION AND I WOULD

6274
04:03:22,640 --> 04:03:23,720
LIKE TO FOLLOW UP ON THAT.

6275
04:03:23,720 --> 04:03:25,600
I WAS WONDERING IF YOU CHECKED

6276
04:03:25,600 --> 04:03:30,200
OR ARE YOU PLANNING TO CHECK THE

6277
04:03:30,200 --> 04:03:33,080
LVR RECEPTIVE FAMILIES

6278
04:03:33,080 --> 04:03:36,160
BASICALLY, EXPRESSION ON THE

6279
04:03:36,160 --> 04:03:38,760
LYMPHATIC VESSEL WALL, BECAUSE

6280
04:03:38,760 --> 04:03:40,120
BASE KRI MY QUESTION IS IN TWO

6281
04:03:40,120 --> 04:03:40,320
PARTS.

6282
04:03:40,320 --> 04:03:43,920
THE PAI-1 AND UATPA, THEY ARE

6283
04:03:43,920 --> 04:03:45,760
REGULATED BY THE ALVEOLI

6284
04:03:45,760 --> 04:03:47,640
RECEPTORS SO PROBABLY YOU HAVE

6285
04:03:47,640 --> 04:03:50,160
SOME EFFECT, SO THAT YOU CAN

6286
04:03:50,160 --> 04:03:52,800
SEE, I KNOW THAT YOU GUYS ARE

6287
04:03:52,800 --> 04:03:54,120
USING APOE BUT YOU MIGHT WANT TO

6288
04:03:54,120 --> 04:03:58,040
CONSIDER USING LDR RECEPTOR

6289
04:03:58,040 --> 04:03:58,720
KNOCKOUT BACKGROUNDS.

6290
04:03:58,720 --> 04:04:00,400
>> THAT'S A GREAT
QUESTION, AND

6291
04:04:00,400 --> 04:04:01,200
GREAT FOLLOW-UP.

6292
04:04:01,200 --> 04:04:05,240
SO YES, ACTUALLY ONE OF THE LAST

6293
04:04:05,240 --> 04:04:06,600
SLIDES OF MY PRESENTATION, I

6294
04:04:06,600 --> 04:04:11,880
WENT NO IT REALLY        INTO II

6295
04:04:11,880 --> 04:04:13,560
HAD A DIAGRAM OF THE DIFFERENT

6296
04:04:13,560 --> 04:04:16,200
PROTEINS KNOWN TO INTERACT WITH

6297
04:04:16,200 --> 04:04:17,960
PAI-1 AND 1 IS WHAT YOU'RE

6298
04:04:17,960 --> 04:04:18,840
SAYING IS THE LDR.

6299
04:04:18,840 --> 04:04:21,800
SO WE'RE DEFINITELY LOOKING INTO

6300
04:04:21,800 --> 04:04:23,880
ALL THESE PROTEINS KNOWN TO

6301
04:04:23,880 --> 04:04:25,160
REGULATE FIBROSIS AND PERHAPS

6302
04:04:25,160 --> 04:04:28,040
THOSE COULD BE THE ONES

6303
04:04:28,040 --> 04:04:29,800
RESPONSIBLE FOR STIFFENING OF

6304
04:04:29,800 --> 04:04:32,000
WHAT WE BELIEVE IS STIFF EPING

6305
04:04:32,000 --> 04:04:34,880
OF THE LYMPHATIC VALVES.

6306
04:04:34,880 --> 04:04:36,760
WHEN WE'RE DOING THESE

6307
04:04:36,760 --> 04:04:39,560
SPAIRNLTS, WE       

6308
04:04:39,560 --> 04:04:43,560
EXPERIMENTS LIE   LIKE THOSE PAE

6309
04:04:43,560 --> 04:04:44,760
PRESSURE CURVES JUST TO TRY TO

6310
04:04:44,760 --> 04:04:46,080
SEE IF THERE WAS EVIDENCE OF

6311
04:04:46,080 --> 04:04:47,840
STIFFENING THE HOLDING FATTY

6312
04:04:47,840 --> 04:04:49,720
WALL, WE COULDN'T REALLY

6313
04:04:49,720 --> 04:04:50,560
DETECT -- THERE WAS A SMALL

6314
04:04:50,560 --> 04:04:52,320
TREND FOR VESSELS TO BE STIFFER

6315
04:04:52,320 --> 04:04:55,320
BUT IT WAS NOT STATISTICALLY

6316
04:04:55,320 --> 04:04:57,600
SIGNIFICANT, BUT WE BELIEVE THAT

6317
04:04:57,600 --> 04:05:00,000
JUST -- THE DATA SHOWING THAT

6318
04:05:00,000 --> 04:05:02,760
THESE LYMPHATIC VALVES FROM THE

6319
04:05:02,760 --> 04:05:05,000
OBESE MICE REQUIRES SO MUCH

6320
04:05:05,000 --> 04:05:06,480
ADVERSE PRESSURE TO CLOSE THEM,

6321
04:05:06,480 --> 04:05:16,960
WE BELIEVE THAT THAT'S -- WE

6322
04:05:18,080 --> 04:05:19,080
COULDN'T FIND ANY OTHER

6323
04:05:19,080 --> 04:05:20,120
STRUCTURAL ABNORMALITIES.

6324
04:05:20,120 --> 04:05:22,760
>> THANK YOU.

6325
04:05:22,760 --> 04:05:31,920
>> NATASZA.

6326
04:05:31,920 --> 04:05:34,360
>> I HAVE A QUESTION FOR
NADA, A

6327
04:05:34,360 --> 04:05:36,120
COMMENT IT WAS A BEAUTIFUL TALK

6328
04:05:36,120 --> 04:05:36,720
AND A VERY IMPORTANT ONE AS

6329
04:05:36,720 --> 04:05:38,000
WELL.

6330
04:05:38,000 --> 04:05:39,840
DO YOUR MUTANTS DEVELOP FATTY

6331
04:05:39,840 --> 04:05:41,840
LIVER DISEASE AND DO YOU KNOW

6332
04:05:41,840 --> 04:05:43,760
HOW THE LIPIDS ENTER THE PORTAL

6333
04:05:43,760 --> 04:05:44,840
CIRCULATION?

6334
04:05:44,840 --> 04:05:47,640
HAVE YOU THOUGHT ABOUT VLDL OR

6335
04:05:47,640 --> 04:05:52,560
PERHAPS HDL AS A CARRIER?

6336
04:05:52,560 --> 04:05:56,480
>> THEY DEVELOP FATTY
LIVER AFER

6337
04:05:56,480 --> 04:05:58,920
THEY EAT -- YOU KNOW, AFTER A

6338
04:05:58,920 --> 04:06:02,040
MEAL, BUT NOT -- WELL, WE

6339
04:06:02,040 --> 04:06:04,120
HAVEN'T REALLY LOOKED AT IT

6340
04:06:04,120 --> 04:06:05,400
EXTENSIVELY, BUT WE KNOW THAT

6341
04:06:05,400 --> 04:06:11,920
THEY HAVE MORE FAT -- THE LIVER

6342
04:06:11,920 --> 04:06:15,520
POST PRAN     

6343
04:06:15,520 --> 04:06:20,160
POSTPRANDIALLY, AFTER A MEAL.

6344
04:06:20,160 --> 04:06:20,360
BUT --

6345
04:06:20,360 --> 04:06:23,760
>> DO YOU HAVE ANY IDEA
HOW THEY

6346
04:06:23,760 --> 04:06:25,280
ENTER THE PORTAL VEIN?

6347
04:06:25,280 --> 04:06:26,640
DO THEY ENTER --

6348
04:06:26,640 --> 04:06:30,360
>> WELL, WE   WE KNOW THAT
THE

6349
04:06:30,360 --> 04:06:31,560
ENDOTHELIUM IS LEAKY TOO.

6350
04:06:31,560 --> 04:06:33,120
THAT'S REALLY WHY.

6351
04:06:33,120 --> 04:06:34,480
AND THAT'S WHAT I WAS TRYING TO

6352
04:06:34,480 --> 04:06:35,680
GET TO AT THE END.

6353
04:06:35,680 --> 04:06:38,160
IT'S HARD TO BE CLEAR IN A

6354
04:06:38,160 --> 04:06:41,880
15-MINUTE TALK, BUT THE

6355
04:06:41,880 --> 04:06:46,960
ENDOTHELIUM IS ALSO LEAKY.

6356
04:06:46,960 --> 04:06:48,720
SO THIS IS PROBABLY HOW THEY GET

6357
04:06:48,720 --> 04:06:52,560
THERE.

6358
04:06:52,560 --> 04:06:52,880
>> THANK YOU.

6359
04:06:52,880 --> 04:06:55,960
>> THE PERICELLULAR
PATHWAY IS

6360
04:06:55,960 --> 04:06:57,920
PROBABLY NOT AS -- AS IT SHOULD

6361
04:06:57,920 --> 04:06:58,360
BE.

6362
04:06:58,360 --> 04:07:00,040
THIS IS WHAT WE ARE TESTING

6363
04:07:00,040 --> 04:07:02,760
RIGHT NOW.

6364
04:07:02,760 --> 04:07:11,080
ONE THING THAT I WOULD LIKE TO

6365
04:07:11,080 --> 04:07:12,800
SAY, WE KNOW LIPIDS GO INTO --

6366
04:07:12,800 --> 04:07:16,560
WE ACTUALLY ARE NOW WORKING ON

6367
04:07:16,560 --> 04:07:18,200
LIPIDS BEING DELIVERED THROUGH

6368
04:07:18,200 --> 04:07:20,560
EXOSOMES, AND I WAS WONDERING,

6369
04:07:20,560 --> 04:07:24,400
IS THERE ANYBODY WORKING ON THE

6370
04:07:24,400 --> 04:07:25,920
LYMPHATIC SYSTEM RELEASING

6371
04:07:25,920 --> 04:07:27,760
EXOSOMES WHICH COULD REGULATE

6372
04:07:27,760 --> 04:07:32,480
OTHER CELLS IN -- BECAUSE THE

6373
04:07:32,480 --> 04:07:34,040
BLOOD ENDOTHELIUM RELEASES A LOT

6374
04:07:34,040 --> 04:07:37,360
OF EXOSOMES, INCLUDING LIPID

6375
04:07:37,360 --> 04:07:38,280
CONTAINING EXOSOMES.

6376
04:07:38,280 --> 04:07:39,200
MAYBE SOMEBODY CAN COMMENT WHEN

6377
04:07:39,200 --> 04:07:40,320
WE HAVE TIME LATER.

6378
04:07:40,320 --> 04:07:42,640
>> YEAH, THAT'S
INTRIGUING.

6379
04:07:42,640 --> 04:07:43,840
SO HAVE YOU LOOKED AT YOUR

6380
04:07:43,840 --> 04:07:47,560
SYSTEM USING TRANSMISSION

6381
04:07:47,560 --> 04:07:47,960
ELECTROMICROSCOPY?

6382
04:07:47,960 --> 04:07:52,520
>> YES.

6383
04:07:52,520 --> 04:07:53,720
WITH RESPECT, YOU MEAN, TO

6384
04:07:53,720 --> 04:07:54,200
STRUCTURE OF --

6385
04:07:54,200 --> 04:07:55,440
>> YEAH, WITH RESPECT TO

6386
04:07:55,440 --> 04:07:57,000
STRUCTURE TO LOOK AT THESE

6387
04:07:57,000 --> 04:07:57,400
VESICLES.

6388
04:07:57,400 --> 04:07:57,600
INTO

6389
04:07:57,600 --> 04:07:58,800
>> YES, WE HAVE.

6390
04:07:58,800 --> 04:07:59,200
YEAH.

6391
04:07:59,200 --> 04:08:03,240
WE CAN DISCUSS THAT LATER ON.

6392
04:08:03,240 --> 04:08:08,320
WE DID CON FOE KOL AND ALSO

6393
04:08:08,320 --> 04:08:08,960
TRANSMISSION ELECTROMICROSCOPY.

6394
04:08:08,960 --> 04:08:10,080
>> THANKS VERY MUCH.

6395
04:08:10,080 --> 04:08:10,840
>> OKAY.

6396
04:08:10,840 --> 04:08:16,680
SO THE NEXT QUESTION FOR DARIA.

6397
04:08:16,680 --> 04:08:21,160
GIVEN THE INTESTINAL PARASITIC

6398
04:08:21,160 --> 04:08:23,600
WORM INFECTION ORDERS THE GUT

6399
04:08:23,600 --> 04:08:24,640
MICROBIOME, CAN YOU SEPARATE THE

6400
04:08:24,640 --> 04:08:27,000
INFERENCE OF THE WORM FROM THE

6401
04:08:27,000 --> 04:08:30,520
GUT MICROBIOME ON LYMPHATIC

6402
04:08:30,520 --> 04:08:30,800
ALTERATIONS?

6403
04:08:30,800 --> 04:08:31,400
>> OKAY.

6404
04:08:31,400 --> 04:08:34,320
IT'S SOMETHING I ANSWERED IN THE

6405
04:08:34,320 --> 04:08:36,640
CHAT BUT BECAUSE FOR OTHERS AS

6406
04:08:36,640 --> 04:08:38,720
WELL, I WILL BRIEFLY SAY T IT'S

6407
04:08:38,720 --> 04:08:40,280
TOUGH TO DO THAT, AND IT'S A

6408
04:08:40,280 --> 04:08:41,160
GREAT QUESTION BECAUSE IF YOU

6409
04:08:41,160 --> 04:08:43,800
HAVE GERM-FREE MICE OR

6410
04:08:43,800 --> 04:08:44,760
ANTIBIOTIC-TREATED MICE, THAT ON

6411
04:08:44,760 --> 04:08:47,640
ITS OWN CHANGES THE LYMPHATICS

6412
04:08:47,640 --> 04:08:49,200
MASSIVELY, SO YOU'RE GOING TO

6413
04:08:49,200 --> 04:08:50,720
LOOK AT A VERY DIFFERENT

6414
04:08:50,720 --> 04:08:51,800
SITUATION.

6415
04:08:51,800 --> 04:08:52,720
THE OTHER IS THAT IN ORDER TO

6416
04:08:52,720 --> 04:08:55,440
GROW THE WORM, WE NEED MICROBES.

6417
04:08:55,440 --> 04:08:57,320
THERE ARE PEOPLE OUT THERE WHO

6418
04:08:57,320 --> 04:08:59,640
HAVE THOSE SPECIFIC MICROBES

6419
04:08:59,640 --> 04:09:01,360
THAT WON'T EXIST IN THE GUT, SO

6420
04:09:01,360 --> 04:09:02,960
ONE COULD TRY THAT WAY.

6421
04:09:02,960 --> 04:09:05,120
BUT WHAT I WILL SAY IS THAT THE

6422
04:09:05,120 --> 04:09:06,240
DUODENUM, WHILE I'M THE LAST ONE

6423
04:09:06,240 --> 04:09:09,760
TO SAY THE DUODENUM PLY CROW

6424
04:09:09,760 --> 04:09:10,400
BIOME ISN'T IMPORTANT BUT IT'S

6425
04:09:10,400 --> 04:09:12,600
NOT VERY HIGHLY POPULATED BY

6426
04:09:12,600 --> 04:09:14,600
MICROBES.

6427
04:09:14,600 --> 04:09:17,120
WHAT I WOULD SUSPECT, SOMETHING

6428
04:09:17,120 --> 04:09:18,640
WE'RE PURSUING NOW WITH AN IDEA,

6429
04:09:18,640 --> 04:09:20,160
WHY YOU MIGHT WANT TO CLOSE UP

6430
04:09:20,160 --> 04:09:21,960
THE LYMPHATICS IS TO ACTUALLY

6431
04:09:21,960 --> 04:09:24,280
PROTECT AGAINST LEAKAGE OF

6432
04:09:24,280 --> 04:09:26,200
BACTERIA, WHETHER YOU CHANGE THE

6433
04:09:26,200 --> 04:09:27,760
COMPOSITION OR NOT, BECAUSE YOU

6434
04:09:27,760 --> 04:09:29,200
OBVIOUSLY DAMAGE THE EPITHELIUM

6435
04:09:29,200 --> 04:09:31,160
WITH A WORM VERY HEAVILY, AND

6436
04:09:31,160 --> 04:09:33,040
THAT MIGHT BE ONE OF THE

6437
04:09:33,040 --> 04:09:33,520
PROTECTIVE MECHANISMS.

6438
04:09:33,520 --> 04:09:36,320
BUT IT SOMETHING THAT IS VERY

6439
04:09:36,320 --> 04:09:37,200
VALID AND A GOOD QUESTION AND

6440
04:09:37,200 --> 04:09:39,400
THE  

6441
04:09:39,400 --> 04:09:44,040
YET TO BE DETERMINED FULLY.

6442
04:09:44,040 --> 04:09:45,560
>> 2 MINUTES REMAINING.

6443
04:09:45,560 --> 04:09:47,480
GLL HOW    

6444
04:09:47,480 --> 04:09:48,360
>> HOW MUCH, JOHN?

6445
04:09:48,360 --> 04:09:49,400
>> 2 MINUTES.

6446
04:09:49,400 --> 04:09:51,280
>> OKAY.

6447
04:09:51,280 --> 04:09:51,480
ZORINA?

6448
04:09:51,480 --> 04:09:51,840
>> HI.

6449
04:09:51,840 --> 04:09:53,800
I THOUGHT I USED TO TWO MINUTES

6450
04:09:53,800 --> 04:09:57,120
TO SEE IF I CAN FIND OUT WHETHER

6451
04:09:57,120 --> 04:09:58,400
WE COULD LEARN MORE ABOUT THE

6452
04:09:58,400 --> 04:10:00,720
ROLE OF THE MICROBIOME IN

6453
04:10:00,720 --> 04:10:02,760
INTERTESSAL ABSORPTION,

6454
04:10:02,760 --> 04:10:03,960
SPECIFICALLY LYMPHATICS SEEMS TO

6455
04:10:03,960 --> 04:10:10,400
BE VERY IMPORTANT, YET I DIDN'T

6456
04:10:10,400 --> 04:10:11,680
HEAR MUCH AND IS THAT BECAUSE OF

6457
04:10:11,680 --> 04:10:12,920
CHALLENGES IN EXPERIMENTATION,

6458
04:10:12,920 --> 04:10:14,160
SO IF ANYBODY WOULD LIKE TO

6459
04:10:14,160 --> 04:10:14,400
COMMENT.

6460
04:10:14,400 --> 04:10:14,880
THANK YOU.

6461
04:10:14,880 --> 04:10:16,440
>> ANYBODY WOULD LIKE TO
COMMENT

6462
04:10:16,440 --> 04:10:19,680
ABOUT THIS?

6463
04:10:19,680 --> 04:10:21,240
>> SO THE ONE THING I
COMMENT ON

6464
04:10:21,240 --> 04:10:22,640
IS THAT I THINK IT IS

6465
04:10:22,640 --> 04:10:23,400
CHALLENGING, BECAUSE AS YOU

6466
04:10:23,400 --> 04:10:25,240
CHANGE THE MICROBIOME, THE

6467
04:10:25,240 --> 04:10:27,720
LYMPHATICS ARE JUST PART OF

6468
04:10:27,720 --> 04:10:29,680
WHAT'S BEING CHANGED.

6469
04:10:29,680 --> 04:10:32,440
IF THE EPITHELIUM STRUCTURE

6470
04:10:32,440 --> 04:10:33,560
CHANGES MASSIVELY, THE WHOLE GUT

6471
04:10:33,560 --> 04:10:35,760
STRUCTURE CHANGES MASSIVELY.

6472
04:10:35,760 --> 04:10:39,160
SMALL INTESTINE -- THE DUODENUM

6473
04:10:39,160 --> 04:10:44,200
HAS TWEIST AS BIG        TWICE .

6474
04:10:44,200 --> 04:10:44,840
SO TO ASSOCIATE BETWEEN THE

6475
04:10:44,840 --> 04:10:47,400
EFFECT OF THE MICROBIOTA ON THE

6476
04:10:47,400 --> 04:10:48,920
EPITHELIUM VERSUS THE LYMPHATICS

6477
04:10:48,920 --> 04:10:53,000
OR INDIRECTLY ON HOW WE ABSORB

6478
04:10:53,000 --> 04:10:54,640
FOOD, AND HOW THE GUT ADAPTS TO

6479
04:10:54,640 --> 04:10:56,360
THE FACT THAT YOU FOR EXAMPLE

6480
04:10:56,360 --> 04:10:57,920
CAN'T FERMENT FIBERS ANYMORE,

6481
04:10:57,920 --> 04:10:59,280
THAT'S THE CHALLENGING PART

6482
04:10:59,280 --> 04:10:59,600
THERE.

6483
04:10:59,600 --> 04:11:01,000
ONE WOULD PROBABLY HAVE TO --

6484
04:11:01,000 --> 04:11:03,440
AND AGAIN, IT'S NOT PERFECT --

6485
04:11:03,440 --> 04:11:06,760
DO EITHER LYMPHATIC SPECIFIC

6486
04:11:06,760 --> 04:11:08,960
KNOCKOUTS OF BACTERIAL SENSORS

6487
04:11:08,960 --> 04:11:12,880
LIKE -- VERSUS THE EPITHELIUM,

6488
04:11:12,880 --> 04:11:14,200
AGAIN -- ALREADY CHANGES SO

6489
04:11:14,200 --> 04:11:14,400
MUCH.

6490
04:11:14,400 --> 04:11:16,640
BUT I WOULD SUSPECT THAT THE

6491
04:11:16,640 --> 04:11:19,840
MICROBIOTA PLAYS A MORE DIRECT

6492
04:11:19,840 --> 04:11:21,840
ROLE ON THE LYMPHATICS LOWER

6493
04:11:21,840 --> 04:11:23,160
DOWN IN THE INTESTINE.

6494
04:11:23,160 --> 04:11:24,640
ON THE UPPER INTESTINE BECAUSE

6495
04:11:24,640 --> 04:11:27,320
IT'S SO IMPORTANT FOR FOOD

6496
04:11:27,320 --> 04:11:28,320
ABSORPTION YOU ALWAYS HAVE THAT

6497
04:11:28,320 --> 04:11:29,640
SORT OF INTERMEDIATE INTERPLAY

6498
04:11:29,640 --> 04:11:30,040
AS WELL.

6499
04:11:30,040 --> 04:11:31,160
>> THANK YOU, DARIA.

6500
04:11:31,160 --> 04:11:34,080
SO TAKING ADVANTAGE AS

6501
04:11:34,080 --> 04:11:34,800
MODERATOR, I'D LIKE TO FINISH

6502
04:11:34,800 --> 04:11:37,560
WITH THE LAST QUESTION ABOUT THE

6503
04:11:37,560 --> 04:11:41,880
LIVER LYMPHATICS.

6504
04:11:41,880 --> 04:11:43,920
WHETHER YOU THINK THE MECHANISM

6505
04:11:43,920 --> 04:11:45,880
OF LYMPHATIC REGRESSION BETWEEN

6506
04:11:45,880 --> 04:11:48,440
TWO WEEKS AND FOUR WEEKS OF

6507
04:11:48,440 --> 04:11:52,800
THE -- DOES THAT OCCUR IN VEGF C

6508
04:11:52,800 --> 04:11:53,000
MICE?

6509
04:11:53,000 --> 04:11:55,440
I WANT TO MENTION THAT -- IS

6510
04:11:55,440 --> 04:11:58,640
SIGNIFICANTLY INCREASED, THAT

6511
04:11:58,640 --> 04:12:00,520
ACTUALLY SUR PRISS THE VESSEL

6512
04:12:00,520 --> 04:12:00,760
GROWTH.

6513
04:12:00,760 --> 04:12:01,680
THAT IS ONE OF THE MECHANISMS

6514
04:12:01,680 --> 04:12:04,480
THAT WE HAVE SEEN A REGRESSION

6515
04:12:04,480 --> 04:12:06,760
OR DECREASE IN LYMPHATIC VESSELS

6516
04:12:06,760 --> 04:12:10,880
AS AND  .

6517
04:12:10,880 --> 04:12:12,280
AND THE OTHER QUESTION ISING

6518
04:12:12,280 --> 04:12:14,240
FROM PATRICIA, THE LYMPHATIC

6519
04:12:14,240 --> 04:12:18,120
VESSEL IN THE LIVER REGENERATE

6520
04:12:18,120 --> 04:12:19,440
IN TRANSPLANTED LIVER?

6521
04:12:19,440 --> 04:12:20,520
THIS IS A VERY GOOD QUESTION,

6522
04:12:20,520 --> 04:12:22,160
ACTUALLY WE ARE STUDYING THIS.

6523
04:12:22,160 --> 04:12:28,480
WE TRANS    TRANSPLANTED THE LIM

6524
04:12:28,480 --> 04:12:30,560
MICE AND DOES IT REGROW OR

6525
04:12:30,560 --> 04:12:31,880
CONNECT TO THE HOST, SO

6526
04:12:31,880 --> 04:12:33,440
HOPEFULLY WE CAN SHOW THAT SOME

6527
04:12:33,440 --> 04:12:34,600
TIME IN THE FUTURE.

6528
04:12:34,600 --> 04:12:35,880
NOW I'D LIKE TO CONCLUDE WITH

6529
04:12:35,880 --> 04:12:36,400
SESSION THREE WILL.

6530
04:12:36,400 --> 04:12:38,280
I'D     .

6531
04:12:38,280 --> 04:12:39,880
I'D LIKE TO THANK ALL THE

6532
04:12:39,880 --> 04:12:41,520
FANTASTIC SPEAKERS AND ALSO THE

6533
04:12:41,520 --> 04:12:42,720
ACTIVE DISCUSSION BY THE

6534
04:12:42,720 --> 04:12:43,480
AUDIENCE.

6535
04:12:43,480 --> 04:12:45,320
THANK YOU VERY MUCH.

6536
04:12:45,320 --> 04:12:47,720
IT IS MY PLEASURE TO INTRODUCE

6537
04:12:47,720 --> 04:12:50,000
DR. TIMOTHY LE CRAS, ASSOCIATE

6538
04:12:50,000 --> 04:12:51,680
DEAN GRADUATE EDUCATION

6539
04:12:51,680 --> 04:12:52,920
UNIVERSITY OF CINCINNATI COLLEGE

6540
04:12:52,920 --> 04:12:55,200
OF MEDICINE, ALSO PROFESSOR IN

6541
04:12:55,200 --> 04:12:56,640
THE DEPARTMENT OF PEDIATRICS.

6542
04:12:56,640 --> 04:12:58,840
HE'S EXPERTS IN VAS QUEUE RASH

6543
04:12:58,840 --> 04:13:00,080
MALFORMATIONS AND DEVELOP.

6544
04:13:00,080 --> 04:13:01,040
HIS LAB MADE IMPORTANT

6545
04:13:01,040 --> 04:13:02,360
CONTRIBUTIONS TO DIAGNOSE AND

6546
04:13:02,360 --> 04:13:03,600
TREATMENT OF LYMPHATIC DISEASE

6547
04:13:03,600 --> 04:13:05,040
INCLUDING DEVELOPMENT OF

6548
04:13:05,040 --> 04:13:07,280
BIOMARKERS THAT ARE AVAILABLE TO

6549
04:13:07,280 --> 04:13:08,280
CLINICAL BLOOD TESTS.

6550
04:13:08,280 --> 04:13:10,560
I WANT TO THANK DR. LE CRAS FOR

6551
04:13:10,560 --> 04:13:12,280
JOINING US AND MODERATING THIS

6552
04:13:12,280 --> 04:13:12,880
EXCITING SESSION.

6553
04:13:12,880 --> 04:13:13,440
DR. LE CRAS.

6554
04:13:13,440 --> 04:13:15,360
>> THANK YOU VERY MUCH.

6555
04:13:15,360 --> 04:13:17,960
CAN YOU HEAR ME OKAY?

6556
04:13:17,960 --> 04:13:18,760
>> YES.

6557
04:13:18,760 --> 04:13:21,360
>> GREAT.

6558
04:13:21,360 --> 04:13:31,280
I'LL SHARE MY SLIDES.

6559
04:13:31,280 --> 04:13:36,040
CAN YOU SEE THE SLIDE OKAY?

6560
04:13:36,040 --> 04:13:36,520
GREAT.

6561
04:13:36,520 --> 04:13:38,560
GOOD AFTERNOON, EVERYBODY.

6562
04:13:38,560 --> 04:13:40,360
THANK YOU FOR YOUR ATTENTION.

6563
04:13:40,360 --> 04:13:42,480
MY NAME IS TIM LE CLAS AND I'M

6564
04:13:42,480 --> 04:13:45,920
GOING TO BE MODERATING SESSION 4

6565
04:13:45,920 --> 04:13:47,120
THIS AFTERNOON.

6566
04:13:47,120 --> 04:13:49,040
SO E WE'LL START WITH MY TALK

6567
04:13:49,040 --> 04:13:51,760
THEN THAT WILL BE FOLLOWED BY

6568
04:13:51,760 --> 04:13:54,360
PRESENTATION DR. MICHAEL

6569
04:13:54,360 --> 04:13:56,760
DELLINGER, THEN DR. EDWARD

6570
04:13:56,760 --> 04:13:59,600
SCHWARZ AND THEN DR. SUSAN

6571
04:13:59,600 --> 04:14:00,600
QUAGGIN.

6572
04:14:00,600 --> 04:14:06,760
I'LL GET STARTED.

6573
04:14:06,760 --> 04:14:08,440
TODAY I'M GOING TO TALK TO YOU

6574
04:14:08,440 --> 04:14:10,960
ABOUT THE PATHOGENESIS AND

6575
04:14:10,960 --> 04:14:17,000
TREATMENT OF COMPOSITE FORM

6576
04:14:17,000 --> 04:14:17,520
LYMPHANGIOMATOSIS.

6577
04:14:17,520 --> 04:14:19,080
BEFORE I FOCUS ON THAT

6578
04:14:19,080 --> 04:14:20,160
PARTICULAR DISEASE I WILL GIVE A

6579
04:14:20,160 --> 04:14:23,560
QUICK INTRODUCTION TO VASCULAR

6580
04:14:23,560 --> 04:14:24,920
ANOMALIES AND THAT AFFECT

6581
04:14:24,920 --> 04:14:27,920
CHILDREN AND CHUNG ADULTS.

6582
04:14:27,920 --> 04:14:31,000
VASCULAR ANOMALIES ARE IN TWO

6583
04:14:31,000 --> 04:14:34,640
MAIN GROUPS.  VASCULAR TUMORS

6584
04:14:34,640 --> 04:14:39,280
BENIGN LIKE HEMANGIOMAS LOCALLY

6585
04:14:39,280 --> 04:14:44,240
AGGRESSIVE LICK HE MANAGE MESS

6586
04:14:44,240 --> 04:14:45,640
SEW THILL OWE MA AND

6587
04:14:45,640 --> 04:14:46,040
ANGIOSARCOMA.

6588
04:14:46,040 --> 04:14:48,000
THE MALFORMATIONS CAN COMPRISE

6589
04:14:48,000 --> 04:14:51,520
OF CAPILLARY MALFORMATIONS,

6590
04:14:51,520 --> 04:14:53,760
VENUS ARTERIO VENUS AND THEN

6591
04:14:53,760 --> 04:14:55,320
LYMPHATIC MALFORMATIONS.

6592
04:14:55,320 --> 04:15:01,880
SO SOME EXAMPLES INCLUDE STOT

6593
04:15:01,880 --> 04:15:02,920
DISEASE AND DR. DELLINGER WILL

6594
04:15:02,920 --> 04:15:06,440
TALK ABOUT THAT DISEASE GORHAM

6595
04:15:06,440 --> 04:15:08,240
IN HIS PRESENTATION H.

6596
04:15:08,240 --> 04:15:09,680
GENERALIZED LYMPHATIC ANOMALY, I

6597
04:15:09,680 --> 04:15:12,040
WILL MENTION TODAY AND I WILL

6598
04:15:12,040 --> 04:15:17,080
FOCUS ON KAPOSIFORM OR KLA.

6599
04:15:17,080 --> 04:15:18,520
THEY CAN BE COMBINED

6600
04:15:18,520 --> 04:15:19,880
MALFORMATIONS THAT ENCOMPASS A

6601
04:15:19,880 --> 04:15:21,520
NUMBER OF COMPONENTS OF THE

6602
04:15:21,520 --> 04:15:26,480
VASCULAR SYSTEM SO LIKE CAPI

6603
04:15:26,480 --> 04:15:29,160
VENUS LYMPHATIC MALFORMATIONS.

6604
04:15:29,160 --> 04:15:33,880
SO KLA WAS ORIGINALLY DESCRIBED

6605
04:15:33,880 --> 04:15:37,880
BY CRETER ET AL IN 2014 SO

6606
04:15:37,880 --> 04:15:39,800
RELATIVELY RECENTLY IDENTIFIED.

6607
04:15:39,800 --> 04:15:41,560
IT AFFECTS CHILDREN AND YOUNG

6608
04:15:41,560 --> 04:15:42,280
ADULTS.

6609
04:15:42,280 --> 04:15:44,760
NO MALE FEMALE BIAS.

6610
04:15:44,760 --> 04:15:46,440
THE FA THOLINGS CHARACTERIZED BY

6611
04:15:46,440 --> 04:15:48,200
DIFFUSE MULTI-FOCAL LESIONS WITH

6612
04:15:48,200 --> 04:15:52,200
FOCAL AREAS OF LYMPHATIC

6613
04:15:52,200 --> 04:15:54,560
ENDTHELIAL CELLS AND MALFORMED

6614
04:15:54,560 --> 04:15:56,000
LYMPHATIC CHANNELS.

6615
04:15:56,000 --> 04:15:57,680
YOU CAN SEE IN THE TOP RIGHT

6616
04:15:57,680 --> 04:15:58,800
PANEL WHICH SHOWS PATHOLOGY FROM

6617
04:15:58,800 --> 04:16:02,320
A PATIENT WITH KLA.

6618
04:16:02,320 --> 04:16:04,280
PATIENTS SUFFER FROM HIGH

6619
04:16:04,280 --> 04:16:06,480
MORBIDITY AND MORTALITY,

6620
04:16:06,480 --> 04:16:08,280
PARTICULARLY CAUSED BY

6621
04:16:08,280 --> 04:16:09,520
HEMORRHAGIC EFFUSIONS, THAT CAN

6622
04:16:09,520 --> 04:16:12,200
INVOLVE THE LUNGS AND

6623
04:16:12,200 --> 04:16:14,160
PERICARDIUM AND CONSUMPTIVE

6624
04:16:14,160 --> 04:16:14,760
COAGULOPATHY.

6625
04:16:14,760 --> 04:16:17,760
ON THE RIGHTEOUS SEE L I HAVE

6626
04:16:17,760 --> 04:16:19,320
BEEN CONTRIBUTIONMPH ANGIOGRAM

6627
04:16:19,320 --> 04:16:22,960
THAT SHOWS THE NORMAL LYMPHATIC

6628
04:16:22,960 --> 04:16:25,760
VESSELS IN THIS PATIENT WITH

6629
04:16:25,760 --> 04:16:25,920
KLA.

6630
04:16:25,920 --> 04:16:27,520
IT IS A VERY CHALLENGING DISEASE

6631
04:16:27,520 --> 04:16:30,000
TO DIAGNOSE AND TREAT.

6632
04:16:30,000 --> 04:16:32,040
AND PATIENTS OFTEN RECEIVE

6633
04:16:32,040 --> 04:16:34,720
INCORRECT DIAGNOSIS AND THE

6634
04:16:34,720 --> 04:16:36,920
CORRECT DIAGNOSIS MAYBE DELAYED

6635
04:16:36,920 --> 04:16:40,080
FOR SEVERAL YEARS.

6636
04:16:40,080 --> 04:16:42,360
SO WE BECAME INTERESTED IN KLA

6637
04:16:42,360 --> 04:16:44,600
WHEN WE WERE INVOLVED IN A

6638
04:16:44,600 --> 04:16:46,200
CLINICAL TRIAL, A PHASE 2

6639
04:16:46,200 --> 04:16:47,760
CLINICAL TRIAL FOR THE TREATMENT

6640
04:16:47,760 --> 04:16:50,920
OF COMPLICATED VASCULAR

6641
04:16:50,920 --> 04:16:54,720
ANOMALIES RAP P MYOSIN, THIS IS

6642
04:16:54,720 --> 04:16:58,080
AN MTOR INHIBITOR LED BY DR.

6643
04:16:58,080 --> 04:16:59,880
DENISE ADAMS PUBLISHED IN 2016.

6644
04:16:59,880 --> 04:17:02,280
IN THIS STUDY CHILDREN AND YOUNG

6645
04:17:02,280 --> 04:17:03,960
ADULTS WERE TREATED WITH

6646
04:17:03,960 --> 04:17:07,240
COMPLICATED ANOMALIES WITH ORAL

6647
04:17:07,240 --> 04:17:09,920
SIROLIMUS THERAPY.

6648
04:17:09,920 --> 04:17:10,600
THE STUDY WAS TO DETERMINE

6649
04:17:10,600 --> 04:17:13,360
EFFICACY AND SAFETY OF SIROLIMUS

6650
04:17:13,360 --> 04:17:15,320
BUT A SECONDARY AIM OUR LAB WAS

6651
04:17:15,320 --> 04:17:17,480
INVOLVED IN WAS TO IDENTIFY

6652
04:17:17,480 --> 04:17:19,800
BLOOD BIOMARKERS.

6653
04:17:19,800 --> 04:17:22,000
SO BLOOD BIOMARKERS MIGHT AVOID

6654
04:17:22,000 --> 04:17:25,840
THE NEED FOR BIOPSY IN THESE

6655
04:17:25,840 --> 04:17:28,400
PATIENTS, POTENTIALLY PROGNOSIS

6656
04:17:28,400 --> 04:17:29,200
TREATMENT RESPONSE AND ALSO

6657
04:17:29,200 --> 04:17:31,240
IDENTIFY FACTORS AND PATHWAYS

6658
04:17:31,240 --> 04:17:34,120
INVOLVED IN THE PATHOGENESIS.

6659
04:17:34,120 --> 04:17:37,760
SO WE MEASURED KNOWN ANGIOGENIC

6660
04:17:37,760 --> 04:17:40,280
FACTORS IN THE PATIENT SERUM

6661
04:17:40,280 --> 04:17:41,720
USING ELISA.

6662
04:17:41,720 --> 04:17:43,160
WE FOUND VERY INTERESTING

6663
04:17:43,160 --> 04:17:44,560
DISCOVERY.

6664
04:17:44,560 --> 04:17:47,400
SO WE FOUND THAT IN TWO

6665
04:17:47,400 --> 04:17:49,520
PARTICULAR PATIENT GROUPS,

6666
04:17:49,520 --> 04:17:51,400
ANGIOPOIETIN 2 LEVELS,

6667
04:17:51,400 --> 04:17:53,120
ANGIOPOIETINS ARE ANGIOGENIC

6668
04:17:53,120 --> 04:17:55,400
FACTOR HIGHLY ELEVATED IN THE

6669
04:17:55,400 --> 04:18:03,080
BLOOD OF PATIENTS WITH KLA,

6670
04:18:03,080 --> 04:18:07,120
KAPOSIFORM HYMANGI ENDOTHELIOMA.

6671
04:18:07,120 --> 04:18:08,680
THE LABS WERE HIGHLY HE WILL

6672
04:18:08,680 --> 04:18:10,520
INVESTIGATED IN KLA PATIENTS

6673
04:18:10,520 --> 04:18:15,120
COMPARED TO PATIENT WITH

6674
04:18:15,120 --> 04:18:16,280
GENERALIZED LYMPHATIC ANOMALY

6675
04:18:16,280 --> 04:18:16,960
AND CONTROLS.

6676
04:18:16,960 --> 04:18:18,600
THERE'S CONTROVERSY WHETHER KLA

6677
04:18:18,600 --> 04:18:22,360
IS A MORE SEVERE FORM OF GLA BUT

6678
04:18:22,360 --> 04:18:24,720
THE LEVELS OF ANGIOPOIETIN 2

6679
04:18:24,720 --> 04:18:26,920
WERE HIGHER IN KLA PATIENTS AND

6680
04:18:26,920 --> 04:18:28,680
THE IDENTIFICATION OF MUTATIONS

6681
04:18:28,680 --> 04:18:31,040
IN THESE DISEASES NOW SUGGEST

6682
04:18:31,040 --> 04:18:34,400
THAT THEY ARE NOT DIFFERENT

6683
04:18:34,400 --> 04:18:37,360
SEVERITY FORMS.

6684
04:18:37,360 --> 04:18:39,280
SO WITH THE FINDING OF HIGHLY

6685
04:18:39,280 --> 04:18:41,480
ELEVATED ANGIOPOIETIN 2 LEVELS

6686
04:18:41,480 --> 04:18:42,800
THIS RAISED THE QUESTION OF WHAT

6687
04:18:42,800 --> 04:18:44,920
IS DRIVING THE ELEVATED

6688
04:18:44,920 --> 04:18:46,360
ANGIOPOIETIN 2 LEVELS IN THESE

6689
04:18:46,360 --> 04:18:49,200
KLA PATIENTS.

6690
04:18:49,200 --> 04:18:50,960
SO ABOUT TWO YEARS LATER AFTER

6691
04:18:50,960 --> 04:18:53,960
WE PUBLISHED THE ELEVATED

6692
04:18:53,960 --> 04:18:55,480
ANGIOPOIETIN 2 LEVELS, THIS

6693
04:18:55,480 --> 04:18:58,200
PAPER WAS PUBLISHED BY BARCLAY

6694
04:18:58,200 --> 04:19:00,280
ET AL AND THEY IDENTIFIED A

6695
04:19:00,280 --> 04:19:02,600
SOMATIC NRAS ACTIVATING MUTATION

6696
04:19:02,600 --> 04:19:05,640
IN THE KLA PATIENT LESIONS.

6697
04:19:05,640 --> 04:19:07,760
SO BY WHOLE EXOME SEQUENCING

6698
04:19:07,760 --> 04:19:12,600
THEY IDENTIFIED THE NRAS Q 61R

6699
04:19:12,600 --> 04:19:15,920
MUTATION IN 10 OUT OF 11 K,LA

6700
04:19:15,920 --> 04:19:16,280
PATIENTS.

6701
04:19:16,280 --> 04:19:18,640
THE ALLELIC FREQUENCY OF NRAS

6702
04:19:18,640 --> 04:19:21,640
MUTATION RANGED FROM ONE TO 28%.

6703
04:19:21,640 --> 04:19:24,920
SO NRAS IS A PROTO ONCOGENE IN

6704
04:19:24,920 --> 04:19:27,240
THE RAS GENE FAMILY THAT CODES

6705
04:19:27,240 --> 04:19:30,720
SMALL GTPASE THAT REGULATES CELL

6706
04:19:30,720 --> 04:19:31,360
PROLIFERATION.

6707
04:19:31,360 --> 04:19:35,240
MANY OF YOU MAY KNOW THIS NRAS Q

6708
04:19:35,240 --> 04:19:39,000
61R MUTATION IS FOUND IN GREATER

6709
04:19:39,000 --> 04:19:40,840
THAN 20% MELANOMAS, THYROID

6710
04:19:40,840 --> 04:19:42,800
CANCER AND OTHER TUMORS.

6711
04:19:42,800 --> 04:19:45,080
IT INCREASES MAP KINASE AND

6712
04:19:45,080 --> 04:19:47,200
KINASE SIGNALING PATHWAYS IN

6713
04:19:47,200 --> 04:19:51,000
UNCHECKED CELL PROLIFERATION.

6714
04:19:51,000 --> 04:19:52,960
SO AT THIS POINT WE KNEW THAT

6715
04:19:52,960 --> 04:19:56,680
KLA WAS CHARACTERIZED BY

6716
04:19:56,680 --> 04:19:58,360
SPINDLED EPITHELIAL CELLS THAN

6717
04:19:58,360 --> 04:19:59,160
NORMAL LYMPHATICS.

6718
04:19:59,160 --> 04:20:03,520
THE PAPER BY BARCLAY ET AL

6719
04:20:03,520 --> 04:20:04,440
IDENTIFY ID THIS MUTATION IN THE

6720
04:20:04,440 --> 04:20:05,600
PATIENT LESIONS.

6721
04:20:05,600 --> 04:20:08,840
AND WE FOUND THAT ANGIOPOIETIN 2

6722
04:20:08,840 --> 04:20:10,400
LEVELS WERE ELEVATED IN THE

6723
04:20:10,400 --> 04:20:11,720
BLOOD OF THE PATIENTS.

6724
04:20:11,720 --> 04:20:12,520
SO WE WERE INTERESTED IN

6725
04:20:12,520 --> 04:20:17,120
DETERMINING THE ROLE OF THIS

6726
04:20:17,120 --> 04:20:19,760
NRAS Q 61R MUTATION IN

6727
04:20:19,760 --> 04:20:20,480
PATHOGENESIS KLA.

6728
04:20:20,480 --> 04:20:23,720
TO ADDRESS THE QUESTIONS WE

6729
04:20:23,720 --> 04:20:27,520
DEVELOPED DOXY SIGH KLINE NRAS Q

6730
04:20:27,520 --> 04:20:29,120
61R AND WILD TYPE LENTO VIRAL

6731
04:20:29,120 --> 04:20:29,360
VECTORS.

6732
04:20:29,360 --> 04:20:30,560
YOU CAN SEE THE CONSTRUCTINGS

6733
04:20:30,560 --> 04:20:33,800
THE NRAS Q 61R VECTOR AT TOP AND

6734
04:20:33,800 --> 04:20:36,400
IN THE BOTTOM RIGHT HAND CORNER

6735
04:20:36,400 --> 04:20:37,360
THE NRS WILD TYPE EXPRESSING

6736
04:20:37,360 --> 04:20:39,080
VECTOR.

6737
04:20:39,080 --> 04:20:41,000
THESE ARE DOCK SIGH CYCLINE

6738
04:20:41,000 --> 04:20:44,440
INDUCIBLE VECTORS AND IT EBB

6739
04:20:44,440 --> 04:20:45,440
CODES RESISTANCE GENE.

6740
04:20:45,440 --> 04:20:47,880
SO WE PACKAGED THESE LENTIVIRAL

6741
04:20:47,880 --> 04:20:50,640
VECTORS INTO LEAN SHY VIRAL

6742
04:20:50,640 --> 04:20:52,520
PARTICLES AND USED THEM TO

6743
04:20:52,520 --> 04:20:53,040
TRANCES IF HE CAN HUMAN

6744
04:20:53,040 --> 04:20:54,440
ENDOTHELIAL PROGENITOR CELLS.

6745
04:20:54,440 --> 04:20:57,080
THESE ARE COMMONLY USED

6746
04:20:57,080 --> 04:20:58,760
ENDOTHELIAL CELL TYPE TO STUDY

6747
04:20:58,760 --> 04:21:00,040
ANGIOGENESIS.

6748
04:21:00,040 --> 04:21:05,120
SO WE ADDED PIRMICIN AND

6749
04:21:05,120 --> 04:21:07,000
SELECTED THE CELLS TAKEN UP NRAS

6750
04:21:07,000 --> 04:21:10,160
MUTANT OR WILD TYPE CONSTRUCTS.

6751
04:21:10,160 --> 04:21:11,840
TO INDUCE EXPRESSION OF MUTANT

6752
04:21:11,840 --> 04:21:14,400
OR WILD TYPE PROTEIN WE ADDED

6753
04:21:14,400 --> 04:21:15,720
DOXY CYCLINE TO THE MEDIA.

6754
04:21:15,720 --> 04:21:18,040
SO I'LL SHOW YOU DATA ON THE

6755
04:21:18,040 --> 04:21:19,480
CHANGES IN CELL SHAPE AND

6756
04:21:19,480 --> 04:21:22,080
SIGNALING PATHWAYS IN THESE

6757
04:21:22,080 --> 04:21:24,080
CELLS, MIGRATION OF

6758
04:21:24,080 --> 04:21:25,760
PROLIFERATION OF THE CELLS

6759
04:21:25,760 --> 04:21:28,880
ANGIOGENESIS MODELING IN V 20 IN

6760
04:21:28,880 --> 04:21:29,720
VIVO AND FINALLY SHOW YOU

6761
04:21:29,720 --> 04:21:33,320
EXPRESSION OF ANGIOPOIETIN 2.

6762
04:21:33,320 --> 04:21:35,520
SO TOP PANEL HERE, YOU CAN SEE

6763
04:21:35,520 --> 04:21:38,480
THAT WHEN WE ADD DOXY CYCLINE TO

6764
04:21:38,480 --> 04:21:42,680
THE MEDIA OF THE NRAS Q 61R

6765
04:21:42,680 --> 04:21:44,960
CELLS AND INDUCE NRAS BUT THE

6766
04:21:44,960 --> 04:21:46,760
CELLS BECOME SPINDLED AND CHANGE

6767
04:21:46,760 --> 04:21:47,280
SHAPE.

6768
04:21:47,280 --> 04:21:49,800
WHEREAS CELLS EXPRESS IN NRAS

6769
04:21:49,800 --> 04:21:50,680
WILD TYPE GENE DON'T.

6770
04:21:50,680 --> 04:21:52,400
WHEN WE QUANTITATED THAT BELOW

6771
04:21:52,400 --> 04:21:54,240
HERE, SO YOU CAN SEE THAT THE

6772
04:21:54,240 --> 04:21:57,040
NRAS EXPRESSING WILD TYPE CELLS

6773
04:21:57,040 --> 04:21:59,080
IN GREEN SO AND THEN THE NRAS

6774
04:21:59,080 --> 04:21:59,840
MUTANT CELLS IN RED.

6775
04:21:59,840 --> 04:22:02,240
SO YOU CAN SEE THAT THEY CHANGE

6776
04:22:02,240 --> 04:22:03,440
THEIR CIRCULARITY WHEN WE

6777
04:22:03,440 --> 04:22:05,920
MEASURE THE CIRCULARITY INDESK.

6778
04:22:05,920 --> 04:22:09,320
SO AT 24 AND 48 HOURS THE CELLS

6779
04:22:09,320 --> 04:22:12,960
EXPRESSING THE NRAS Q 61R MUTANT

6780
04:22:12,960 --> 04:22:16,520
PROTEIN BECOME SPINDLE AND

6781
04:22:16,520 --> 04:22:18,880
CHANGE CIRCULARITY.

6782
04:22:18,880 --> 04:22:20,320
WE ALSO LOOKED AT SIGNALING

6783
04:22:20,320 --> 04:22:21,920
PATHWAYS IN THE MUTANT CELLS.

6784
04:22:21,920 --> 04:22:23,600
YOU CAN SEE OUTLINED IN THE RED

6785
04:22:23,600 --> 04:22:24,960
BOX HERE THAT WE PARTICULARLY

6786
04:22:24,960 --> 04:22:27,240
SAW INCREASES IN PHOSPHOERG

6787
04:22:27,240 --> 04:22:30,360
WHICH IS PART OF THE MAP KINASE

6788
04:22:30,360 --> 04:22:33,880
PATHWAY, IN THE NRAS Q 61R

6789
04:22:33,880 --> 04:22:34,840
EXPRESSING CELLSN'T ON THE RIGHT

6790
04:22:34,840 --> 04:22:38,320
YOU CAN SEE A GRAPH WE CORRECTED

6791
04:22:38,320 --> 04:22:41,920
THE PHOSPHOERG TO TOTAL NRAS,

6792
04:22:41,920 --> 04:22:46,360
TWO DAYS AND 17 DAYS ON DOXY

6793
04:22:46,360 --> 04:22:47,600
CYCLINE WE SUSTAINED LEVELS IN

6794
04:22:47,600 --> 04:22:48,280
THE MUTANTS CELLS.

6795
04:22:48,280 --> 04:22:49,760
SO WE WENT TO LOOK AT MIGRATION

6796
04:22:49,760 --> 04:22:53,160
OF THE CELLS, SO YOU CAN SEE

6797
04:22:53,160 --> 04:22:55,600
HERE WE PLATE CELLS AND THEN

6798
04:22:55,600 --> 04:22:57,240
ALLOW THEM TO CONFLUENT, REMOVE

6799
04:22:57,240 --> 04:22:59,960
A CHAMBER TO EXPOSE A GAP ON THE

6800
04:22:59,960 --> 04:23:01,840
PLATE AND THEN CELLS MIGRATED

6801
04:23:01,840 --> 04:23:03,120
INTO THAT SPACE AND WE BLOCK

6802
04:23:03,120 --> 04:23:04,400
PROLIFERATION.

6803
04:23:04,400 --> 04:23:06,160
SO YOU CAN SEE THAT IN RED HERE

6804
04:23:06,160 --> 04:23:09,760
THAT THE NRAS Q 161R EXPRESSING

6805
04:23:09,760 --> 04:23:11,320
MUTANT CELLS MIGRATED FASTER

6806
04:23:11,320 --> 04:23:13,760
RATE AND CLOSED THAT GAP QUICKER

6807
04:23:13,760 --> 04:23:17,120
THAN NRAS WILD TYPE CELLS.

6808
04:23:17,120 --> 04:23:18,200
SIMILARLY WITH CELL

6809
04:23:18,200 --> 04:23:20,160
PROLIFERATION WE SAW THAT THE

6810
04:23:20,160 --> 04:23:22,200
NRAS K Q 61R MUTANT CELLS

6811
04:23:22,200 --> 04:23:23,360
PROLIFERATED HIGHER RATES THAN

6812
04:23:23,360 --> 04:23:26,520
THE NRAS WILD TYPE CELLS.

6813
04:23:26,520 --> 04:23:28,840
SO WE THEN WENT TO STUDY THE

6814
04:23:28,840 --> 04:23:30,840
NRAS WILD TYPE VERSUS MUTANT

6815
04:23:30,840 --> 04:23:34,920
CELLS, AND IN VITRO ANGIOGENESIS

6816
04:23:34,920 --> 04:23:35,760
ASSAY.

6817
04:23:35,760 --> 04:23:38,080
THIS WORK WAS DONE BY DR. SAM

6818
04:23:38,080 --> 04:23:41,440
AND LISA BUSCALO'S LAB.

6819
04:23:41,440 --> 04:23:43,080
YOU TAKE THE ENDOTHELIAL CELLS

6820
04:23:43,080 --> 04:23:47,320
AND COAT ON TO BEADS THEN THEY

6821
04:23:47,320 --> 04:23:50,040
SUSPENDED IN FIBRIN GEL WITH

6822
04:23:50,040 --> 04:23:51,120
FIBROBLASTS AT THE TOP.

6823
04:23:51,120 --> 04:23:53,280
WE ADDED DOXY CYCLINE TO THE

6824
04:23:53,280 --> 04:23:55,040
MEDIA AND IMAGED THE CELLS SEVEN

6825
04:23:55,040 --> 04:23:56,560
DAYS LATER.

6826
04:23:56,560 --> 04:23:58,720
SO HERE YOU CAN SEE CONFOCAL

6827
04:23:58,720 --> 04:24:00,400
IMAGING BUT YOU SEE THE CELLS

6828
04:24:00,400 --> 04:24:02,600
EXPRESSING THE WILD TYPE NRAS

6829
04:24:02,600 --> 04:24:05,760
FORM TUBES BETWEEN BEADS IN

6830
04:24:05,760 --> 04:24:06,160
GREEN.

6831
04:24:06,160 --> 04:24:09,480
THE NRAS Q 361R EXPRESSING CELLS

6832
04:24:09,480 --> 04:24:12,040
FORM LARGE DISORGANIZED

6833
04:24:12,040 --> 04:24:12,520
STRUCTURES.

6834
04:24:12,520 --> 04:24:14,120
WHEN YOU OUTLINE THESE STRUCTURE

6835
04:24:14,120 --> 04:24:16,000
AND THEN QUANTITATE IT, YOU CAN

6836
04:24:16,000 --> 04:24:17,880
SEE THAT THE VASCULAR AREAS

6837
04:24:17,880 --> 04:24:19,080
SIGNIFICANTLY INCREASE IN THE

6838
04:24:19,080 --> 04:24:24,760
CELLS EXPRESSING THE MUTANT NR 

6839
04:24:24,760 --> 04:24:26,080
NRAS.

6840
04:24:26,080 --> 04:24:29,880
WE THEN DID IN VIVO MODEL

6841
04:24:29,880 --> 04:24:30,240
XENOGRAPH MODEL?

6842
04:24:30,240 --> 04:24:30,640
MICE.

6843
04:24:30,640 --> 04:24:34,000
WE SUSPEND IN MATRIGEL AND

6844
04:24:34,000 --> 04:24:36,760
INJECT ON THE SKIN OF NUDE MICE.

6845
04:24:36,760 --> 04:24:39,720
THEY WERE FED DOXY CYCLINE DIET

6846
04:24:39,720 --> 04:24:42,680
AND REMOVE THE MATRIGEL PLUGS

6847
04:24:42,680 --> 04:24:43,320
EIGHT DAYS.

6848
04:24:43,320 --> 04:24:44,800
YOU CAN SEE THE PLUGS REMOVED

6849
04:24:44,800 --> 04:24:49,640
AFTER 8 DAYS AND THE CELLS, NRAS

6850
04:24:49,640 --> 04:24:51,680
Q 61R CELLS DEVELOP LARGE PLUGS

6851
04:24:51,680 --> 04:24:52,800
THAT ARE BLOODY.

6852
04:24:52,800 --> 04:24:54,680
WHEN WE SECTION THROUGH THE

6853
04:24:54,680 --> 04:24:56,440
PLUGS HERE YOU CAN SEE IN THE

6854
04:24:56,440 --> 04:24:57,920
BOTTOM RIGHT HAND CORNER HERE

6855
04:24:57,920 --> 04:25:01,760
THAT NRAS Q 61R MUTANT CELLS ON

6856
04:25:01,760 --> 04:25:03,360
DOXY CYCLINE HAVE LARGE CHANNELS

6857
04:25:03,360 --> 04:25:05,480
THAT ARE BLOODY AND WE

6858
04:25:05,480 --> 04:25:07,360
QUANTITATED THAT ON THE RIGHT

6859
04:25:07,360 --> 04:25:08,680
AND YOU CAN SEE THE INCREASE IN

6860
04:25:08,680 --> 04:25:09,360
VASCULAR AREA.

6861
04:25:09,360 --> 04:25:10,560
>> TWO MINUTES REMAIN.

6862
04:25:10,560 --> 04:25:11,960
>> THANK YOU.

6863
04:25:11,960 --> 04:25:13,640
SO FINALLY WE LOOKED AT

6864
04:25:13,640 --> 04:25:16,040
EXPRESSION OF ANGIOPOIETIN 2 AND

6865
04:25:16,040 --> 04:25:18,680
FOUND THE EXPRESSION OF

6866
04:25:18,680 --> 04:25:19,720
ANGIOPOIETIN 2 BY WESTERN BLOT

6867
04:25:19,720 --> 04:25:21,000
ANALYSIS WAS SIGNIFICANTLY

6868
04:25:21,000 --> 04:25:22,760
INCREASE IN NRAS MUTANT CELLS

6869
04:25:22,760 --> 04:25:24,760
COMPARED TO WILD TYPE.

6870
04:25:24,760 --> 04:25:28,120
WHEN WE MEASURE ANGIOPOIETIN 2

6871
04:25:28,120 --> 04:25:29,280
IN CELL CULTURE YOU CAN SEE

6872
04:25:29,280 --> 04:25:31,200
MUTANT CELLS ARE SECRETING MUCH

6873
04:25:31,200 --> 04:25:33,200
HIGHER LEVELS OF ANGIOPOIETIN 2

6874
04:25:33,200 --> 04:25:36,960
INTO THE CELL CULTURE NEEDSIA.

6875
04:25:36,960 --> 04:25:38,680
NOW THIS SHOWS A NUMBER OF

6876
04:25:38,680 --> 04:25:40,240
MUTATIONS THAT WE IDENTIFIED

6877
04:25:40,240 --> 04:25:42,000
VARIOUS VASCULAR ANOMALIES AND

6878
04:25:42,000 --> 04:25:44,040
SIGNALING PATHWAYS DOWNSTREAM.

6879
04:25:44,040 --> 04:25:45,960
SO DOWNSTREAM NRAS WHICH IS

6880
04:25:45,960 --> 04:25:48,880
IDENTIFIED IN KLA IS BOTH MAP

6881
04:25:48,880 --> 04:25:51,320
KINASE SIGNALING AND PI 3 KINASE

6882
04:25:51,320 --> 04:25:52,240
SIGNALING PATHWAYS.

6883
04:25:52,240 --> 04:25:54,680
SO I WILL SHOW BRIEFLY SOME DATA

6884
04:25:54,680 --> 04:25:58,840
USING INHIBITORS UO 1D 6 AND

6885
04:25:58,840 --> 04:26:01,840
TRINATNIP AND RAPAMYCIN MTOR.

6886
04:26:01,840 --> 04:26:04,840
SO IN THIS WESTERN BLOT HERE YOU

6887
04:26:04,840 --> 04:26:08,160
SEE UO 126 BLOCKED PHOSPHOERG

6888
04:26:08,160 --> 04:26:11,000
LEVELS IN MUTANT CELLS AND

6889
04:26:11,000 --> 04:26:12,480
RAPAMYCIN BLOCKS DOWNSTREAM OF

6890
04:26:12,480 --> 04:26:13,840
PI 3 KINASE PATHWAY.

6891
04:26:13,840 --> 04:26:15,480
SO WE LOOK AT MORPHOLOGY OF THE

6892
04:26:15,480 --> 04:26:16,840
CELLS YOU CAN SEE THAT THE MAP

6893
04:26:16,840 --> 04:26:19,400
KINASE INHIBITOR UO 126 BLOCKS

6894
04:26:19,400 --> 04:26:22,120
THE SPINDLING OF THE NRAS MUTANT

6895
04:26:22,120 --> 04:26:23,640
CELLS WHICH RAPAMYCIN DOESN'T.

6896
04:26:23,640 --> 04:26:25,840
YOU CAN SEE THAT QUANTITATIVE

6897
04:26:25,840 --> 04:26:28,080
BELOW HERE WHERE UO 126 MAP

6898
04:26:28,080 --> 04:26:29,360
KINASE INHIBITOR BOXES THE

6899
04:26:29,360 --> 04:26:31,400
CHANGE IN CELL SHAPE.

6900
04:26:31,400 --> 04:26:32,760
WHEREAS RAPAMYCIN DOES NOT.

6901
04:26:32,760 --> 04:26:35,720
THEN WE LOOK AT EFFECT OF UO 126

6902
04:26:35,720 --> 04:26:39,040
IN TRIMATNIB INHIBITOR USED TO

6903
04:26:39,040 --> 04:26:39,600
TREAT PATIENTS.

6904
04:26:39,600 --> 04:26:42,560
YOU CAN SEE THE BOTH MAP KINASE

6905
04:26:42,560 --> 04:26:43,920
INHIBITORS BLOCK THE INCREASES

6906
04:26:43,920 --> 04:26:45,960
IN ANGIOPOIETIN 2 IN THE MUTANT

6907
04:26:45,960 --> 04:26:47,280
CELLS.

6908
04:26:47,280 --> 04:26:49,080
SO IN SUMMARY WHAT I HAVE SHOWN

6909
04:26:49,080 --> 04:26:52,840
YOU IS THAT THE NRAS Q 61R

6910
04:26:52,840 --> 04:26:55,080
MUTATION INTRODUCED TO HUMAN

6911
04:26:55,080 --> 04:26:56,080
ENDOTHELIAL CELLS INDUCES MAP

6912
04:26:56,080 --> 04:26:57,440
KINASE SIGNALING INDUCES A

6913
04:26:57,440 --> 04:26:59,240
SPINDLING OF THE ENDOTHELIAL

6914
04:26:59,240 --> 04:27:01,080
CELLS, AND INCREASES EXPRESSION

6915
04:27:01,080 --> 04:27:02,880
OF ANGIOPOIETIN 2.

6916
04:27:02,880 --> 04:27:04,400
SO FUTURE WE ARE INTERESTED IN

6917
04:27:04,400 --> 04:27:06,800
DETERMINING THE ROLE OF

6918
04:27:06,800 --> 04:27:08,680
ANGIOPOIETIN 2 AND

6919
04:27:08,680 --> 04:27:10,560
PATHOPHYSIOLOGY OF KLA.

6920
04:27:10,560 --> 04:27:13,200
SO IN SUMMARY I SHOWN YOU THESE

6921
04:27:13,200 --> 04:27:15,640
NRAS K 61R MODELS ARE USED TO

6922
04:27:15,640 --> 04:27:16,960
UNDERSTAND THE PATHOGENESIS OF

6923
04:27:16,960 --> 04:27:18,760
KLA AND TWO, POTENTIALLY SCREEN

6924
04:27:18,760 --> 04:27:20,280
NEW DRUGS AND TREATMENTS FOR

6925
04:27:20,280 --> 04:27:22,280
THIS DEVASTATING DISEASE.

6926
04:27:22,280 --> 04:27:24,400
THIS WORK WAS RECENTLY PUBLISHED

6927
04:27:24,400 --> 04:27:27,080
IN THE JOURNAL ANGIOGENESIS.

6928
04:27:27,080 --> 04:27:29,480
SO LASTLY, I WOULD LIKE TO

6929
04:27:29,480 --> 04:27:32,440
MENTION WE DEVELOPED A CLINICAL

6930
04:27:32,440 --> 04:27:33,160
ANGIOPOIETIN 2 TEST AT SINCENATY

6931
04:27:33,160 --> 04:27:33,960
CHILDRENS AND THIS CAN BE

6932
04:27:33,960 --> 04:27:36,160
ORDERED BY PHYSICIANS AND THEY

6933
04:27:36,160 --> 04:27:39,760
CAN SEND PATIENT SERUM TO OUR

6934
04:27:39,760 --> 04:27:41,600
HEMOSTASIS LABORATORY.

6935
04:27:41,600 --> 04:27:42,760
USUALLY RESULTS ARE REPORTED IN

6936
04:27:42,760 --> 04:27:44,480
TWO WEEKS.

6937
04:27:44,480 --> 04:27:46,280
SO THANKS TO ALL MY

6938
04:27:46,280 --> 04:27:48,080
COLLABORATORS, DR. DENISE ADAMS,

6939
04:27:48,080 --> 04:27:49,840
CHILDREN'S HOSPITAL

6940
04:27:49,840 --> 04:27:52,880
PHILADELPHIA, DR. LISA BUSCALO,

6941
04:27:52,880 --> 04:27:54,800
A LOT OF WORK DONE IN

6942
04:27:54,800 --> 04:27:56,640
COMBINATION WITH HER LAB,

6943
04:27:56,640 --> 04:28:00,640
DEVELOPED THE LENTIVIRAL VECTORS

6944
04:28:00,640 --> 04:28:02,600
TRISHA, SONDRA, GRIFFITH

6945
04:28:02,600 --> 04:28:04,160
MCDANIEL WHO JOINED THIS LAB,

6946
04:28:04,160 --> 04:28:08,600
DR. ADRIENNE AAMMILL AND THE

6947
04:28:08,600 --> 04:28:09,920
STEEL FAMILIES FOR SUPPORTING

6948
04:28:09,920 --> 04:28:11,800
THE WORK OVER SEVERAL YEARS.

6949
04:28:11,800 --> 04:28:14,080
FUNDING WAS FINAL THE LMI AND

6950
04:28:14,080 --> 04:28:16,160
LGDA ORIGINALLY AND MOST

6951
04:28:16,160 --> 04:28:17,520
RECENTLY FROM NATIONAL HEART

6952
04:28:17,520 --> 04:28:18,440
LUNG AND BLOOD INSTITUTE.

6953
04:28:18,440 --> 04:28:19,360
THANK YOU SO MUCH FOR YOUR

6954
04:28:19,360 --> 04:28:21,240
ATTENTION.

6955
04:28:21,240 --> 04:28:23,480
IN TERMS OF GABS NEEDS AND

6956
04:28:23,480 --> 04:28:24,800
OPPORTUNITIES, WE STILL NEED TO

6957
04:28:24,800 --> 04:28:26,720
IDENTIFY OTHER GENES AND

6958
04:28:26,720 --> 04:28:28,400
PATHWAYS AND FACTORS THAT

6959
04:28:28,400 --> 04:28:30,040
CONTRIBUTE TO THE PATHOGENESIS

6960
04:28:30,040 --> 04:28:31,520
OF THESE VASCULAR ANOMALIES.

6961
04:28:31,520 --> 04:28:34,400
WE HAVE MADE A GOOD START BUT

6962
04:28:34,400 --> 04:28:36,440
THERE'S CERTAINLY MORE GENES AND

6963
04:28:36,440 --> 04:28:37,440
PATHWAYS OUT THERE.

6964
04:28:37,440 --> 04:28:38,680
THAT COULD ALSO BE TARGETED FOR

6965
04:28:38,680 --> 04:28:39,080
TREATMENT.

6966
04:28:39,080 --> 04:28:41,080
WE DON'T KNOW HOW MUTANT

6967
04:28:41,080 --> 04:28:42,960
ENDOTHELIAL CELLS AFFECT NORMAL

6968
04:28:42,960 --> 04:28:43,680
ENDOTHELIAL CELLS.

6969
04:28:43,680 --> 04:28:46,480
WE NEED TO BE ABLE TO IDENTIFY

6970
04:28:46,480 --> 04:28:48,440
AND TARGET MUTANT ENDOTHELIAL

6971
04:28:48,440 --> 04:28:50,320
CELLS TO REDUCE SIDE EFFECTS OF

6972
04:28:50,320 --> 04:28:51,680
DRUGS ON NORMAL ENDOTHELIAL

6973
04:28:51,680 --> 04:28:53,280
CELLS.

6974
04:28:53,280 --> 04:28:55,360
WE ALSO NEED MORE NON-INVASIVE

6975
04:28:55,360 --> 04:28:56,520
DIAGNOSTIC TESTS FOR THESE

6976
04:28:56,520 --> 04:28:58,360
DISEASES.

6977
04:28:58,360 --> 04:28:59,800
THANKS SO MUCH.

6978
04:28:59,800 --> 04:29:02,400
I WILL TURN IT OVER TO DR.

6979
04:29:02,400 --> 04:29:06,040
MICHAEL DELLINGER.

6980
04:29:06,040 --> 04:29:06,760
YOU READY?

6981
04:29:06,760 --> 04:29:16,640
>> I AM.

6982
04:29:16,640 --> 04:29:18,320
THANK YOU, TIM.

6983
04:29:18,320 --> 04:29:19,720
I WOULD LIKE TO THANK THE

6984
04:29:19,720 --> 04:29:20,960
ORGANIZERS FOR GIVING ME THIS

6985
04:29:20,960 --> 04:29:23,400
OPPORTUNITY TO PRESENT MY LAB'S

6986
04:29:23,400 --> 04:29:27,640
WORK ON COMPLEX LYMPHATIC

6987
04:29:27,640 --> 04:29:27,920
ANOMALIES.

6988
04:29:27,920 --> 04:29:30,080
COMPLEX LYMPHATIC ANOMALIES ARE

6989
04:29:30,080 --> 04:29:32,200
RARE, SPORADICALLY OCCURRING

6990
04:29:32,200 --> 04:29:33,680
DISEASES THAT ARE CHARACTERIZED

6991
04:29:33,680 --> 04:29:35,440
BY PRESENCE OF MULTI-FOCAL

6992
04:29:35,440 --> 04:29:38,240
LYMPHATIC MALFORMATIONS.

6993
04:29:38,240 --> 04:29:39,400
COMPLEX LYMPHATIC ANOMALIES

6994
04:29:39,400 --> 04:29:42,600
INCLUDE GENERALIZED LYMPHATIC

6995
04:29:42,600 --> 04:29:49,480
ANOMALY, GORHAM SCOUT DISEASE,

6996
04:29:49,480 --> 04:29:51,320
KAPOSIFORM LYMPHANGIOMATOSIS AND

6997
04:29:51,320 --> 04:29:52,120
LYMPHATIC ANOMALY.

6998
04:29:52,120 --> 04:29:53,840
THESE DISEASES ARE DIAGNOSED IN

6999
04:29:53,840 --> 04:29:55,080
CHILDREN AND YOUNG ADULTS AND

7000
04:29:55,080 --> 04:29:57,600
ARE DIFFICULT TO TREAT.

7001
04:29:57,600 --> 04:29:58,960
THESE DISTINCT YET SIMILAR

7002
04:29:58,960 --> 04:30:00,000
DISEASE SHARE SEVERAL

7003
04:30:00,000 --> 04:30:01,840
OVERLAPPING FEATURES AND SOME OF

7004
04:30:01,840 --> 04:30:04,400
THE COMMON CHARACTERISTICS OF

7005
04:30:04,400 --> 04:30:05,960
KLA ARE LYMPHATIC MALL

7006
04:30:05,960 --> 04:30:07,600
FORMATIONS IN THE LUNG AND SOFT

7007
04:30:07,600 --> 04:30:10,400
TISSUE, INK INVASION OF BONE AND

7008
04:30:10,400 --> 04:30:11,240
COLLAR THORAX.

7009
04:30:11,240 --> 04:30:14,440
IN THE ANOMALY MY LAB IS

7010
04:30:14,440 --> 04:30:18,240
INTERESTED IN IS GORHAM STOUT

7011
04:30:18,240 --> 04:30:18,480
DISEASE.

7012
04:30:18,480 --> 04:30:20,680
IT IS CHARACTERIZED BY LYMPHATIC

7013
04:30:20,680 --> 04:30:22,240
INVASION OF BONE AND MASSIVE

7014
04:30:22,240 --> 04:30:24,520
BONE LOSS AND PATIENTS CAN HAVE

7015
04:30:24,520 --> 04:30:25,560
LYMPHATIC MALL FORMATIONS IN

7016
04:30:25,560 --> 04:30:30,120
SOFT TISSUES AND ORGANS.

7017
04:30:30,120 --> 04:30:31,760
SINCE FORHAM AND STOUT PUBLISHED

7018
04:30:31,760 --> 04:30:33,960
THEIR PAPER IN 1955, MORE THAN

7019
04:30:33,960 --> 04:30:36,040
300 CASES HAVE BEEN PUBLISHED.

7020
04:30:36,040 --> 04:30:37,040
INs THIS CASE REPORTS

7021
04:30:37,040 --> 04:30:38,600
INCREASED OUR UNDERSTANDING OF

7022
04:30:38,600 --> 04:30:39,400
THE CLINICAL FEATURES OF THE

7023
04:30:39,400 --> 04:30:42,800
DISEASE.

7024
04:30:42,800 --> 04:30:43,640
GORHAM STOUT DISEASE COURSE OF

7025
04:30:43,640 --> 04:30:46,080
THE DISEASE IS UNPREDICTSABLE IN

7026
04:30:46,080 --> 04:30:48,360
SOME PATIENTS THE OSTEOLYTIC

7027
04:30:48,360 --> 04:30:50,680
PROCESS OCCURS SLOWLY OVER

7028
04:30:50,680 --> 04:30:52,680
PERIOD OF YEARS, WHEREAS OTHERS

7029
04:30:52,680 --> 04:30:55,200
OCCURS RAPIDLY OVER MONTHS.

7030
04:30:55,200 --> 04:30:57,560
ONE INTERESTING FEATURE OF

7031
04:30:57,560 --> 04:30:59,440
DISEASE IS IT IS REPORTED TO

7032
04:30:59,440 --> 04:31:02,760
SPONTANEOUSLY ARREST AFTER A

7033
04:31:02,760 --> 04:31:04,000
PERIOD OF INACTIVITY.

7034
04:31:04,000 --> 04:31:05,840
NO EVIDENCE OF BONE FORMATION

7035
04:31:05,840 --> 04:31:07,040
AFTER THE DISEASE ARRESTS ONCE

7036
04:31:07,040 --> 04:31:08,720
THE BONE DISAPPEARS IT DOESN'T

7037
04:31:08,720 --> 04:31:09,760
REGENERATE.

7038
04:31:09,760 --> 04:31:11,880
THIS DISEASE CAN AFFECT ONE BONE

7039
04:31:11,880 --> 04:31:13,680
BUT USUALLY AFFECTS MULTIPLE

7040
04:31:13,680 --> 04:31:14,040
BONES.

7041
04:31:14,040 --> 04:31:15,600
WHEN MULTIPLE BONES ARE AFFECTED

7042
04:31:15,600 --> 04:31:17,480
THEY ARE TYPICALLY BONES NEXT TO

7043
04:31:17,480 --> 04:31:19,120
ONE ANOTHER.

7044
04:31:19,120 --> 04:31:21,240
WE DON'T TYPICALLY OBSERVE SKIP

7045
04:31:21,240 --> 04:31:23,640
LESIONS IN PATIENTS.

7046
04:31:23,640 --> 04:31:24,560
THE DISEASE CAN AFFECT ANY BONE

7047
04:31:24,560 --> 04:31:26,880
IN THE BODY BUT TYPICALLY

7048
04:31:26,880 --> 04:31:28,680
AFFECTS MOST FREQUENTLY AFFECTS

7049
04:31:28,680 --> 04:31:30,320
THE RIBS AND VARIETY BRAY.

7050
04:31:30,320 --> 04:31:32,360
AND UNFORTUNATELY THORACIC

7051
04:31:32,360 --> 04:31:34,000
INVOLVEMENT IS ASSOCIATED WITH

7052
04:31:34,000 --> 04:31:36,640
POOR PROGNOSIS BECAUSE PATIENTS

7053
04:31:36,640 --> 04:31:37,920
DEVELOP COLLAR THORAX WHICH

7054
04:31:37,920 --> 04:31:40,040
CAUSES RESPIRATORY DISTRESS,

7055
04:31:40,040 --> 04:31:41,440
FAILURE AND DEATH.

7056
04:31:41,440 --> 04:31:43,080
AT THE TIME WE STARTED OUR WORK

7057
04:31:43,080 --> 04:31:46,240
ON GORHAM STOUT DISEASE

7058
04:31:46,240 --> 04:31:49,680
MOLECULAR MECHANISMS DRIVING

7059
04:31:49,680 --> 04:31:50,600
LYMPHOANGIOGENESIS DRIVING THE

7060
04:31:50,600 --> 04:31:51,720
DISEASE ARE NOT KNOWN.

7061
04:31:51,720 --> 04:31:54,440
A LOT WAS KNOWN ABOUT MOLECULAR

7062
04:31:54,440 --> 04:31:56,240
MECHANISMS CONTROLLING THE

7063
04:31:56,240 --> 04:31:57,440
DEVELOPMENT OF LYMPHATIC VESSELS

7064
04:31:57,440 --> 04:31:59,880
AND OVER 20 YEARS VEGF C EMERGED

7065
04:31:59,880 --> 04:32:07,040
AS PRINCIPLE DRIVER OF LIMB FANG

7066
04:32:07,040 --> 04:32:08,120
OWE GENESIS.

7067
04:32:08,120 --> 04:32:09,720
COMPARISON OF VESSELS WHICH

7068
04:32:09,720 --> 04:32:12,360
CONVERSELY OVEREXPRESSION OF

7069
04:32:12,360 --> 04:32:15,040
VEGF C STIMULATES FORMATION OF

7070
04:32:15,040 --> 04:32:16,080
LYMPHATIC VESSELS.

7071
04:32:16,080 --> 04:32:18,240
BASED ON THOSE OBSERVATIONS

7072
04:32:18,240 --> 04:32:20,720
WHICH HYPOTHESIZE OVEREXPRESSION

7073
04:32:20,720 --> 04:32:23,000
OF VEGF C IN BONE CELLS WHICH

7074
04:32:23,000 --> 04:32:24,120
STIMULATE LYMPHATIC VESSEL

7075
04:32:24,120 --> 04:32:26,720
INVASION OF BONE AND BONE LOSS.

7076
04:32:26,720 --> 04:32:30,280
TO TEST THIS HYPOTHESIS WE BRED

7077
04:32:30,280 --> 04:32:32,480
MICE TOGETHER TO OVEREXPRESS

7078
04:32:32,480 --> 04:32:35,760
VEGF C IN OSTEOBLASTS,

7079
04:32:35,760 --> 04:32:37,240
OSTEOCYTES AND CHONDROCYTES.

7080
04:32:37,240 --> 04:32:38,920
WE FOUND THAT OVEREXPRESSION OF

7081
04:32:38,920 --> 04:32:42,000
VEGF C BY BONE CELL STIMULATED

7082
04:32:42,000 --> 04:32:42,720
LYMPHATIC INVASION OF BENEFIT

7083
04:32:42,720 --> 04:32:45,200
AND OSTEOCLAST MEDIATED BONE

7084
04:32:45,200 --> 04:32:46,680
RESORPTION.

7085
04:32:46,680 --> 04:32:49,720
WE ALSO FOUND INHIBITION OF VEGF

7086
04:32:49,720 --> 04:32:50,800
RECEPTOR 3 TO PREVENT INVASION

7087
04:32:50,800 --> 04:32:52,400
OF BONE AND BONE LOSS.

7088
04:32:52,400 --> 04:32:54,760
WE ALSO FOUND THAT INHIBITING

7089
04:32:54,760 --> 04:32:57,240
EXPRESSION OF VEGF C REVERSE

7090
04:32:57,240 --> 04:32:59,480
DISEASE IN MICE WITH ESTABLISHED

7091
04:32:59,480 --> 04:33:00,040
DISEASE.

7092
04:33:00,040 --> 04:33:01,680
WE THEN WENT TO FURTHER

7093
04:33:01,680 --> 04:33:03,240
CHARACTERIZE THE FORMATION OF

7094
04:33:03,240 --> 04:33:05,560
BONE ASSOCIATED LYMPHATICS AND

7095
04:33:05,560 --> 04:33:07,120
FOUND THESE LYMPHATICS DEVELOP

7096
04:33:07,120 --> 04:33:09,440
IN STEP WISE FASHION WHERE

7097
04:33:09,440 --> 04:33:11,840
REGIONAL LYMPHATICS GROW, BREECH

7098
04:33:11,840 --> 04:33:12,880
THE PERIOUTSIDE YUM, BECOME

7099
04:33:12,880 --> 04:33:14,720
ASSOCIATED WITH OSTEOCLASTS,

7100
04:33:14,720 --> 04:33:17,000
WHICH APPEAR TO CREATE A PATH

7101
04:33:17,000 --> 04:33:18,560
THROUGH THE BONE OR LYMPHATICS

7102
04:33:18,560 --> 04:33:20,120
UNTIL THEY REACH THE MARROW

7103
04:33:20,120 --> 04:33:21,520
CALFTY.

7104
04:33:21,520 --> 04:33:22,240
-- CAVITY.

7105
04:33:22,240 --> 04:33:23,640
WHILE WE WERE DOING THIS WORK WE

7106
04:33:23,640 --> 04:33:26,760
FORM AD COLLABORATION WITH MIKA

7107
04:33:26,760 --> 04:33:28,240
AND HIS GROUP SAW PATIENT

7108
04:33:28,240 --> 04:33:32,080
RECEIVED DIAGNOSIS OF GORHAM

7109
04:33:32,080 --> 04:33:32,720
STOUT DISEASE AFTER PRESENTING

7110
04:33:32,720 --> 04:33:36,400
WITH OSTEOLYTIC LESIONS IN

7111
04:33:36,400 --> 04:33:37,120
MALFORMATIONS.

7112
04:33:37,120 --> 04:33:38,680
BONES WERE AFFECTED IN THIS

7113
04:33:38,680 --> 04:33:39,800
PATIENT AND SHE WAS TREATED WITH

7114
04:33:39,800 --> 04:33:40,920
SEVERAL MEDICATIONS ALL WITH

7115
04:33:40,920 --> 04:33:42,560
MINOR OR NO RESPONSE.

7116
04:33:42,560 --> 04:33:44,520
AND UNFORTUNATELY THIS PATIENT

7117
04:33:44,520 --> 04:33:45,520
PASSED WHEN SHE WAS 37 YEARS

7118
04:33:45,520 --> 04:33:49,200
OLD.

7119
04:33:49,200 --> 04:33:53,760
TO TEST THE HYPOTHESIS THAT

7120
04:33:53,760 --> 04:33:54,760
GORHAM STOUT DISEASE IS CAUSED

7121
04:33:54,760 --> 04:33:56,640
BY GENETIC MY TALKS HEARSAY

7122
04:33:56,640 --> 04:33:58,400
GROUP SEQUENCED AFFECTED AND

7123
04:33:58,400 --> 04:33:59,400
UNAFFECTED TISSUE FROM PATIENT

7124
04:33:59,400 --> 04:34:01,200
AND IDENTIFIED SOMATIC

7125
04:34:01,200 --> 04:34:04,320
ACTIVATING MUTATION IN KRAS.

7126
04:34:04,320 --> 04:34:07,080
THE VARIANT IDENTIFIED IS G 12B

7127
04:34:07,080 --> 04:34:09,400
VARIANT, A WELL KNOWN ONCOGENIC

7128
04:34:09,400 --> 04:34:13,400
MUTATION IN KRAS.

7129
04:34:13,400 --> 04:34:15,400
KRAS IS A SMALL G PROTEIN THAT

7130
04:34:15,400 --> 04:34:18,120
FUNCTIONS AS MOLECULAR SWITCH,

7131
04:34:18,120 --> 04:34:20,760
WHEN BOUND TO GDP IT IS

7132
04:34:20,760 --> 04:34:23,440
INACTIVE, WHEN BOUND TO GTP IT

7133
04:34:23,440 --> 04:34:24,920
UNDERGOES A CONFIRMATIONAL

7134
04:34:24,920 --> 04:34:26,760
SWITCH WHICH ALLOWS INTERACTING

7135
04:34:26,760 --> 04:34:28,640
WITH DOWNSTREAM EFFECTOR

7136
04:34:28,640 --> 04:34:30,080
PROTEINS AND PROMOTES SIGNAL

7137
04:34:30,080 --> 04:34:30,760
TRANSDUCTION.

7138
04:34:30,760 --> 04:34:32,400
TWO RECOGNIZED BEST UNDERSTOOD

7139
04:34:32,400 --> 04:34:35,080
PATHWAYS DOWNSTREAM OF KRAS ARE

7140
04:34:35,080 --> 04:34:37,040
PI 3 KINASE AND MAP KINASE

7141
04:34:37,040 --> 04:34:37,840
PATHWAYS.

7142
04:34:37,840 --> 04:34:39,800
MUTATION THAT THE PATIENT HAD

7143
04:34:39,800 --> 04:34:42,680
IMPAIRS GTP HYDROLYSIS RESULTING

7144
04:34:42,680 --> 04:34:47,240
IN CONSTITUTIVE RAS SIGNALING.

7145
04:34:47,240 --> 04:34:48,760
TO DETERMINE THE EFFECT

7146
04:34:48,760 --> 04:34:50,240
HYPERACTIVITY RAS SIGNALING HAS

7147
04:34:50,240 --> 04:34:51,800
ON FORMATION OF LYMPHATIC

7148
04:34:51,800 --> 04:34:53,880
VESSELS, WE USE A CRE LOCK

7149
04:34:53,880 --> 04:34:57,560
SYSTEM TO EXPRESS MUTANT FORM OF

7150
04:34:57,560 --> 04:34:58,760
KRAS IN LYMPHATIC ENDOTHELIAL

7151
04:34:58,760 --> 04:35:03,280
CELLS.

7152
04:35:03,280 --> 04:35:05,400
THIS EXPERT WE FED NEWBORN MICE

7153
04:35:05,400 --> 04:35:07,200
TAMOXIFEN TO INDUCE EXPRESSION

7154
04:35:07,200 --> 04:35:11,160
OF KRAS LIMB LYMPHATIC

7155
04:35:11,160 --> 04:35:12,200
ENDOTHELIAL CELLS AND COLLECTED

7156
04:35:12,200 --> 04:35:13,560
BONE FROM MICE AT 7 WEEKS.

7157
04:35:13,560 --> 04:35:15,360
WE STAINED AND PUT INTO MARK

7158
04:35:15,360 --> 04:35:17,040
LYMPHATICS AND FOUND THAT BONES

7159
04:35:17,040 --> 04:35:19,160
FROM CONTROL ANIMALS DIDN'T

7160
04:35:19,160 --> 04:35:20,360
CONTAIN LYMPHATIC VESSELS,

7161
04:35:20,360 --> 04:35:22,000
WHEREAS BONES FROM OUR MUTANT

7162
04:35:22,000 --> 04:35:23,560
ANIMALS DID CONTAIN LYMPHATIC

7163
04:35:23,560 --> 04:35:24,400
VESSELS.

7164
04:35:24,400 --> 04:35:26,640
SO THESE RESULTS SUGGEST THAT

7165
04:35:26,640 --> 04:35:28,920
HYPERACTIVE RAS SIGNALING IN

7166
04:35:28,920 --> 04:35:30,160
LYMPHATIC ENDOTHELIAL CELLS

7167
04:35:30,160 --> 04:35:31,520
STIMULATE FORMATION OF LYMPHATIC

7168
04:35:31,520 --> 04:35:34,200
VESSELS IN BONE.

7169
04:35:34,200 --> 04:35:37,120
WHEN PERFORMING THIS EXPERIMENT,

7170
04:35:37,120 --> 04:35:39,800
WE FOUND TWO INTERESTING

7171
04:35:39,800 --> 04:35:43,520
OBSERVATIONS, FIRST WE FOUND

7172
04:35:43,520 --> 04:35:45,720
MUTANT ANIMALS DEVELOPED LARGE

7173
04:35:45,720 --> 04:35:47,840
CYSTS AND THESE CYSTS WERE

7174
04:35:47,840 --> 04:35:50,240
CONSISTENT WITH MACRO CYSTIC

7175
04:35:50,240 --> 04:35:51,600
LYMPHATIC MALFORMATIONS AND

7176
04:35:51,600 --> 04:35:53,680
THESE TYPICALLY OCCURRED IN THE

7177
04:35:53,680 --> 04:35:56,120
HIND REGIONS OF THE ANIMALS BUT

7178
04:35:56,120 --> 04:35:58,920
WE SAW THEM ALSO ON THE FACE.

7179
04:35:58,920 --> 04:36:00,480
WE ALSO FOUND THAT OUR MUTANT

7180
04:36:00,480 --> 04:36:02,280
ANIMALS HAD SHORTER LIFE SPAN

7181
04:36:02,280 --> 04:36:03,520
THAN CONTROL ANIMALS.

7182
04:36:03,520 --> 04:36:06,560
THIS IS BECAUSE OUR MUTANT

7183
04:36:06,560 --> 04:36:08,000
ANIMALS DEVELOP THORAX WHICH

7184
04:36:08,000 --> 04:36:09,000
CONTINUE RESPONSIBLE FOR THEIR

7185
04:36:09,000 --> 04:36:12,400
DEATH.

7186
04:36:12,400 --> 04:36:14,960
THAT'S ASSOCIATESSED WITH

7187
04:36:14,960 --> 04:36:16,120
LYMPHATIC VALVE DEFECTS SO THAT

7188
04:36:16,120 --> 04:36:18,600
LED US TO LOOK AT LYMPHATIC

7189
04:36:18,600 --> 04:36:20,280
VALVES IN MUTANT ANIMALS.

7190
04:36:20,280 --> 04:36:23,920
WE TREATED NEWBORN ANIMALS WITH

7191
04:36:23,920 --> 04:36:25,720
TAMOXIFEN AND COLLECTED EAR SKIN

7192
04:36:25,720 --> 04:36:28,600
FROM MICE AT 21 DAYS AND STAINED

7193
04:36:28,600 --> 04:36:30,480
FOR GFP TO MARK FOR LYMPHATIC

7194
04:36:30,480 --> 04:36:31,280
VESSELS.

7195
04:36:31,280 --> 04:36:33,200
WE FOUND THAT THE LYMPHATIC

7196
04:36:33,200 --> 04:36:35,680
NETWORK IN OUR MUTANT ANIMALS

7197
04:36:35,680 --> 04:36:36,800
WAS LESS COMPLEX THAN THAT IN

7198
04:36:36,800 --> 04:36:38,880
CONTROL ANIMALS SO THAT MUTANT

7199
04:36:38,880 --> 04:36:41,960
ANIMALS HAD SIGNIFICANTLY FEWER

7200
04:36:41,960 --> 04:36:43,520
LYMPHATIC BRANCH POINTS THAN

7201
04:36:43,520 --> 04:36:44,920
CONTROL ANIMALS AND LYMPHATIC

7202
04:36:44,920 --> 04:36:47,200
VESSEL DIAMETERS WERE GREATER IN

7203
04:36:47,200 --> 04:36:48,520
MUTANT ANIMALS AND CONTROL

7204
04:36:48,520 --> 04:36:49,120
ANIMALS.

7205
04:36:49,120 --> 04:36:52,640
WHEN WE LOOK AT LYMPHATIC

7206
04:36:52,640 --> 04:36:55,560
VALVES, WE FOUND MUTANT ANIMALS

7207
04:36:55,560 --> 04:36:56,840
HAD FEWER LYMPHATIC VALVES THAN

7208
04:36:56,840 --> 04:36:58,760
CONTROL ANIMALS SO THESE RESULT

7209
04:36:58,760 --> 04:37:00,680
SUGGEST HYPERACTIVE KRAS

7210
04:37:00,680 --> 04:37:05,920
SIGNALING IN LYMPHATIC

7211
04:37:05,920 --> 04:37:07,320
ENDOTHELIAL CELLS CAN AFFECT

7212
04:37:07,320 --> 04:37:08,440
FORMATION OF CELLS.

7213
04:37:08,440 --> 04:37:11,960
DO PATIENTS WITH GORHAM STOUT

7214
04:37:11,960 --> 04:37:13,720
HAVE THOSE EFFECTS?

7215
04:37:13,720 --> 04:37:15,560
THEY ARE LIMITED NUMBERS OF

7216
04:37:15,560 --> 04:37:17,040
STUDIES THAT CHARACTERIZED

7217
04:37:17,040 --> 04:37:17,880
LYMPHATIC FUNCTION IN PATIENT

7218
04:37:17,880 --> 04:37:20,800
WITH GORHAM STOUT DISEASE,

7219
04:37:20,800 --> 04:37:22,440
CONTRAST AGENTS ARE REPORTED TO

7220
04:37:22,440 --> 04:37:23,680
REFLUX IN THE BONES WITH

7221
04:37:23,680 --> 04:37:28,840
PATIENTS WITH GORHAM STOUT

7222
04:37:28,840 --> 04:37:30,160
DISEASE AND RETRO GRADE

7223
04:37:30,160 --> 04:37:31,520
LYMPHOWAS OBSERVED IN PATIENTS

7224
04:37:31,520 --> 04:37:32,680
WITH THE DISEASE.

7225
04:37:32,680 --> 04:37:33,880
THESE RESULTSES SUGGEST THAT

7226
04:37:33,880 --> 04:37:35,800
PATIENTS WITH THE DISEASE CAN

7227
04:37:35,800 --> 04:37:41,120
HAVE LYMPHATIC VALVE DEFECTS.

7228
04:37:41,120 --> 04:37:43,800
HYPE ACTIVE RAS SIGNALING IN

7229
04:37:43,800 --> 04:37:45,320
LYMPHATIC ENDOTHELIAL CELLS

7230
04:37:45,320 --> 04:37:47,640
AFFECT FORMATION OF LYMPHATIC

7231
04:37:47,640 --> 04:37:48,040
VALVES.

7232
04:37:48,040 --> 04:37:49,960
WE ASK WHETHER IT AFFECTS

7233
04:37:49,960 --> 04:37:51,600
MAINTENANCE OF LYMPHATIC VALVES.

7234
04:37:51,600 --> 04:37:53,640
WE EXAMINED THE VALVES IN

7235
04:37:53,640 --> 04:37:54,840
MESENTARY IN CONTROL OF THESE

7236
04:37:54,840 --> 04:37:55,880
ANIMALS BECAUSE THESE VESSELS

7237
04:37:55,880 --> 04:37:58,080
ARE REPORTED TO DEVELOP

7238
04:37:58,080 --> 04:38:00,640
LYMPHATIC VALVES DURING

7239
04:38:00,640 --> 04:38:02,640
EMBRYONIC DEVELOPMENT SO WE FED

7240
04:38:02,640 --> 04:38:04,920
NEWBORN MICE TAMOXIFEN TO INDUCE

7241
04:38:04,920 --> 04:38:07,960
EXPRESSION OF K, AREAS IN

7242
04:38:07,960 --> 04:38:10,040
LYMPHATIC ENDOTHELIAL CELLS AND

7243
04:38:10,040 --> 04:38:11,960
ISOLATED MESENTARY FROM 12 DAY

7244
04:38:11,960 --> 04:38:13,720
OLD MICE AND FOUND MUTANT

7245
04:38:13,720 --> 04:38:15,560
ANIMALS HAD FEWER LYMPHATIC

7246
04:38:15,560 --> 04:38:17,360
VALVES THAN CONTROL ANIMALS.

7247
04:38:17,360 --> 04:38:18,840
SO THESE RESULTS SUGGEST THAT

7248
04:38:18,840 --> 04:38:21,160
HYPERACTIVE RAS SIGNALING AFFECT

7249
04:38:21,160 --> 04:38:22,560
THE MAINTENANCE OF LYMPHATIC

7250
04:38:22,560 --> 04:38:25,160
VALVES.

7251
04:38:25,160 --> 04:38:29,720
WE THEN ASSESSED THE ABILITY OF

7252
04:38:29,720 --> 04:38:33,240
LYMPHATIC IN CONTROL MUTANT

7253
04:38:33,240 --> 04:38:37,360
ANIMALS TO PROMOTOR FORWARD

7254
04:38:37,360 --> 04:38:37,840
LYMPH FLOW.

7255
04:38:37,840 --> 04:38:43,120
WE INJECTED MESENTARYIC DYE IN

7256
04:38:43,120 --> 04:38:43,720
THORACIC DUCT.

7257
04:38:43,720 --> 04:38:45,880
YOU CAN SEE THE NICE APPEARING

7258
04:38:45,880 --> 04:38:47,200
NORA SICK DUCT.

7259
04:38:47,200 --> 04:38:49,200
WHEREAS MUTANT THE EVIDENCE DYE

7260
04:38:49,200 --> 04:38:51,440
WEPT UP AND REFLUXED TO THE

7261
04:38:51,440 --> 04:38:52,520
INTERCOSTAL LYMPHATICS.

7262
04:38:52,520 --> 04:38:56,040
SO THESE RESULT SUGGEST THAT

7263
04:38:56,040 --> 04:38:58,160
HYPERACTIVE RAS SIGNALING IN

7264
04:38:58,160 --> 04:39:03,120
CELLS CAN CAUSE RETRO GRADE

7265
04:39:03,120 --> 04:39:04,160
LYMPH FLOW.

7266
04:39:04,160 --> 04:39:07,600
NEXT WE ASSESSED TRAMATNIB ON

7267
04:39:07,600 --> 04:39:08,480
MICE.

7268
04:39:08,480 --> 04:39:10,480
IT IS AN FDA APPROVED MEK

7269
04:39:10,480 --> 04:39:12,720
INHIBITOR USED TO TREAT DISEASE

7270
04:39:12,720 --> 04:39:14,840
CAUSED BY HYPE ACTIVE RAS MAP

7271
04:39:14,840 --> 04:39:15,680
KINASE SIGNALING.

7272
04:39:15,680 --> 04:39:18,240
IN THIS EXPERIMENT, WE FOUND

7273
04:39:18,240 --> 04:39:22,160
THAT TRAMATNIB CAN PREVENT

7274
04:39:22,160 --> 04:39:23,400
LYMPHATIC VALVE LOSS IN OUR

7275
04:39:23,400 --> 04:39:25,280
MUTANT ANIMALS.

7276
04:39:25,280 --> 04:39:29,720
SO TO SUMMARIZE, IDENTIFIED

7277
04:39:29,720 --> 04:39:32,040
ACTIVATING MUTATION IN KRAS IN A

7278
04:39:32,040 --> 04:39:34,600
PATIENT WITH GORHAM STOUT

7279
04:39:34,600 --> 04:39:36,560
DISEASE, IN CONCURRENT WITH OUR

7280
04:39:36,560 --> 04:39:37,400
STUDY ODE GROUP IDENTIFIED

7281
04:39:37,400 --> 04:39:39,040
SOMATIC ACTIVATING MUTATION IN

7282
04:39:39,040 --> 04:39:43,120
KRAS IN A DIFFERENT PATIENT.

7283
04:39:43,120 --> 04:39:45,440
WE WENT ON TO SHOW THAT HYPE

7284
04:39:45,440 --> 04:39:47,960
ACTIVE KRAS SIGNALING IN

7285
04:39:47,960 --> 04:39:49,520
LYMPHATIC ENDOTHELIAL CELLS

7286
04:39:49,520 --> 04:39:50,800
LEADS TO FORMATION OF TOPIC

7287
04:39:50,800 --> 04:39:52,480
LYMPHATICS IN BONE AND HYPE

7288
04:39:52,480 --> 04:39:55,720
ACTIVE RAS SIGNALING AFFECTING

7289
04:39:55,720 --> 04:39:57,800
DEVELOPMENT AND MAINTENANCE OF

7290
04:39:57,800 --> 04:39:58,840
LYMPHATIC VALVES.

7291
04:39:58,840 --> 04:40:02,640
AND LASTLY,RAMATNIB CAN PREVENT

7292
04:40:02,640 --> 04:40:04,320
LOSS IN MUTANT ANIMALS.

7293
04:40:04,320 --> 04:40:05,640
WE PERFORMED THE FIRST MOUSE

7294
04:40:05,640 --> 04:40:06,080
MODELS.

7295
04:40:06,080 --> 04:40:09,160
THE FIRST GENERATION MODEL WAS

7296
04:40:09,160 --> 04:40:11,680
VEGF C TRANSGENIC MODEL USING

7297
04:40:11,680 --> 04:40:13,560
VEGFC TO DRIVE ACTIVATION OF

7298
04:40:13,560 --> 04:40:15,440
PATHWAYS MISREGULATED IN

7299
04:40:15,440 --> 04:40:17,200
PATIENTS WITH COMPLEX LYMPHATIC

7300
04:40:17,200 --> 04:40:18,160
ANOMALIES.

7301
04:40:18,160 --> 04:40:20,080
IN OUR SECOND GENERATION MODEL,

7302
04:40:20,080 --> 04:40:22,640
WE USED GENETIC TOOLS TO DRIVE

7303
04:40:22,640 --> 04:40:24,480
EXPRESSION OF MUTANT FORM OF

7304
04:40:24,480 --> 04:40:27,120
KRAS WHICH WE IDENTIFIED IN A

7305
04:40:27,120 --> 04:40:28,360
PATIENT TO PROMOTE DISEASE IN

7306
04:40:28,360 --> 04:40:29,760
MICE.

7307
04:40:29,760 --> 04:40:31,640
SO THESE ANIMAL MODELS ARE

7308
04:40:31,640 --> 04:40:32,920
HELPING US DEVELOP BETTER

7309
04:40:32,920 --> 04:40:34,960
UNDERSTANDING OF THE

7310
04:40:34,960 --> 04:40:36,760
PATHOPHYSIOLOGY OF LYMPHATIC

7311
04:40:36,760 --> 04:40:38,160
ANOMALIES AND OUR HOPE IS THAT

7312
04:40:38,160 --> 04:40:40,400
OUR WORK LEAD TO REPURPOSING OF

7313
04:40:40,400 --> 04:40:42,480
EPI APPROVED DRUGS AND ENABLE A

7314
04:40:42,480 --> 04:40:45,640
PRECISION MEDICINE APPROACH TO

7315
04:40:45,640 --> 04:40:46,760
THE TREATMENT OF COMPLEX

7316
04:40:46,760 --> 04:40:49,360
LYMPHATIC ANOMALIES.

7317
04:40:49,360 --> 04:40:51,040
WITH RESPECT TO GAPS

7318
04:40:51,040 --> 04:40:53,720
OPPORTUNITIES AND NEEDS, A BIG

7319
04:40:53,720 --> 04:40:55,440
QUESTION IN THE FIELD IS HOW IS

7320
04:40:55,440 --> 04:40:56,680
THE MICROENVIRONMENT ALTERED IN

7321
04:40:56,680 --> 04:40:58,080
LESIONS AND DOES IT CONTRIBUTE

7322
04:40:58,080 --> 04:40:59,920
TO DISEASE PROGRESSION?

7323
04:40:59,920 --> 04:41:01,400
SO BETTER UNDERSTANDING OF THE

7324
04:41:01,400 --> 04:41:04,120
CELLULAR MOLECULAR CHANGES IN

7325
04:41:04,120 --> 04:41:05,400
LESIONS COULD YIELD KNEW

7326
04:41:05,400 --> 04:41:06,880
TREATMENT TO USE IN COMBINATION

7327
04:41:06,880 --> 04:41:09,120
WITH TARGETED THERAPIES, ANOTHER

7328
04:41:09,120 --> 04:41:11,440
QUESTION IS HOW CLA POSITIVE

7329
04:41:11,440 --> 04:41:13,760
GENETIC MUTATIONS AFFECT

7330
04:41:13,760 --> 04:41:15,760
ENDTHELIAL CELL POPULATIONS AND

7331
04:41:15,760 --> 04:41:18,480
HOW DO MUTANT LECs AFFECT

7332
04:41:18,480 --> 04:41:19,640
NORMAL LECs.

7333
04:41:19,640 --> 04:41:21,840
ONE AREA WE ARE INTERESTED IN

7334
04:41:21,840 --> 04:41:23,280
EXPLORING IS AFFECT MUTANT

7335
04:41:23,280 --> 04:41:26,720
MUTATIONS HAVE WHETHER MUTATION

7336
04:41:26,720 --> 04:41:29,160
OCCURS IN A LIMB ANGIOBLAST OR

7337
04:41:29,160 --> 04:41:31,160
PART OF EXISTING VESSEL AND

7338
04:41:31,160 --> 04:41:32,760
LASTLY MORE VASCULAR ANOMALY

7339
04:41:32,760 --> 04:41:34,440
CENTERS ARE NEEDED FOR ADULT

7340
04:41:34,440 --> 04:41:36,520
PATIENTS.  PATIENTS WITH A

7341
04:41:36,520 --> 04:41:39,000
COMPLEX LYMPHATIC ANOMALY ARE

7342
04:41:39,000 --> 04:41:40,880
SEEN AT VAS QUEUE ALREADY

7343
04:41:40,880 --> 04:41:42,520
ANOMALY CENTER AT CHILDREN'S

7344
04:41:42,520 --> 04:41:43,960
HOSPITALS, SO YOUNG ADULTS NEED

7345
04:41:43,960 --> 04:41:47,080
A PLACE TO GO TO CONTINUE THEIR

7346
04:41:47,080 --> 04:41:48,640
CARE AFTER THEY AGE OUT

7347
04:41:48,640 --> 04:41:49,880
CHILDREN'S HOSPITAL AND NEWLY

7348
04:41:49,880 --> 04:41:52,000
DIAGNOSED ADULT PATIENTS NEED

7349
04:41:52,000 --> 04:41:53,440
SPECIAL CENTERS WITHIN

7350
04:41:53,440 --> 04:41:55,040
EXPERIENCE MULTI-DISCIPLINARY

7351
04:41:55,040 --> 04:41:57,640
TEAM FOR THEIR CARE.

7352
04:41:57,640 --> 04:41:59,080
WITH THAT THANKS TO PEOPLE IN MY

7353
04:41:59,080 --> 04:42:00,920
LAB THAT WORKED ON THESE

7354
04:42:00,920 --> 04:42:01,480
PROJECTS.

7355
04:42:01,480 --> 04:42:03,880
MY COLLABORATORS AND FUNDING

7356
04:42:03,880 --> 04:42:04,480
RESOURCES.

7357
04:42:04,480 --> 04:42:05,800
THANK YOU FOR YOUR ATTENTION.

7358
04:42:05,800 --> 04:42:14,160
HAPPY TO ANSWER YOUR QUESTIONS.

7359
04:42:14,160 --> 04:42:17,200
>> THANKS VERY MUCH, MIKE.

7360
04:42:17,200 --> 04:42:18,200
WE WILL TAKE THE QUESTIONS AT

7361
04:42:18,200 --> 04:42:20,840
THE END SO WE'LL MOVE TO DR.

7362
04:42:20,840 --> 04:42:21,320
EDWARD SCHWARZ.

7363
04:42:21,320 --> 04:42:25,120
TAKE IT AWAY, DR. SCHWARZ.

7364
04:42:25,120 --> 04:42:27,840
>> HANKS SO MUCH TIM AND
FOR THE

7365
04:42:27,840 --> 04:42:28,960
ORGANIZERS FOR GIVING ME THE

7366
04:42:28,960 --> 04:42:30,080
OPPORTUNITY TO TELL YOU ABOUT

7367
04:42:30,080 --> 04:42:31,560
ARTHRITIS.

7368
04:42:31,560 --> 04:42:34,120
THESE ARE MY DISCLOSURES.

7369
04:42:34,120 --> 04:42:37,120
SO RHEUMATOID ARTHRITIS WE TEACH

7370
04:42:37,120 --> 04:42:39,280
IS THE MOST PREVALENT AUTOIMMUNE

7371
04:42:39,280 --> 04:42:42,880
DISEASE AFFECTING UP TO 1%

7372
04:42:42,880 --> 04:42:44,520
POPULATION IN GENERAL AND AS WE

7373
04:42:44,520 --> 04:42:49,840
AGE PATIENTS OVER 65, 53 TO 5%.

7374
04:42:49,840 --> 04:42:51,440
THE -- 3 TO 5%.

7375
04:42:51,440 --> 04:42:53,240
THE ETIOLOGY REMAINS UNKNOWN BUT

7376
04:42:53,240 --> 04:42:57,080
THE DISEASE LARGELY MANIFESTSIST

7377
04:42:57,080 --> 04:43:02,120
BY INFLAMMATION IN AFFECTED

7378
04:43:02,120 --> 04:43:02,840
JOINTS, DRIVEN BY

7379
04:43:02,840 --> 04:43:05,920
PROINFLAMMATORY CYTOKINES INTO A

7380
04:43:05,920 --> 04:43:07,800
VICIOUS CYCLE AND RESULTS IN

7381
04:43:07,800 --> 04:43:10,880
THIS LARGE TISSUE WHICH WE CALL

7382
04:43:10,880 --> 04:43:13,520
PANES TISSUE WHICH NOW EXPERTS

7383
04:43:13,520 --> 04:43:14,920
AT OSTEOCLAST AT THE LEADING

7384
04:43:14,920 --> 04:43:16,840
EDGE THAT ERODE THE BONE AND

7385
04:43:16,840 --> 04:43:20,280
CARTILAGE.

7386
04:43:20,280 --> 04:43:22,920
NOW, I AM MY METEOROLOGIST BY

7387
04:43:22,920 --> 04:43:24,600
TRAINING AND NOBODY WANTED

7388
04:43:24,600 --> 04:43:27,280
RHEUMATOID ARTHRITIS TO BE AN

7389
04:43:27,280 --> 04:43:28,440
AUTOIMMUNE DISEASE MORE THAN ME.

7390
04:43:28,440 --> 04:43:32,480
THE PROBLEM IS THAT IT IS NOT.

7391
04:43:32,480 --> 04:43:34,880
SO MY LAB IS FOLLOWING AND

7392
04:43:34,880 --> 04:43:38,000
TESTING MULTIPLE HYPOTHESES TO

7393
04:43:38,000 --> 04:43:39,040
PROVE THAT THEORY.

7394
04:43:39,040 --> 04:43:41,800
WE KNOW THIS BECAUSE THE

7395
04:43:41,800 --> 04:43:44,640
AUTOIMMUNE HYPOTHESIS DOESN'T

7396
04:43:44,640 --> 04:43:47,720
FULFILL POSTULATES.

7397
04:43:47,720 --> 04:43:50,720
THERE ARE PATIENTS WITHOUT

7398
04:43:50,720 --> 04:43:52,360
AUTOANTIBODIES WHICH IS WHERE

7399
04:43:52,360 --> 04:43:54,240
AUTO-IMMUNITY TERM COMES FROM,

7400
04:43:54,240 --> 04:43:56,920
SERO NEGATIVE.

7401
04:43:56,920 --> 04:43:58,480
THERE ARE LOTS OF PEOPLE THAT

7402
04:43:58,480 --> 04:44:02,760
HAVE AUTOANTIBODIES, MOST DON'T

7403
04:44:02,760 --> 04:44:05,000
HAVE RHEUMATOID ARTHRITIS AND ON

7404
04:44:05,000 --> 04:44:07,160
AVERAGE PATIENTS DEVELOP

7405
04:44:07,160 --> 04:44:07,960
AUTOANTIBODIES AT LEAST TEN

7406
04:44:07,960 --> 04:44:09,080
YEARS BEFORE THEY DEVELOP ANY

7407
04:44:09,080 --> 04:44:13,880
SIGNS AND SYMPTOMS.

7408
04:44:13,880 --> 04:44:15,320
AUTOANTIBODIES FOUND IN PATIENTS

7409
04:44:15,320 --> 04:44:19,160
DON'T DIRECTLY INDUCE JOINT

7410
04:44:19,160 --> 04:44:20,560
INFLAMMATION AND DAMAGE

7411
04:44:20,560 --> 04:44:21,160
DIRECTLY.

7412
04:44:21,160 --> 04:44:23,280
THE AUTOANTIBODIES WE USE IN

7413
04:44:23,280 --> 04:44:24,600
ANIMAL MODELS RHEUMATOID

7414
04:44:24,600 --> 04:44:25,280
ARTHRITIS DO NOT EXIST IN

7415
04:44:25,280 --> 04:44:28,360
PEOPLE.

7416
04:44:28,360 --> 04:44:29,800
MOST SIGNIFICANTLY CLINICALLY

7417
04:44:29,800 --> 04:44:32,880
AND FOR THIS TALK, THE

7418
04:44:32,880 --> 04:44:35,680
AUTOANTIBODIES THAT EXISTED IN

7419
04:44:35,680 --> 04:44:38,000
RHEUMATOID ARTHRITIS, THE

7420
04:44:38,000 --> 04:44:39,800
TITLERS DON'T INCREASE, THERE'S

7421
04:44:39,800 --> 04:44:43,800
NO CHANGE IN AUTOIMMUNE PROFILE

7422
04:44:43,800 --> 04:44:46,880
DURING A FLAIR, AFFECTIVE

7423
04:44:46,880 --> 04:44:48,360
THERAPY THAT TREATS RHEUMATOID

7424
04:44:48,360 --> 04:44:50,480
ARTHRITIS DOES NOT DECREASE

7425
04:44:50,480 --> 04:44:51,480
AUTOANTIBODY TITERS.

7426
04:44:51,480 --> 04:44:53,320
THERE IS A FUNDAMENTAL

7427
04:44:53,320 --> 04:44:55,880
DISCONNECT BETWEEN THAT.

7428
04:44:55,880 --> 04:44:58,680
STARTING AS POST DOC 30 YEARS

7429
04:44:58,680 --> 04:45:03,520
AGO, STILL TODAY I USE TNF

7430
04:45:03,520 --> 04:45:04,600
TRANSGENIC MOUSE MODEL,

7431
04:45:04,600 --> 04:45:06,320
PRECURSOR TO THE ONE YOU ALREADY

7432
04:45:06,320 --> 04:45:08,400
HEARD THIS MORNING.

7433
04:45:08,400 --> 04:45:11,640
IT DOESN'T HAVE INFLAMMATORY

7434
04:45:11,640 --> 04:45:13,360
BOWEL DISEASE BUT CHRONIC LOW

7435
04:45:13,360 --> 04:45:16,200
LEVEL TNF EXPRESSION WHICH LEADS

7436
04:45:16,200 --> 04:45:19,480
IN TO THE JOINT DESTRUCTION YOU

7437
04:45:19,480 --> 04:45:21,760
CAN SEE HERE IN THE KNEE JOINT

7438
04:45:21,760 --> 04:45:27,400
OF ME IN THIS CUSS, TIBIAL AND

7439
04:45:27,400 --> 04:45:28,120
FEMUR SIDES.

7440
04:45:28,120 --> 04:45:30,480
SO THIS UNABATING MODEL WAS MOST

7441
04:45:30,480 --> 04:45:31,960
INTERESTING TO ME BECAUSE IT

7442
04:45:31,960 --> 04:45:33,840
LOOKS MOST LIKE RHEUMATOID

7443
04:45:33,840 --> 04:45:34,480
ARTHRITIS.

7444
04:45:34,480 --> 04:45:36,000
AND OF COURSE THE GREAT

7445
04:45:36,000 --> 04:45:39,800
VALIDATION OF IT CAME FROM W THE

7446
04:45:39,800 --> 04:45:44,800
ANTI-TNF THERAPY.

7447
04:45:44,800 --> 04:45:45,560
AROUND 2006 WE WERE STILL

7448
04:45:45,560 --> 04:45:48,800
WORKING ON THIS MODEL AND MOST

7449
04:45:48,800 --> 04:45:51,400
TNF SIGNALING HAVE BEEN

7450
04:45:51,400 --> 04:45:54,840
ELUCIDATED BY VARIOUS FIELDS.

7451
04:45:54,840 --> 04:45:57,680
SO THERE IS ONE QUESTION

7452
04:45:57,680 --> 04:45:59,160
REMAINING FOR US TO ANSWER IN

7453
04:45:59,160 --> 04:46:01,720
TERMS OF UNDERSTANDING THE ROLE

7454
04:46:01,720 --> 04:46:04,360
TNF AND OSTEOCLAST GENESIS AND

7455
04:46:04,360 --> 04:46:06,520
JOINT DESTRUCTION THIS THIS

7456
04:46:06,520 --> 04:46:07,400
MODEL.

7457
04:46:07,400 --> 04:46:09,400
THAT WAS WHAT WAS THE FACTORS

7458
04:46:09,400 --> 04:46:12,680
THAT RELEASING THESE OSTEOCLAST

7459
04:46:12,680 --> 04:46:15,800
PRECURSORS FROM BONE MARROW BY

7460
04:46:15,800 --> 04:46:16,760
TNF.

7461
04:46:16,760 --> 04:46:18,400
I THINK STILL TODAY WHEN STUCK

7462
04:46:18,400 --> 04:46:23,240
YOU DO A MICROARRAY OR SPATIAL

7463
04:46:23,240 --> 04:46:27,200
TRANSCRIPTOMICS SO THIS WORK WAS

7464
04:46:27,200 --> 04:46:30,680
DONE BY LEEANN'S LAB WHERE SHE

7465
04:46:30,680 --> 04:46:34,520
DID MICROARRAY ANALYSIS OF THESE

7466
04:46:34,520 --> 04:46:37,680
BONE MARROW DERIVED OSTEOCLAST

7467
04:46:37,680 --> 04:46:38,680
PRECURSORS AND BLOOD CELLS FROM

7468
04:46:38,680 --> 04:46:43,600
THE WILD TYPE AND TNF MICE THE

7469
04:46:43,600 --> 04:46:44,960
FACT SHE FOUND THE GENE FOUND

7470
04:46:44,960 --> 04:46:47,600
MOST LIELY INDUCED IN OSTEOCLAST

7471
04:46:47,600 --> 04:46:51,040
PRECURSORS WAS VEGF C WHICH ALL

7472
04:46:51,040 --> 04:46:54,640
OF YOU KNOW IS LYMPHATIC GROWTH

7473
04:46:54,640 --> 04:46:55,120
FACTOR.

7474
04:46:55,120 --> 04:46:57,880
THAT ESSENTIALLY CHANGED THE

7475
04:46:57,880 --> 04:47:01,280
DIRECTION OF OUR LABORATORY EVER

7476
04:47:01,280 --> 04:47:01,760
SINCE.

7477
04:47:01,760 --> 04:47:03,280
HER LAB WENT TO SPECIFICALLY

7478
04:47:03,280 --> 04:47:06,560
SHOW THAT VEGF C IS HIGHLY

7479
04:47:06,560 --> 04:47:08,760
EXPRESSED IN OSTEOCLAST

7480
04:47:08,760 --> 04:47:13,640
PRECURSORS AND OSTEOCLAST TNF

7481
04:47:13,640 --> 04:47:14,400
TRANSGENIC MICE AND PATIENTS

7482
04:47:14,400 --> 04:47:16,120
WITH RHEUMATOID ARTHRITIS WITH

7483
04:47:16,120 --> 04:47:18,160
FOCAL EROSIONS AN THESE ARE THE

7484
04:47:18,160 --> 04:47:19,800
OSTEOCLASTS THAT THE -- IN THE

7485
04:47:19,800 --> 04:47:24,120
JOINT ERODING THE BONE AWAY.

7486
04:47:24,120 --> 04:47:26,240
THE NEXT APPROACH THAT WE

7487
04:47:26,240 --> 04:47:29,360
DECIDED TO DO IS IF YOU STUDY

7488
04:47:29,360 --> 04:47:30,920
FLAIR YOU HAVE TO HAVE OUTCOME

7489
04:47:30,920 --> 04:47:32,600
MEASURES WHAT HAPPENS BEFORE THE

7490
04:47:32,600 --> 04:47:33,760
FLAIR DURING THE FLAIR AND AFTER

7491
04:47:33,760 --> 04:47:37,680
THE FLAIR.

7492
04:47:37,680 --> 04:47:40,320
SO I WAS BREADS TO HAVE STEVEN

7493
04:47:40,320 --> 04:47:42,800
PRU AS Ph.D. SUNT IN MY LAB,

7494
04:47:42,800 --> 04:47:45,320
YOU KNOW HIM BETTER THAN ME AND

7495
04:47:45,320 --> 04:47:46,600
HE'S MADE SEVERAL MAJOR

7496
04:47:46,600 --> 04:47:48,360
CONTRIBUTIONS TO THIS FIELD, THE

7497
04:47:48,360 --> 04:47:51,480
FIRST IS DEVELOPING LONGITUDINAL

7498
04:47:51,480 --> 04:47:52,960
CONTRAST ENHANCED MRI FOR THE

7499
04:47:52,960 --> 04:47:53,480
MOUSE.

7500
04:47:53,480 --> 04:47:57,240
THIS IS ACTUALLY UTILIZING THE

7501
04:47:57,240 --> 04:47:59,160
CLINICAL PRE-TEST THE MAGNET

7502
04:47:59,160 --> 04:48:00,840
DEVELOP SURFACE COILS THE MOUSE

7503
04:48:00,840 --> 04:48:05,040
CAN GO INTO CLINICAL INSTRUMENT.

7504
04:48:05,040 --> 04:48:08,920
AT THAT TIME WE ARE LOOKING TO

7505
04:48:08,920 --> 04:48:12,440
REALLY 3-D RENDERING OF SYNOVIAL

7506
04:48:12,440 --> 04:48:14,960
TISSUE IN THESE MICE WITH ANKLE

7507
04:48:14,960 --> 04:48:16,320
ARTHRITIS, YOU CAN SEE HE

7508
04:48:16,320 --> 04:48:18,400
SUCCEEDED IN THAT BY GENERATING

7509
04:48:18,400 --> 04:48:20,000
THIS CONTRAST ENHANCEMENT WHICH

7510
04:48:20,000 --> 04:48:21,160
ENABLES THE 3-D REMEMBER

7511
04:48:21,160 --> 04:48:22,440
DEERING.

7512
04:48:22,440 --> 04:48:23,600
-- RENDERING.

7513
04:48:23,600 --> 04:48:26,240
I TOLD HIM HE HAD A TUMOR IN HIS

7514
04:48:26,240 --> 04:48:28,080
MOUSE, I HAD NO IDEA WHAT THIS

7515
04:48:28,080 --> 04:48:30,320
WAS, PROBABLY SURE MOST KNOW

7516
04:48:30,320 --> 04:48:33,280
THIS THE POPLY TEAL LYMPH NODE.

7517
04:48:33,280 --> 04:48:36,040
SO -- THIS DRAINS THE ANKLE SO

7518
04:48:36,040 --> 04:48:38,680
HE WENT TO DEVELOP ADDITIONAL

7519
04:48:38,680 --> 04:48:43,680
OUTCOME MEASURES INCLUDING 3-D

7520
04:48:43,680 --> 04:48:46,680
CT AND NEAR INFRARED ICG IMAGING

7521
04:48:46,680 --> 04:48:48,720
WHICH I'M SURE WE WILL HEAR MORE

7522
04:48:48,720 --> 04:48:50,920
ABOUT DURING THIS MEETING WHICH

7523
04:48:50,920 --> 04:48:53,720
THIS SIMPLE FLUORESCENT DYE IS

7524
04:48:53,720 --> 04:48:55,360
INJECTED IN THE FOOT PAD OF THE

7525
04:48:55,360 --> 04:48:58,880
MOUSE AND TRAVELS THROUGH THE --

7526
04:48:58,880 --> 04:49:02,760
TO DOMINANT LYMPHATIC VESSELS TO

7527
04:49:02,760 --> 04:49:06,240
THE POPLITEAL LYMPH NODE AND

7528
04:49:06,240 --> 04:49:08,840
PERFORMED REAL TIME TO QUANTIFY

7529
04:49:08,840 --> 04:49:10,560
VARIOUS METRICS OF IT INCLUDING

7530
04:49:10,560 --> 04:49:12,680
THE CONTRACTIONS WHICH ARE

7531
04:49:12,680 --> 04:49:14,680
OBVIOUSLY INCREASED IN THE

7532
04:49:14,680 --> 04:49:17,880
SETTING OF INFLAMMATION AND

7533
04:49:17,880 --> 04:49:19,320
OTHER ASPECTS I WILL TALK ABOUT

7534
04:49:19,320 --> 04:49:21,400
IN A LITTLE BIT.

7535
04:49:21,400 --> 04:49:22,960
HAVING DEVELOPED THESE THREE

7536
04:49:22,960 --> 04:49:25,160
LONGITUDINAL OUTCOME MEASURES,

7537
04:49:25,160 --> 04:49:27,440
STEVE WAS ABLE TO IDENTIFY SOME

7538
04:49:27,440 --> 04:49:29,400
VERY INTERESTING BEHAVIORS IN

7539
04:49:29,400 --> 04:49:32,000
THIS MOUSE MODEL OF CHRONIC

7540
04:49:32,000 --> 04:49:34,800
INFLAMMATORY EROSIVE ARTHRITIS.

7541
04:49:34,800 --> 04:49:36,520
WHAT HE FOUND IS THAT IN THE

7542
04:49:36,520 --> 04:49:39,600
BEGINNING OF THE DISEASE, BEFORE

7543
04:49:39,600 --> 04:49:43,440
THERE IS ANY INFLAMMATION IN THE

7544
04:49:43,440 --> 04:49:46,640
KNEE JOINT HERE POPLITEAL LYMPH

7545
04:49:46,640 --> 04:49:47,880
NODE GETS LARGE AND CONTRAST

7546
04:49:47,880 --> 04:49:50,840
ENHANCING.

7547
04:49:50,840 --> 04:49:54,000
AND THEN ALL OF A SUDDEN

7548
04:49:54,000 --> 04:49:55,280
SPONTANEOUSLY HE OBSERVE IT IS

7549
04:49:55,280 --> 04:49:57,360
COLLAPSE OF THAT LYMPH NODE SUCH

7550
04:49:57,360 --> 04:50:00,200
THAT IT IS NO LONGER TAKING UP

7551
04:50:00,200 --> 04:50:02,760
CONTRAST AND SIMULTANEOUS WITH

7552
04:50:02,760 --> 04:50:05,880
THAT WE COULD SEE THE FLAIR AS

7553
04:50:05,880 --> 04:50:09,000
EVIDENCED BY IMAGING OF THE MRI

7554
04:50:09,000 --> 04:50:10,720
OF THE SYNOVIAL.

7555
04:50:10,720 --> 04:50:13,040
THIS IS AN EXAMPLE OF THE

7556
04:50:13,040 --> 04:50:16,080
LONGITUDINAL DATA IN WHICH YOU

7557
04:50:16,080 --> 04:50:17,960
CAN SEE EXPANSION OF THE LYMPH

7558
04:50:17,960 --> 04:50:21,840
NODE BOTH IN SIZE AND CONTRAST

7559
04:50:21,840 --> 04:50:23,320
ENHANCEMENT AND THEN SUDDEN

7560
04:50:23,320 --> 04:50:26,160
DECREASE IN THAT WHICH WE CALL

7561
04:50:26,160 --> 04:50:28,200
THE COLLAPSE.

7562
04:50:28,200 --> 04:50:31,760
HERE YOU CAN SEE THERE IS NO

7563
04:50:31,760 --> 04:50:35,720
KNEE ARTHRITIS DURING THIS

7564
04:50:35,720 --> 04:50:37,360
INFLAMMATORY PERIOD UNTIL THE

7565
04:50:37,360 --> 04:50:38,080
COLLAPSE OCCURS.

7566
04:50:38,080 --> 04:50:40,720
YOU CAN SEE OF COURSE THE

7567
04:50:40,720 --> 04:50:44,920
INDIVIDUAL IMAGES OF THIS, SO

7568
04:50:44,920 --> 04:50:47,360
DURING THE EXPANDING PHASE YOU

7569
04:50:47,360 --> 04:50:49,120
HAVE DRAINAGE FROM FOOT PAD.

7570
04:50:49,120 --> 04:50:50,160
NOT MUCH ARTHRITIS.

7571
04:50:50,160 --> 04:50:51,840
YOU HAVE A LARGE LYMPH NODE WITH

7572
04:50:51,840 --> 04:50:55,360
LARGE SINUS SPACES, AND VERY FEW

7573
04:50:55,360 --> 04:50:56,080
OSTEOCLASTS AND DURING THE

7574
04:50:56,080 --> 04:50:59,440
COLLAPSE THERE IS NO MORE

7575
04:50:59,440 --> 04:51:01,480
DRAINAGE THE LYMPH NODE IS

7576
04:51:01,480 --> 04:51:02,640
SMALL, THIS IS THAT TISSUE I WAS

7577
04:51:02,640 --> 04:51:03,760
TELLING YOU ABOUT AND THESE ARE

7578
04:51:03,760 --> 04:51:05,920
ALL THE OSTEOCLASTS DEVOURING

7579
04:51:05,920 --> 04:51:09,360
THE BONE.

7580
04:51:09,360 --> 04:51:12,360
THE LAST INTERESTING POINT ABOUT

7581
04:51:12,360 --> 04:51:16,720
IMAGING AND TNF MOUSE MODEL I

7582
04:51:16,720 --> 04:51:18,440
PREFERENTIALLY USE AMONG ALL

7583
04:51:18,440 --> 04:51:19,520
ELSE, BOTH THINGS CAN BE

7584
04:51:19,520 --> 04:51:20,840
HAPPENING IN THE SAME ANIMAL AT

7585
04:51:20,840 --> 04:51:21,360
THE SAME TIME.

7586
04:51:21,360 --> 04:51:26,560
SO THIS IS A MOUSE WHICH IN LEFT

7587
04:51:26,560 --> 04:51:29,960
LEG EXPANDING WITH NO EVIDENCE

7588
04:51:29,960 --> 04:51:32,280
OF ARTHRITIS AND EROSION AND AT

7589
04:51:32,280 --> 04:51:33,520
THE SAME TIME RIGHT LEG HAS

7590
04:51:33,520 --> 04:51:36,280
COLLAPSED POPLITEAL LYMPH NODE

7591
04:51:36,280 --> 04:51:40,920
WITH A KNEE FLAIR IN TERMS OF

7592
04:51:40,920 --> 04:51:42,840
SYNOVITIS AND FOCAL EROSIONS.

7593
04:51:42,840 --> 04:51:44,760
HAVING DONE THIS NOW WENT TO

7594
04:51:44,760 --> 04:51:46,400
CHARACTERIZE WHAT IS GOING ON IN

7595
04:51:46,400 --> 04:51:49,200
THESE LYMPH NODES, I WILL

7596
04:51:49,200 --> 04:51:53,200
SUMMARIZE A LOT OF IN SITU AND

7597
04:51:53,200 --> 04:51:56,600
IN VITRO AND EXVIVO DATA TO SAY

7598
04:51:56,600 --> 04:51:59,760
THE MAJOR FINDING OF THIS IS

7599
04:51:59,760 --> 04:52:01,880
EXPANSION OF B CELLS.

7600
04:52:01,880 --> 04:52:04,240
SO IN THE EXPANDING LYMPH NODE

7601
04:52:04,240 --> 04:52:06,800
THESE ARE THE FOLLICLES WHERE

7602
04:52:06,800 --> 04:52:07,760
NON-ACTIVATED B CELLS SHOULD BE

7603
04:52:07,760 --> 04:52:08,560
LIVING.

7604
04:52:08,560 --> 04:52:10,560
THESE ARE VERY LARGE SINUS

7605
04:52:10,560 --> 04:52:12,120
SPACES, THE ONLY CELLS WE

7606
04:52:12,120 --> 04:52:14,160
PRIMARILY FIND IN THE SINUSES

7607
04:52:14,160 --> 04:52:16,800
ARE ACTIVATED MACROPHAGES COMING

7608
04:52:16,800 --> 04:52:18,960
FROM INFLAMED JOINTS.

7609
04:52:18,960 --> 04:52:21,400
THEN COLLAPSE PHASE IT APPEARS B

7610
04:52:21,400 --> 04:52:23,840
CELLS MIGRATED OUT OF FOLLICLES

7611
04:52:23,840 --> 04:52:25,280
AND ARE NOW CLOGGING THE

7612
04:52:25,280 --> 04:52:26,480
SINUSES.

7613
04:52:26,480 --> 04:52:29,320
IN COLLABORATION WITH ANDREA WHO

7614
04:52:29,320 --> 04:52:31,640
IS A BONA FIDE CELL

7615
04:52:31,640 --> 04:52:33,200
IMMUNOLOGIST, HE SCREENED THESE

7616
04:52:33,200 --> 04:52:35,960
B CELLS BY HUNDREDS OF SURFACE

7617
04:52:35,960 --> 04:52:38,480
MARKERS AND IDENTIFIED THIS

7618
04:52:38,480 --> 04:52:40,840
PHENOTYPE WHICH HE TERMED B CELL

7619
04:52:40,840 --> 04:52:43,280
AND INFLAMED LYMPH NODES OR BN

7620
04:52:43,280 --> 04:52:46,120
CELLS, THAT'S WHAT IMMUNOLOGISTS

7621
04:52:46,120 --> 04:52:46,560
DO.

7622
04:52:46,560 --> 04:52:48,920
BUT AGAIN, AUTOIMMUNE HYPOTHESIS

7623
04:52:48,920 --> 04:52:51,080
FAILS IN THAT ANY EXPERIMENT WE

7624
04:52:51,080 --> 04:52:54,040
CAN DO IN BULK WE FOUND NO

7625
04:52:54,040 --> 04:52:54,920
SIGNIFICANT DIFFERENCES IN THE

7626
04:52:54,920 --> 04:52:57,800
NUMBER OF THESE B CELLS, THERE

7627
04:52:57,800 --> 04:53:00,080
WERE NO ACTIVATION MARKERS, B

7628
04:53:00,080 --> 04:53:01,480
CELLS ARE POLYCLONAL.

7629
04:53:01,480 --> 04:53:05,440
THEY DON'T HAVE MARKERS FOR

7630
04:53:05,440 --> 04:53:08,000
PROLIFERATION OR CHANGES IN

7631
04:53:08,000 --> 04:53:09,000
CHEMOKINES OR CHEMOKINE

7632
04:53:09,000 --> 04:53:09,480
RECEPTORS.

7633
04:53:09,480 --> 04:53:11,600
SO THE SOLUTION WAS THEY WERE

7634
04:53:11,600 --> 04:53:14,040
PLAYING THAT PASSIVE ROLE IN

7635
04:53:14,040 --> 04:53:15,720
COLLAPSE AND ARTHRITIC FLAIR.

7636
04:53:15,720 --> 04:53:18,800
THE NEXT ON THE SCENE WAS A

7637
04:53:18,800 --> 04:53:22,080
Ph.D. STUDENT IN MY LAB WHO

7638
04:53:22,080 --> 04:53:26,040
DEVELOPED THIS IMMUNOFLUORESCENT

7639
04:53:26,040 --> 04:53:29,520
INTRAVITAL MICROSCOPY OF

7640
04:53:29,520 --> 04:53:31,280
POPLITEAL LYMPHATIC VESSELS

7641
04:53:31,280 --> 04:53:34,840
INJECTING FLUORESCENTLY LABELED

7642
04:53:34,840 --> 04:53:36,280
ANTI-CD 11B ANTIBODY INTO THE

7643
04:53:36,280 --> 04:53:39,480
FOOT PAD, YOU CAN SEE FROM THE

7644
04:53:39,480 --> 04:53:42,480
REAL TIME VIDEO, THE MACROPHAGES

7645
04:53:42,480 --> 04:53:47,040
ARE FLYING THROUGH THIS

7646
04:53:47,040 --> 04:53:48,600
POPLITEAL VESSEL BEING EXPANDED

7647
04:53:48,600 --> 04:53:52,480
BUT NO MOVEMENT AT ALL IN THE

7648
04:53:52,480 --> 04:53:54,560
COLLAPSED.

7649
04:53:54,560 --> 04:53:56,160
SO BECAUSE WE KNEW THERE WERE B

7650
04:53:56,160 --> 04:53:58,800
CELLS IN THE LYMPH NODE THAT WE

7651
04:53:58,800 --> 04:54:01,400
PROPOSED THAT WERE CLOGGING AND

7652
04:54:01,400 --> 04:54:05,000
BECAUSE ANTI-CD 20 IS AN FDA

7653
04:54:05,000 --> 04:54:06,560
APPROVED DRUG FOR PATIENTS WHEN

7654
04:54:06,560 --> 04:54:10,160
THEY FAIL ANTI-TNF THERAPY, IT

7655
04:54:10,160 --> 04:54:13,280
IS CALLED RETUXIMAB, IF YOU

7656
04:54:13,280 --> 04:54:16,360
TREAT THESE TNF MICE WITH

7657
04:54:16,360 --> 04:54:18,480
PLACEBO OBVIOUSLY THEY WILL

7658
04:54:18,480 --> 04:54:19,000
FLAIR.

7659
04:54:19,000 --> 04:54:21,080
BUT IF YOU TREAT THEM WITH

7660
04:54:21,080 --> 04:54:22,880
ANTI-TNF -- ANTI-CD 20 THEY WILL

7661
04:54:22,880 --> 04:54:24,720
NOT FLAIR.

7662
04:54:24,720 --> 04:54:27,440
MORE INTERESTINGLY HE SHOWED IF

7663
04:54:27,440 --> 04:54:30,600
YOU WAIT FOR MICE TO FLAIR,

7664
04:54:30,600 --> 04:54:32,160
MEANING THEY HAVE A COLLAPSE OF

7665
04:54:32,160 --> 04:54:35,360
THE LYMPH NODE, THEY HAVE THE

7666
04:54:35,360 --> 04:54:39,960
LARGE SYNOVITIS AND ICG ISN'T

7667
04:54:39,960 --> 04:54:42,040
DRAINING, TWO WEEKS AFTER B CELL

7668
04:54:42,040 --> 04:54:44,240
DEPLETION THERAPY THE FIRST SIGN

7669
04:54:44,240 --> 04:54:47,080
IS INCREASE IN GADOLINIUM WHICH

7670
04:54:47,080 --> 04:54:50,000
IS OCCUPYING THE SINUS SPACES

7671
04:54:50,000 --> 04:54:52,480
THAT ARE CLEARED OF B CELLS.

7672
04:54:52,480 --> 04:54:56,360
THE SYNOVITIS IN THE KNEE MELTS

7673
04:54:56,360 --> 04:54:58,440
AWAY AND YOU RECOVER THE

7674
04:54:58,440 --> 04:55:01,840
LYMPHATIC FLOW FROM THE FOOT

7675
04:55:01,840 --> 04:55:02,280
PAD.

7676
04:55:02,280 --> 04:55:04,920
SHE ALSO WENT ON TO SHOW EVEN

7677
04:55:04,920 --> 04:55:07,200
THOUGH THIS IS ANTI-CD 20

7678
04:55:07,200 --> 04:55:09,560
DOESN'T ACTUALLY TOUCH THESE

7679
04:55:09,560 --> 04:55:11,600
MACROPHAGES, THIS IS A B CELL

7680
04:55:11,600 --> 04:55:12,280
SPECIFIC MARKER.

7681
04:55:12,280 --> 04:55:14,400
THESE MACROPHAGES APPEAR STUCK

7682
04:55:14,400 --> 04:55:16,840
OR ELIMINATED FOLLOWING ANTI-CD

7683
04:55:16,840 --> 04:55:18,440
20 THERAPY.

7684
04:55:18,440 --> 04:55:21,320
BUT SHE DID GO ON TO SHOW THAT

7685
04:55:21,320 --> 04:55:23,440
EVEN THOUGH YOU RESTORE SOME

7686
04:55:23,440 --> 04:55:26,880
FLOW YOU DO NOT RESTORE

7687
04:55:26,880 --> 04:55:27,560
CONTRACTIONS.

7688
04:55:27,560 --> 04:55:30,040
SO THIS WAS PRESUMED TO BE

7689
04:55:30,040 --> 04:55:31,600
PASSIVE FLOW IN ORDER TO

7690
04:55:31,600 --> 04:55:37,360
UNDERSTAND THAT BETTER, ECHO AND

7691
04:55:37,360 --> 04:55:38,440
KAREN BENTLEY PERFORMED

7692
04:55:38,440 --> 04:55:40,880
TRANSMISSION ELECTRON MICROSCOPY

7693
04:55:40,880 --> 04:55:42,240
TO CHARACTERIZE AND CROSS

7694
04:55:42,240 --> 04:55:43,800
SECTIONAL ANALYSIS THE NATURAL

7695
04:55:43,800 --> 04:55:45,560
HISTORY OF WHAT HAPPENS.

7696
04:55:45,560 --> 04:55:47,560
THESE ARE ACTIVATED MACROPHAGES

7697
04:55:47,560 --> 04:55:50,040
THAT ARE INITIALLY ADHERING.

7698
04:55:50,040 --> 04:55:52,480
WE CAN SEE DEGENERATION OF THE

7699
04:55:52,480 --> 04:55:55,080
ENDOTHELIAL CELLS IN SMOOTH

7700
04:55:55,080 --> 04:55:57,440
MUSCLE AND ULTIMATELY APOPTOSIS

7701
04:55:57,440 --> 04:55:58,320
OF THE CELLS.

7702
04:55:58,320 --> 04:56:00,400
THEN JUST LIKE EVERYBODY ELSE WE

7703
04:56:00,400 --> 04:56:03,840
JUMPED ON A PLANE AND WENT TO

7704
04:56:03,840 --> 04:56:07,720
COLUMBIA TO MIKE DAVIS' LAB AND

7705
04:56:07,720 --> 04:56:09,280
WORK WITH JOSH TO CAN LATE

7706
04:56:09,280 --> 04:56:12,280
VESSELS FROM WILD TYPE TNF

7707
04:56:12,280 --> 04:56:14,600
TRANSGENIC MICE WITH EXPANDING

7708
04:56:14,600 --> 04:56:17,520
LYMPH NODES AND THE COLLAPSE AND

7709
04:56:17,520 --> 04:56:20,120
YOU CAN SEE THAT THIS IS AN

7710
04:56:20,120 --> 04:56:21,440
INTRINSIC PHENOTYPE TO THE

7711
04:56:21,440 --> 04:56:23,640
VESSELS THAT SEEM TO BE DAMAGED

7712
04:56:23,640 --> 04:56:25,680
FROM THE CHRONIC INFLAMMATION.

7713
04:56:25,680 --> 04:56:31,360
SO MOST RECENTLY MARK AND UA

7714
04:56:31,360 --> 04:56:33,440
PAGE IN THE LAB HAVE DONE AN

7715
04:56:33,440 --> 04:56:35,920
EXPERIMENT THE SEE IF THIS IS

7716
04:56:35,920 --> 04:56:38,360
REVERSIBLE WITH THE ANTS TNF

7717
04:56:38,360 --> 04:56:38,920
THERAPY.

7718
04:56:38,920 --> 04:56:42,400
THEY TREATED MICE WITH DISEASE

7719
04:56:42,400 --> 04:56:49,080
WE ALREADY KNEW WE HAD LOST

7720
04:56:49,080 --> 04:56:52,840
LYMPHATIC SMOOTH MUSCLE ACTIN ON

7721
04:56:52,840 --> 04:56:56,720
THESE ANTI-TNF THERAPY DOESN'T

7722
04:56:56,720 --> 04:56:57,320
RESTORE THAT.

7723
04:56:57,320 --> 04:56:58,920
WE LOOKED CAREFULLY TO SEE IF WE

7724
04:56:58,920 --> 04:57:01,440
CAN SEE ANY REPAIR REGENERATION

7725
04:57:01,440 --> 04:57:05,600
BY BRD LABELING, WE DIDN'T SEE

7726
04:57:05,600 --> 04:57:08,120
EVIDENCE OF REPAIR REGENERATION.

7727
04:57:08,120 --> 04:57:11,720
OF THESE VESSELS.

7728
04:57:11,720 --> 04:57:13,160
THOUGH WE CAN SEE REPAIR AND

7729
04:57:13,160 --> 04:57:14,200
REGENERATION OF THE BONE.

7730
04:57:14,200 --> 04:57:15,680
LASTLY I WOULD LIKE TO POINT OUT

7731
04:57:15,680 --> 04:57:19,560
WITH PUBLISH PILOT STUDIES

7732
04:57:19,560 --> 04:57:21,680
EVERYTHING IN THE TNF MICE WE

7733
04:57:21,680 --> 04:57:23,440
ARE ABLE TO RECAPITULATE IN

7734
04:57:23,440 --> 04:57:25,400
HUMANS THIS IS A PATIENT UPON

7735
04:57:25,400 --> 04:57:27,560
INITIAL DIAGNOSIS OF RHEUMATOID

7736
04:57:27,560 --> 04:57:30,040
ARTHRITIS, YOU CAN SO E THE

7737
04:57:30,040 --> 04:57:33,080
INFLAMED SYNOVIUM BONE MARROW

7738
04:57:33,080 --> 04:57:34,560
EDEMA WHERE EROSIONS ARE AND THE

7739
04:57:34,560 --> 04:57:39,320
LARGE LYMPH NODES AND THIS IS AN

7740
04:57:39,320 --> 04:57:40,960
RA PATIENT PRE-TOTAL KNEE

7741
04:57:40,960 --> 04:57:42,440
REPLACEMENT AFTER 32 YEARS

7742
04:57:42,440 --> 04:57:43,040
DISEASE.

7743
04:57:43,040 --> 04:57:45,800
THE SYNOVIUM AND IF YOU WEREN'T

7744
04:57:45,800 --> 04:57:47,040
LOOKING CAREFULLY YOU WOULDN'T

7745
04:57:47,040 --> 04:57:49,760
FIND THESE COLLAPSED LYMPH

7746
04:57:49,760 --> 04:57:51,280
NODES.

7747
04:57:51,280 --> 04:57:53,240
RESECTION OF THOSE LYMPH NODES

7748
04:57:53,240 --> 04:57:57,000
CONFIRM THEY DO HAVE THE SAME BN

7749
04:57:57,000 --> 04:57:57,560
CELLS.

7750
04:57:57,560 --> 04:58:01,880
LASTLY WITH THE HELP OF CHRIS

7751
04:58:01,880 --> 04:58:03,320
RICHMOND, RICHARD BELL AND RON

7752
04:58:03,320 --> 04:58:05,680
WOOD WE COMPLETED A PILOT STUDY

7753
04:58:05,680 --> 04:58:08,480
OF ICG IMAGING IN HEALTHY

7754
04:58:08,480 --> 04:58:09,480
CONTROLS AND RHEUMATOID

7755
04:58:09,480 --> 04:58:10,920
ARTHRITIS PATIENTS AND WERE ABLE

7756
04:58:10,920 --> 04:58:14,320
TO CONFIRM THE LYMPHATIC DEFECTS

7757
04:58:14,320 --> 04:58:16,840
IN THE HANDS OF PATIENTS WITH

7758
04:58:16,840 --> 04:58:17,120
FLARE.

7759
04:58:17,120 --> 04:58:22,960
IN SUMMARY, WE CURRENTLY HAVE A

7760
04:58:22,960 --> 04:58:24,160
MODEL OF IMPORTANCE OF

7761
04:58:24,160 --> 04:58:25,160
LYMPHATICS IN PARTICULAR

7762
04:58:25,160 --> 04:58:27,880
LYMPHATIC FLOW.

7763
04:58:27,880 --> 04:58:30,280
IN INDUCTION OF FLARE.

7764
04:58:30,280 --> 04:58:31,800
WE BELIEVE RHEUMATOID ARTHRITIS

7765
04:58:31,800 --> 04:58:34,840
IS A COMPLICATED DYNDROME, IT IS

7766
04:58:34,840 --> 04:58:35,880
POSSIBLE NO TWO PATIENT VERSUS

7767
04:58:35,880 --> 04:58:38,080
THE SAME DISEASE BUT IT MAN

7768
04:58:38,080 --> 04:58:40,480
FASTS IN CHRONIC INFLAMMATION IN

7769
04:58:40,480 --> 04:58:46,120
THE JOINTS AND THE LYMPHATICS

7770
04:58:46,120 --> 04:58:47,800
ANDLY FANG OWE GENESIS IS A

7771
04:58:47,800 --> 04:58:48,920
PROTECTIVE MECHANISM TO REPAIR

7772
04:58:48,920 --> 04:58:51,280
THE JOINT WHICH WORKS FOR MANY

7773
04:58:51,280 --> 04:58:51,800
YEARS.

7774
04:58:51,800 --> 04:58:54,120
DUE TO THE CHRONIC INFLAMMATION

7775
04:58:54,120 --> 04:58:55,840
AND BREAK DOWN OF VESSELS, THE

7776
04:58:55,840 --> 04:58:58,120
LYMPHATIC FLOW IS LOST, WE HAVE

7777
04:58:58,120 --> 04:58:59,800
STAGNATION OF THESE ACTIVATED

7778
04:58:59,800 --> 04:59:02,320
MACROPHAGES THAT PRODUCE AMONG

7779
04:59:02,320 --> 04:59:05,160
OTHER THINGS CXCL 13 WHICH

7780
04:59:05,160 --> 04:59:08,440
RECRUIT B CELLS IN THIS MODEL

7781
04:59:08,440 --> 04:59:12,480
INCLUDES UNPUBLISHED SPATIAL

7782
04:59:12,480 --> 04:59:14,880
TRANSCRIPTOMIC DATA WHICH WE

7783
04:59:14,880 --> 04:59:17,240
IDENTIFIED IMPORTANT P CELL AND

7784
04:59:17,240 --> 04:59:19,520
PLASMA CELL DIFFERENTIATION AS

7785
04:59:19,520 --> 04:59:21,320
BEING INVOLVED IN THIS.

7786
04:59:21,320 --> 04:59:24,120
SO THIS WORK IS PURSUING.

7787
04:59:24,120 --> 04:59:25,600
WITH THAT I WOULD LIKE TO THANK

7788
04:59:25,600 --> 04:59:28,320
A LONG LIST OF COLLEAGUES AND

7789
04:59:28,320 --> 04:59:29,840
COLLABORATORS, I WOULD LIKE TO

7790
04:59:29,840 --> 04:59:31,760
POINT OUT I'M LARGELY FUNDED BY

7791
04:59:31,760 --> 04:59:33,440
THE NATIONAL INSTITUTE OF

7792
04:59:33,440 --> 04:59:36,400
ARTHRITIS AND MUSCULOSKELETAL

7793
04:59:36,400 --> 04:59:37,680
SKIN DISEASE.

7794
04:59:37,680 --> 04:59:39,080
THAT IN TERMS OF THE THREE

7795
04:59:39,080 --> 04:59:41,760
QUESTIONS I WAS ASKED TO ADVANCE

7796
04:59:41,760 --> 04:59:44,560
THE FIELD, BE VERY DIFFICULT TO

7797
04:59:44,560 --> 04:59:46,120
MOVE FORWARD WITHOUT FIRST AND

7798
04:59:46,120 --> 04:59:48,080
FOREMOST TRANSGENIC MODELS WITH

7799
04:59:48,080 --> 04:59:53,120
CONDITIONAL INDUCIBLE CRE IN

7800
04:59:53,120 --> 04:59:54,800
LYMPHATIC MUSCLE CELLS,

7801
04:59:54,800 --> 04:59:57,560
LYMPHATIC MUSCLE CELL LINES IN

7802
04:59:57,560 --> 05:00:00,640
MICE, AND ICG IMAGING, THE

7803
05:00:00,640 --> 05:00:03,120
CLINICAL IMAGING WE NEED SOME

7804
05:00:03,120 --> 05:00:05,000
MEANS TO DEVELOP IT INTO MORE

7805
05:00:05,000 --> 05:00:06,480
QUANTITATIVE SYSTEM.

7806
05:00:06,480 --> 05:00:08,400
WITH THAT, I'M HAPPY TO ANSWER

7807
05:00:08,400 --> 05:00:12,320
ANY QUESTIONS.

7808
05:00:12,320 --> 05:00:14,200
>> THANKS VERY MUCH, DR.

7809
05:00:14,200 --> 05:00:14,640
SCHWARZ.

7810
05:00:14,640 --> 05:00:16,040
WE WILL TAKE THE QUESTIONS AT

7811
05:00:16,040 --> 05:00:21,480
THE END SO WE'LL MOVE TO DR.

7812
05:00:21,480 --> 05:00:22,120
QUAGGIN.

7813
05:00:22,120 --> 05:00:28,000
>> THANKS, TIM.

7814
05:00:28,000 --> 05:00:35,960
JUST GOING TO FIND MY CAN YOU

7815
05:00:35,960 --> 05:00:39,360
SEE MY SLIDES?

7816
05:00:39,360 --> 05:00:40,360
>> WE CAN.

7817
05:00:40,360 --> 05:00:42,160
>> TERRIFIC.

7818
05:00:42,160 --> 05:00:43,160
THANK YOU, VERY MUCH, I WOULD

7819
05:00:43,160 --> 05:00:45,680
LIKE TO THANK THE ORGANIZERS FOR

7820
05:00:45,680 --> 05:00:48,000
INCLUDING ME IN THIS WORKSHOP

7821
05:00:48,000 --> 05:00:51,400
THAT'S BEEN ABSOLUTELY FANTASTIC

7822
05:00:51,400 --> 05:00:52,640
TODAY AND I WAS ASKED TO TALK

7823
05:00:52,640 --> 05:00:54,680
ABOUT LYMPHATICS IN THE KIDNEY.

7824
05:00:54,680 --> 05:00:56,520
WHAT I THOUGHT I WOULD DO IS TO

7825
05:00:56,520 --> 05:01:01,240
GIVE A RELATIVELY BROAD HIGH

7826
05:01:01,240 --> 05:01:03,120
LEVEL OVERVIEW AND FLAVOR WHERE

7827
05:01:03,120 --> 05:01:07,200
WE ARE WITH PARTICULAR FOCUS HOW

7828
05:01:07,200 --> 05:01:08,960
WE MIGHT BE ABLE TO MODULATE

7829
05:01:08,960 --> 05:01:12,520
LYMPHATICS TO TREAT KIDNEY

7830
05:01:12,520 --> 05:01:14,120
DISEASE.

7831
05:01:14,120 --> 05:01:15,800
IN MY OWN GROUP VASCULAR

7832
05:01:15,800 --> 05:01:17,960
BIOLOGIST AS WELL AS NEFFOLOGIST

7833
05:01:17,960 --> 05:01:19,280
AND WE ARE VERY INTERESTED IN

7834
05:01:19,280 --> 05:01:21,640
THE VASCULATURE IN THE KIDNEY.

7835
05:01:21,640 --> 05:01:22,440
DURING DEVELOPMENT AND IN

7836
05:01:22,440 --> 05:01:24,480
DISEASE.

7837
05:01:24,480 --> 05:01:26,480
WHAT I WANT YOU TO LEAVE HERE

7838
05:01:26,480 --> 05:01:28,240
AFTER THE NEXT 13 MINUTES OR SO

7839
05:01:28,240 --> 05:01:29,480
IS REALLY UNDERSTANDING THAT

7840
05:01:29,480 --> 05:01:31,280
THERE IS INCREDIBLE

7841
05:01:31,280 --> 05:01:33,200
HETEROGENEITY OF ENDOTHELIAL

7842
05:01:33,200 --> 05:01:35,520
CELLS WITHIN THE KIDNEY AND

7843
05:01:35,520 --> 05:01:37,080
DEVELOPMENT IN DISEASE

7844
05:01:37,080 --> 05:01:37,720
LYMPHATICS AND BLOOD.

7845
05:01:37,720 --> 05:01:40,120
THAT MODULATING KIDNEY

7846
05:01:40,120 --> 05:01:41,560
LYMPHATICS CAN AFFECT OUTCOME

7847
05:01:41,560 --> 05:01:43,240
FROM MULTIPLE DIFFERENT KIDNEY

7848
05:01:43,240 --> 05:01:45,720
DISEASES AND LYMPHATICS ARE

7849
05:01:45,720 --> 05:01:48,080
PRETTY EXCITING CANDIDATE

7850
05:01:48,080 --> 05:01:49,160
THERAPEUTIC TARGETS.

7851
05:01:49,160 --> 05:01:52,120
SO TO INTRODUCE YOU TO KIDNEY WE

7852
05:01:52,120 --> 05:01:54,320
HEARD ABOUT SOME OTHER ORGANS

7853
05:01:54,320 --> 05:01:55,280
TODAY.

7854
05:01:55,280 --> 05:01:57,480
THE KIDNEY IS PRETTY AMAZING

7855
05:01:57,480 --> 05:02:00,040
ORGAN, THE SIZE OF YOUR FIST, IT

7856
05:02:00,040 --> 05:02:02,280
RECEIVES ABOUT 25% CARDIAC

7857
05:02:02,280 --> 05:02:04,120
OUTPUT SO IT IS INCREDIBLY

7858
05:02:04,120 --> 05:02:04,840
VASCULAR ORGAN.

7859
05:02:04,840 --> 05:02:07,400
WHEN WE THINK ABOUT THE NORMAL

7860
05:02:07,400 --> 05:02:09,600
FUNCTION, THIS IS JUST A

7861
05:02:09,600 --> 05:02:11,760
SCHEMATIC OF A SPECIALIZED

7862
05:02:11,760 --> 05:02:14,680
MICROVASCULAR BEDS, THE

7863
05:02:14,680 --> 05:02:15,080
GLOMERULAR.

7864
05:02:15,080 --> 05:02:16,160
YOU HAVE ON THE ORDER OF A

7865
05:02:16,160 --> 05:02:19,000
MILLION OF THESE IN YOUR TUBE

7866
05:02:19,000 --> 05:02:22,600
KIDNEY, AND PRODUCE ON THE ORDER

7867
05:02:22,600 --> 05:02:27,160
OF 18 180 LITERS OF FILTRATE EAH

7868
05:02:27,160 --> 05:02:28,040
DAY.

7869
05:02:28,040 --> 05:02:30,280
YOU DON'T EXCRETE AT YOUR END SO

7870
05:02:30,280 --> 05:02:32,680
IT REQUIRES A COMPLEX NETWORK OF

7871
05:02:32,680 --> 05:02:34,120
SPECIALIZED MICROVASCULAR BEDS

7872
05:02:34,120 --> 05:02:38,400
TO ABSORB THE FLUID, SOLUTES AND

7873
05:02:38,400 --> 05:02:38,960
OTHER SUBSTANCES.

7874
05:02:38,960 --> 05:02:40,720
THE CORTEX OUTER PART OF THE

7875
05:02:40,720 --> 05:02:42,840
KIDNEY YOU HAVE PERITUBULAR

7876
05:02:42,840 --> 05:02:44,400
CAPILLARIES AND IN THE MEDULLA

7877
05:02:44,400 --> 05:02:46,400
OR INNER PART OF THE KIDNEY,

7878
05:02:46,400 --> 05:02:47,560
IMPORTANTLY FOR THIS GROUP

7879
05:02:47,560 --> 05:02:49,360
THERE'S NO CLASSIC LIMB

7880
05:02:49,360 --> 05:02:50,640
LYMPHATICS, BUT YOU DO HAVE

7881
05:02:50,640 --> 05:02:53,640
DESCENDING AND ASCENDING

7882
05:02:53,640 --> 05:02:55,520
VASORECK TIN AND THIS IS WHERE

7883
05:02:55,520 --> 05:02:58,640
YOU FINE TUNE SOLUTES, EXCRETION

7884
05:02:58,640 --> 05:03:01,440
AS WELL AS RESORB A LOT OF WATER

7885
05:03:01,440 --> 05:03:02,600
AND WATER BALANCE.

7886
05:03:02,600 --> 05:03:05,400
KIDNEY HAS A LOT OF ADDITIONAL

7887
05:03:05,400 --> 05:03:07,280
ROLES, REGULATING BLOOD PRESSURE

7888
05:03:07,280 --> 05:03:10,080
THROUGH THE RAS SYSTEM AND

7889
05:03:10,080 --> 05:03:12,840
PRODUCING HORMONES TO REGULATE

7890
05:03:12,840 --> 05:03:17,320
BLOOD CELL DEVELOPMENT AS WELL

7891
05:03:17,320 --> 05:03:18,040
AS (INAUDIBLE).

7892
05:03:18,040 --> 05:03:21,800
SO IF WE OVERLAY LYMPHATICS NOW,

7893
05:03:21,800 --> 05:03:24,160
WHICH WAS SHOWN IN DARK BLUE IN

7894
05:03:24,160 --> 05:03:26,400
THIS SCHEMATIC YOU CAN NOTICE

7895
05:03:26,400 --> 05:03:28,440
LOTS SPARSER IN THE BLOOD

7896
05:03:28,440 --> 05:03:30,080
VASCULATURE, THEY ARE ABSENT

7897
05:03:30,080 --> 05:03:30,960
FROM THE MEDULLA.

7898
05:03:30,960 --> 05:03:33,840
PRESENT IN THE CORTEX.

7899
05:03:33,840 --> 05:03:37,120
THEN TRACK ALONG ARTERIALS AND

7900
05:03:37,120 --> 05:03:41,560
WE THROUGH THE HYLUM.

7901
05:03:41,560 --> 05:03:43,480
THE PAST DECADES WE CAN

7902
05:03:43,480 --> 05:03:45,120
RECOGNIZE THE DIFFERENT VASCULAR

7903
05:03:45,120 --> 05:03:46,720
BEDS THROUGH HISTOLOGIC METHODS

7904
05:03:46,720 --> 05:03:48,960
BUT NOT REALLY UNTIL OMICS CAME

7905
05:03:48,960 --> 05:03:50,200
ON THE SCENE THAT WE COULD

7906
05:03:50,200 --> 05:03:52,520
REALLY START TO UNDERSTAND THE

7907
05:03:52,520 --> 05:03:54,320
MOLECULAR FINGER PRINTS OF THESE

7908
05:03:54,320 --> 05:03:56,880
DIFFERENT VASCULAR BEDS.

7909
05:03:56,880 --> 05:03:59,160
THIS IS JUST AN IMAGE FROM ONE

7910
05:03:59,160 --> 05:04:03,560
OF SHAHIM'S PAPER WHERE HE'S

7911
05:04:03,560 --> 05:04:04,880
LATED ENDOTHELIAL CELLS FROM

7912
05:04:04,880 --> 05:04:07,560
DEVELOPING ADULT KIDNEY ABLE

7913
05:04:07,560 --> 05:04:09,320
DEMONSTRATE MULTIPLE CLUSTERS

7914
05:04:09,320 --> 05:04:11,320
AND INDIVIDUAL MOLECULAR

7915
05:04:11,320 --> 05:04:12,640
FINGERPRINTS FOR DIFFERENT

7916
05:04:12,640 --> 05:04:14,840
ENDOTHELIAL SUBPOPULATIONS.

7917
05:04:14,840 --> 05:04:16,360
IMPORTANTLY, MOST OF THE DATA

7918
05:04:16,360 --> 05:04:18,120
SETS OUT THERE INCLUDING FROM

7919
05:04:18,120 --> 05:04:21,320
HUMAN DATA SETS THAT CLUMP

7920
05:04:21,320 --> 05:04:22,440
ENDOTHELIAL CELLS TOGETHER BUT

7921
05:04:22,440 --> 05:04:26,560
NOTICE IN THIS DATA SET, WE ARE

7922
05:04:26,560 --> 05:04:34,000
MISSING LYMPHATIC ENDOTHELIAL,

7923
05:04:34,000 --> 05:04:36,200
BUT BECAUSE THEY ARE SPARSE THEY

7924
05:04:36,200 --> 05:04:37,520
ARE HARD TO FIND IN SINGLE CELL

7925
05:04:37,520 --> 05:04:40,640
DATA SETS SO THIS IS A SLIDES

7926
05:04:40,640 --> 05:04:45,120
THAT WAS PROVIDED BY A NEW

7927
05:04:45,120 --> 05:04:46,160
INVESTIGATOR AT NORTHWESTERN AND

7928
05:04:46,160 --> 05:04:48,240
HE DEVELOPED A NUMBER OF NEW

7929
05:04:48,240 --> 05:04:50,920
TRANSGENIC MOUSE MODELS WHERE HE

7930
05:04:50,920 --> 05:04:53,120
IS ABLE TO BOOST DEVELOPMENT OF

7931
05:04:53,120 --> 05:04:56,880
LYMPHATICS IN THE BOTTOM HERE.

7932
05:04:56,880 --> 05:04:58,320
WITHOUT MORPHOLOGY OF KIDNEY.

7933
05:04:58,320 --> 05:05:00,000
YOU CAN DO IT IN CELL AND TIME

7934
05:05:00,000 --> 05:05:01,160
SPECIFIC WAYS.

7935
05:05:01,160 --> 05:05:03,480
BECAUSE HE'S BEEN ABLE TO BOOST

7936
05:05:03,480 --> 05:05:07,360
THIS POPULATION WITHIN KIDNEY,

7937
05:05:07,360 --> 05:05:09,120
WHEN HE PERFORMS SINGLE CELL

7938
05:05:09,120 --> 05:05:13,320
ANALYSIS HE IS ABLE THE IDENTIFY

7939
05:05:13,320 --> 05:05:15,960
DIFFERENT CLUSTERS OF BLOOD

7940
05:05:15,960 --> 05:05:17,640
ENDOTHELIAL CELLS BUT VARIOUS

7941
05:05:17,640 --> 05:05:19,600
POPULATION OF KIDNEY SPECIFIC

7942
05:05:19,600 --> 05:05:21,200
LYMPHATIC ENDOTHELIAL CELLS AND

7943
05:05:21,200 --> 05:05:25,080
HE INCREASED PROPORTION.

7944
05:05:25,080 --> 05:05:26,400
NOT ONLY GIVING HIM THE ABILITY

7945
05:05:26,400 --> 05:05:28,320
TO LOOK AT MOLECULAR

7946
05:05:28,320 --> 05:05:29,120
FINGERPRINTS IN HEALTH AND

7947
05:05:29,120 --> 05:05:30,400
DISEASE IN THE KIDNEY BUT ALSO

7948
05:05:30,400 --> 05:05:32,680
ALLOWS HIM TO USE THIS DATA SET

7949
05:05:32,680 --> 05:05:36,840
TO INTERROGATE OTHER DATA SETS

7950
05:05:36,840 --> 05:05:40,240
AND PULL OUT SMALL POPULATIONS

7951
05:05:40,240 --> 05:05:43,240
OF BLOCKS IN PUBLISHED HUMAN AND

7952
05:05:43,240 --> 05:05:44,080
OTHER CLINICAL MODELS.

7953
05:05:44,080 --> 05:05:46,000
I WANT TO TALK ABOUT DEVELOPMENT

7954
05:05:46,000 --> 05:05:48,200
OF THE LYMPHATICS IN THE KIDNEY,

7955
05:05:48,200 --> 05:05:51,640
AND WE HAVE HEARD A LOT OFFER

7956
05:05:51,640 --> 05:05:52,600
BEAUTIFUL TALKS EARLIER TODAY.

7957
05:05:52,600 --> 05:05:56,040
THIS IS AN IMAGE FROM ONE OF DR.

7958
05:05:56,040 --> 05:05:58,760
DANIEL JAFFRY AND DAVID LONGS

7959
05:05:58,760 --> 05:06:00,320
WONDERFUL PAPERS AND THEY HAVE

7960
05:06:00,320 --> 05:06:01,760
DONE MOST OF THE WORK LOOKING AT

7961
05:06:01,760 --> 05:06:04,880
THE DEVELOPMENT OF LYMPHATICS IN

7962
05:06:04,880 --> 05:06:06,520
THE KIDNEY USING IMAGING AND

7963
05:06:06,520 --> 05:06:10,040
OTHER TECHNIQUES.

7964
05:06:10,040 --> 05:06:12,360
WHAT THEY WERE ABLE TO SHOW IS

7965
05:06:12,360 --> 05:06:14,000
LYMPHATIC DEVELOPMENT STARTS

7966
05:06:14,000 --> 05:06:15,680
AFTER THE BLOOD ENDOTHELIAL

7967
05:06:15,680 --> 05:06:19,800
DEVELOPMENT, FOUR DAYS INTO META

7968
05:06:19,800 --> 05:06:21,920
OR ADULT KIDNEY DEVELOPMENT IN

7969
05:06:21,920 --> 05:06:23,120
THE MOUSE EMBRYO.

7970
05:06:23,120 --> 05:06:25,840
IT BEGINS FROM CLUSTERS OF THE

7971
05:06:25,840 --> 05:06:27,080
LYMPHATIC CELLS WITHIN THE

7972
05:06:27,080 --> 05:06:30,840
KIDNEY, AROUND THE HYLUM AND

7973
05:06:30,840 --> 05:06:34,760
EXPANDS UP OVER THE FOLLOWING

7974
05:06:34,760 --> 05:06:37,720
FOUR DAYS.

7975
05:06:37,720 --> 05:06:41,200
I WANTED TO PROVIDE DATA FROM

7976
05:06:41,200 --> 05:06:43,160
OUR OWN GROUP, WE HEARD IN TIM'S

7977
05:06:43,160 --> 05:06:45,800
TALK ABOUT ANGIOPOIETIN 2, WE

7978
05:06:45,800 --> 05:06:48,880
WORK ON VASCULAR TYROSINE KINASE

7979
05:06:48,880 --> 05:06:51,240
SIGNALING PATHWAYS AND CLEARLY

7980
05:06:51,240 --> 05:06:53,000
IMPORTANT BOTH FOR BLOOD AND

7981
05:06:53,000 --> 05:06:54,760
LYMPHATIC VASCULAR DEVELOPMENT

7982
05:06:54,760 --> 05:06:56,440
AND OVER THE YEARS WE DEVELOPED

7983
05:06:56,440 --> 05:06:57,840
A NUMBER OF DIFFERENT MOUSE

7984
05:06:57,840 --> 05:06:59,960
MODELS SO WE CAN MANIPULATE THE

7985
05:06:59,960 --> 05:07:02,520
LIGANDS AND RECEPTORS IN TIME

7986
05:07:02,520 --> 05:07:03,520
CELL SPECIFIC WAYS.

7987
05:07:03,520 --> 05:07:07,480
ONE BIG SURPRISES WE HAD WHEN

7988
05:07:07,480 --> 05:07:09,760
REMOVED MOST BOTH MAJOR

7989
05:07:09,760 --> 05:07:11,520
ANGIOPOIETIN LIGANDS, THEY

7990
05:07:11,520 --> 05:07:13,840
BREED, THEY APPEAR RELATIVELY

7991
05:07:13,840 --> 05:07:15,280
OKAY EXCEPT THEY DO HAVE

7992
05:07:15,280 --> 05:07:19,880
INTERESTING PHENOTYPES.

7993
05:07:19,880 --> 05:07:21,880
THESE ARE BULGING PHENOTYPES AS

7994
05:07:21,880 --> 05:07:23,360
WE CALL IN THE EYES OF THE MOUSE

7995
05:07:23,360 --> 05:07:25,600
AND ALSO IN THE KIDNEY.

7996
05:07:25,600 --> 05:07:28,040
I'M EMBARRASSED TO SAY THOUGH

7997
05:07:28,040 --> 05:07:32,320
I'M NEFFOLOGIST, WE FIGURED OUT

7998
05:07:32,320 --> 05:07:35,440
THE I PHENOTYPE FIRST DUE TO

7999
05:07:35,440 --> 05:07:38,440
BULGING OF THE ANTERIOR CHAMBER

8000
05:07:38,440 --> 05:07:40,840
BECAUSE MICE ARE LACKING

8001
05:07:40,840 --> 05:07:44,560
CIRCULAR VESSEL SHOWN IN GREEN

8002
05:07:44,560 --> 05:07:48,360
HERE, THIS VESSEL IS LYMPHATIC

8003
05:07:48,360 --> 05:07:49,960
LIKE, IT IS DESCRIBED AS A

8004
05:07:49,960 --> 05:07:54,440
HYBRID VESSEL THAT DERIVE THE

8005
05:07:54,440 --> 05:07:57,000
VENUS VEINS AROUND THE EYE.

8006
05:07:57,000 --> 05:07:59,400
THERE ARE SPROUTS TIP CELLS

8007
05:07:59,400 --> 05:08:01,560
AGGREGATE AND WHEN CANLYZES IT

8008
05:08:01,560 --> 05:08:03,080
STARTS TO TAKE ON LYMPHATIC FATE

8009
05:08:03,080 --> 05:08:06,560
SO IT STARTS TO EXPRESS PROX 1

8010
05:08:06,560 --> 05:08:09,080
VEGF RECEPTOR 3 BUT CONTINUES TO

8011
05:08:09,080 --> 05:08:10,400
EXPRESS BLOOD ENDOTHELIAL

8012
05:08:10,400 --> 05:08:12,640
MARKERS AND NEVER EXPRESSES LIVE

8013
05:08:12,640 --> 05:08:14,600
ONES SO DOESN'T GO ALL THE WAY,

8014
05:08:14,600 --> 05:08:17,840
A TRUE HYBRID VESSEL.

8015
05:08:17,840 --> 05:08:19,160
CLEARLY IN OUR MICE THEY ARE

8016
05:08:19,160 --> 05:08:23,000
COMPLETELY MISSING, THIS BIG

8017
05:08:23,000 --> 05:08:24,320
JUICY SCHLEMM'S CANAL AND THE

8018
05:08:24,320 --> 05:08:26,840
MICE HAVE A SEVERE GLAUCOMA FORM

8019
05:08:26,840 --> 05:08:31,040
WHICH TURNS OUT TO BE RELATIVELY

8020
05:08:31,040 --> 05:08:34,040
SIGNIFICANT CAUSE OF CONGENITAL

8021
05:08:34,040 --> 05:08:35,400
GLAUCOMA IN CHILDREN.

8022
05:08:35,400 --> 05:08:38,480
AFTER WE FIGURED OUT THE EYE

8023
05:08:38,480 --> 05:08:39,720
PHENOTYPE, WE WERE ABLE TO GO

8024
05:08:39,720 --> 05:08:42,080
BACK AND LOOK AT THESE KIDNEYS,

8025
05:08:42,080 --> 05:08:44,280
AND AS YOU CAN SEE THERE ARE

8026
05:08:44,280 --> 05:08:47,080
CYSTS IN KIDNEYS BUT NOT TUBULAR

8027
05:08:47,080 --> 05:08:48,920
CYSTS, INSTEAD THEY ARE

8028
05:08:48,920 --> 05:08:50,520
INTERSTITIAL SPACES THAT ARE

8029
05:08:50,520 --> 05:08:51,560
FILLED WITH FLUID.

8030
05:08:51,560 --> 05:08:53,120
THE REASON THEY DEVELOP THESE

8031
05:08:53,120 --> 05:08:54,720
BULGING KIDNEYS IS BECAUSE THEY

8032
05:08:54,720 --> 05:09:00,960
ARE MISSING THE ASCENDING

8033
05:09:00,960 --> 05:09:01,560
VASORECTA.

8034
05:09:01,560 --> 05:09:03,320
IN THE MEDULLA OF THE KIDNEY NO

8035
05:09:03,320 --> 05:09:05,320
CLASSIC LYMPHATICS THERE'S

8036
05:09:05,320 --> 05:09:08,080
ASCENDING VASORECTA THAT LACK

8037
05:09:08,080 --> 05:09:11,640
COVERAGE BUT ARE FIN STRAIT AND

8038
05:09:11,640 --> 05:09:13,640
HAVE FLOW, MOLECULARLY IDENTICAL

8039
05:09:13,640 --> 05:09:16,640
TO SCHLEMM'S CANAL SO THEY TAKE

8040
05:09:16,640 --> 05:09:20,440
ON MARKERS, PHLOX 1 VEGFR 3 BUT

8041
05:09:20,440 --> 05:09:24,120
NEVER EXPRESS POTOPLATIN.

8042
05:09:24,120 --> 05:09:29,600
SO SIMILAR TO SCHLEMM'S CANAL,

8043
05:09:29,600 --> 05:09:31,000
ANOTHER SWEAR MEDIATE WITH

8044
05:09:31,000 --> 05:09:31,840
ENDOTHELIAL CHARACTERISTICS.

8045
05:09:31,840 --> 05:09:33,280
IN THE FINAL FEW MINUTES I

8046
05:09:33,280 --> 05:09:35,000
WANTED TO TURN TO THE ROLE OF

8047
05:09:35,000 --> 05:09:36,240
LYMPHATICS IN KIDNEY DISEASE.

8048
05:09:36,240 --> 05:09:38,040
THERE'S BEEN A LOT OF WORK ON

8049
05:09:38,040 --> 05:09:39,920
THE ENDOTHELIUM AND KIDNEY

8050
05:09:39,920 --> 05:09:42,600
DISEASE MOSTLY WITH DROP OUT

8051
05:09:42,600 --> 05:09:44,480
BLOOD ENDOTHELIUM, LOTS OF

8052
05:09:44,480 --> 05:09:47,080
PHARMA INTERESTED IN IF BOOSTING

8053
05:09:47,080 --> 05:09:48,880
BLOOD OR VASCULAR CAPILLARY

8054
05:09:48,880 --> 05:09:51,040
DEVELOPMENT TO PROTECT KIDNEY.

8055
05:09:51,040 --> 05:09:53,040
CONVERSELY, UNLIKE THE DROP OUT

8056
05:09:53,040 --> 05:09:54,400
OF CAPILLARIES THERE IS

8057
05:09:54,400 --> 05:09:56,160
EXPANSION OF LYMPHATICS IN MANY

8058
05:09:56,160 --> 05:09:58,880
DIFFERENT KIDNEY DISEASES, AS WE

8059
05:09:58,880 --> 05:09:59,920
HAVE HEARD, IN OTHER ORGAN

8060
05:09:59,920 --> 05:10:02,000
DISEASES WHERE THERE'S

8061
05:10:02,000 --> 05:10:03,160
INCLINATION.

8062
05:10:03,160 --> 05:10:05,800
SIMILAR TO THE LIVER AS FIBROSIS

8063
05:10:05,800 --> 05:10:08,120
GETS WORSE, INFLAMMATION GETS

8064
05:10:08,120 --> 05:10:09,480
WORSE THERE ARE MORE LYMPHATICS

8065
05:10:09,480 --> 05:10:10,680
SO YOU MIGHT THINK THAT

8066
05:10:10,680 --> 05:10:13,240
EXPANSION OF LYMPHATICS IS A BAD

8067
05:10:13,240 --> 05:10:16,160
THING IN KIDNEY DISEASE.

8068
05:10:16,160 --> 05:10:18,360
HOWEVER THERE'S BEEN NUMBER OF

8069
05:10:18,360 --> 05:10:19,960
RELATIVELY RECENT PAPERS THAT

8070
05:10:19,960 --> 05:10:22,680
ARE CHALLENGING THIS.

8071
05:10:22,680 --> 05:10:25,760
THIS IS ONE PAPER FROM DAVID

8072
05:10:25,760 --> 05:10:28,040
LONG'S GROUP SHOWING POLYCYSTIC

8073
05:10:28,040 --> 05:10:30,240
KIDNEY DISEASE WHICH IS THE

8074
05:10:30,240 --> 05:10:32,920
COMMONEST CAUSE OF GENETIC

8075
05:10:32,920 --> 05:10:33,840
KIDNEY DISEASE.

8076
05:10:33,840 --> 05:10:37,280
THERE IS PRETTY ROBUST EXPANSION

8077
05:10:37,280 --> 05:10:40,760
OF LYMPHATICS AROUND THE CYST.

8078
05:10:40,760 --> 05:10:45,040
WHEN THEY DELIVER VEGF C AND

8079
05:10:45,040 --> 05:10:51,040
ABLE TO BOOST ANGIOGENESIS

8080
05:10:51,040 --> 05:10:52,640
AROUND THE CYST, THEY REDUCE THE

8081
05:10:52,640 --> 05:10:56,680
INJURY IN THIS MODELS.

8082
05:10:56,680 --> 05:10:58,800
TRANSPLANT WHERE KIDNEY IS TAKEN

8083
05:10:58,800 --> 05:11:01,200
FROM ANOTHER INDIVIDUAL, LOTS OF

8084
05:11:01,200 --> 05:11:03,520
INFLAMMATION, AGAIN, BOOSTING

8085
05:11:03,520 --> 05:11:05,720
LYMPHATICS HAS PRODUCED IMPROVED

8086
05:11:05,720 --> 05:11:06,480
OUTCOMES.

8087
05:11:06,480 --> 05:11:09,320
ACUTE KIDNEY INJURY, VERY, VERY

8088
05:11:09,320 --> 05:11:11,000
COMMON CAUSE OF HOSPITAL

8089
05:11:11,000 --> 05:11:13,160
MEDIATED KIDNEY FAILURE

8090
05:11:13,160 --> 05:11:15,680
LYMPHATICS START TO BECOME

8091
05:11:15,680 --> 05:11:17,520
APPARENT AROUND SEVEN DAYS AND

8092
05:11:17,520 --> 05:11:18,880
AGAIN PRE-CLINICAL MODELS IF YOU

8093
05:11:18,880 --> 05:11:20,800
BOOST LYMPHATICS YOU CAN PROTECT

8094
05:11:20,800 --> 05:11:23,120
THE KIDNEYS, MOST IMPORTANTLY WE

8095
05:11:23,120 --> 05:11:25,160
LIKE TO PREVENT PROGRESSION OF

8096
05:11:25,160 --> 05:11:27,600
ACUTE KIDNEY INJURY ON CHRONIC

8097
05:11:27,600 --> 05:11:29,680
KIDNEY DISEASE WE SEE LYMPHATIC

8098
05:11:29,680 --> 05:11:31,400
GROWTH AND EMERGING EVIDENCE

8099
05:11:31,400 --> 05:11:32,480
THAT IS BENEFICIAL.

8100
05:11:32,480 --> 05:11:34,920
I DON'T HAVE TIME TO GO INTO ALL

8101
05:11:34,920 --> 05:11:36,840
THE PAPERS PRESENTED.

8102
05:11:36,840 --> 05:11:40,560
SUFFICE TO SAY IN THIS CHART

8103
05:11:40,560 --> 05:11:42,240
FROM MIKE DAWN'S REVIEW THERE'S

8104
05:11:42,240 --> 05:11:43,800
BENEFICIAL STUDIES AS WELL AS

8105
05:11:43,800 --> 05:11:45,200
SOME DETRIMENTAL CONSEQUENCES SO

8106
05:11:45,200 --> 05:11:48,640
REALLY HIGHLIGHTING THAT WE NEED

8107
05:11:48,640 --> 05:11:49,560
MORE INVESTIGATION BEFORE WE CAN

8108
05:11:49,560 --> 05:11:50,320
HARNESS.

8109
05:11:50,320 --> 05:11:51,880
AND LIKE THE OTHER ORGANS YOU

8110
05:11:51,880 --> 05:11:53,640
HAVE HEARD, WE KNOW LYMPHATICS

8111
05:11:53,640 --> 05:11:56,520
ARE NOT SIMPLY PASSIVE CONDUITS

8112
05:11:56,520 --> 05:11:59,000
OF EXCESS FLUID OR DAMAGE CELLS,

8113
05:11:59,000 --> 05:12:01,320
BUT ALSO CELLULAR CROSS TALK AND

8114
05:12:01,320 --> 05:12:03,080
WE BELIEVE PRODUCING SECRETED

8115
05:12:03,080 --> 05:12:05,280
FACTORS THAT LIKELY ARE GOING TO

8116
05:12:05,280 --> 05:12:07,680
BE PROTECTIVE.

8117
05:12:07,680 --> 05:12:09,240
IN THE FINAL 30 SECONDS I WANTED

8118
05:12:09,240 --> 05:12:11,000
TO LEAVE YOU WITH A PROVOCATIVE

8119
05:12:11,000 --> 05:12:13,440
THOUGHT.

8120
05:12:13,440 --> 05:12:14,560
WE HEARD FROM (INAUDIBLE) AND

8121
05:12:14,560 --> 05:12:19,800
RACHEL EARLIER TODAY, THIS

8122
05:12:19,800 --> 05:12:21,200
EMERGING MODEL LYMPHATIC

8123
05:12:21,200 --> 05:12:22,600
ENDOTHELIAL CELLS PRODUCE

8124
05:12:22,600 --> 05:12:27,080
SUBSTANCES THAT PROTECT PROMOTE

8125
05:12:27,080 --> 05:12:31,920
DEVELOPMENT GROWTH OF ORGANS AND

8126
05:12:31,920 --> 05:12:33,640
E PAIR AND (INAUDIBLE) PAPER.

8127
05:12:33,640 --> 05:12:35,960
SHE DEVELOPED IN THIS RISK

8128
05:12:35,960 --> 05:12:38,440
FACTOR FROM LYMPHATICS, THEY HAD

8129
05:12:38,440 --> 05:12:42,320
SMALLER HEARTS THAN EMBRYO SIZE.

8130
05:12:42,320 --> 05:12:45,160
UNPUBLISHED WORK FROM DR.

8131
05:12:45,160 --> 05:12:46,280
MCDONNA WHEN HE REMOVES

8132
05:12:46,280 --> 05:12:47,160
LYMPHATICS FROM DEVELOPING

8133
05:12:47,160 --> 05:12:49,920
KIDNEYINGS THE KIDNEYS ARE

8134
05:12:49,920 --> 05:12:52,080
SMALLER COMPARED TO TOTAL BODY.

8135
05:12:52,080 --> 05:12:54,440
SO IN CLOSING I HOPE THAT I HAVE

8136
05:12:54,440 --> 05:12:56,800
CONVINCED YOU THERE'S A HUGE LET

8137
05:12:56,800 --> 05:12:58,400
REGENEITY OF ENDOTHELIAL CELLS.

8138
05:12:58,400 --> 05:13:00,720
A LOT OF EVIDENCE THAT EMERGING

8139
05:13:00,720 --> 05:13:02,480
EVIDENCE THAT PROMOTING WITH

8140
05:13:02,480 --> 05:13:03,240
ANGIOGENERAL AT THIS MIGHT BE

8141
05:13:03,240 --> 05:13:05,640
BENEFICIAL BUT WE REALLY NEED TO

8142
05:13:05,640 --> 05:13:07,360
UNDERSTAND BENEFITS VERSUS

8143
05:13:07,360 --> 05:13:10,280
ADVERSE EFFECTS IF WE ARE GOING

8144
05:13:10,280 --> 05:13:12,080
TO HARNESS THIS FOR PATIENTS.

8145
05:13:12,080 --> 05:13:16,200
MY FINAL SLIDE FROM DR. MIKE

8146
05:13:16,200 --> 05:13:18,200
DONAN WHO SHARED HIS SLIDES AND

8147
05:13:18,200 --> 05:13:20,480
PRELIMINARY DATA, OTHER AMAZING

8148
05:13:20,480 --> 05:13:21,080
INDIVIDUALS IN GROUP WHO HAVE

8149
05:13:21,080 --> 05:13:22,920
DONE A LOT OF WORK IN LYMPHATICS

8150
05:13:22,920 --> 05:13:23,680
OVER THE YEARS.

8151
05:13:23,680 --> 05:13:25,440
WITH THAT I WILL CLOSE AND THANK

8152
05:13:25,440 --> 05:13:26,520
THE FUNDING SOURCES.

8153
05:13:26,520 --> 05:13:34,040
THANKS VERY MUCH.

8154
05:13:34,040 --> 05:13:38,000
>> THANK YOU, DR. QUAGGIN,

8155
05:13:38,000 --> 05:13:38,600
FANTASTIC.

8156
05:13:38,600 --> 05:13:41,560
WE ARE NOW GOING TO MOVE ON TO

8157
05:13:41,560 --> 05:13:42,080
ANSWER QUESTIONS.

8158
05:13:42,080 --> 05:13:44,200
I JUST LIKE TO REMIND ANYBODY

8159
05:13:44,200 --> 05:13:47,600
THAT IS USING THE NIH VIDEOCAST

8160
05:13:47,600 --> 05:13:49,720
THAT THEY CAN SEND QUESTIONS

8161
05:13:49,720 --> 05:13:52,800
USING THE LIVE FEEDBACK

8162
05:13:52,800 --> 05:13:53,200
FUNCTION.

8163
05:13:53,200 --> 05:13:56,560
PLEASE SEND ADDITIONAL QUESTIONS

8164
05:13:56,560 --> 05:13:57,800
THAT WAY.

8165
05:13:57,800 --> 05:13:59,960
BUT WE WILL GO AHEAD AND GET

8166
05:13:59,960 --> 05:14:00,960
START WITH QUESTIONS WE RECEIVE

8167
05:14:00,960 --> 05:14:01,800
MISDEMEANOR THE Q&A AND THE

8168
05:14:01,800 --> 05:14:07,920
RECEIVEDIN THE Q&A IN THE
CHAT.

8169
05:14:07,920 --> 05:14:09,240
I WILL START WITH THE ONES I

8170
05:14:09,240 --> 05:14:10,960
RECEIVED.

8171
05:14:10,960 --> 05:14:16,520
SO HAD A GREAT QUESTION FROM

8172
05:14:16,520 --> 05:14:21,480
YONG ASKING WHAT IS THE SENTINEL

8173
05:14:21,480 --> 05:14:24,760
ORIGIN OF KLA, BLOOD OR

8174
05:14:24,760 --> 05:14:26,520
LYMPHATIC ENDOTHELIAL CELLS

8175
05:14:26,520 --> 05:14:28,160
CONTRIBUTING TO THE DISEASE?

8176
05:14:28,160 --> 05:14:29,400
ANSWER IS WE DON'T KNOW.

8177
05:14:29,400 --> 05:14:31,520
IT IS DIFFICULT TO GET TISSUE

8178
05:14:31,520 --> 05:14:35,000
FROM PATIENTS TAKING TISSUE IS

8179
05:14:35,000 --> 05:14:35,400
RISKY.

8180
05:14:35,400 --> 05:14:37,600
SO WE -- I THINK WE NEED MORE

8181
05:14:37,600 --> 05:14:41,040
MODELS TO BEGIN TO ADDRESS THAT

8182
05:14:41,040 --> 05:14:43,080
QUESTION.

8183
05:14:43,080 --> 05:14:44,640
MY LAB IS WORKING ON THAT NOW,

8184
05:14:44,640 --> 05:14:47,400
WE DON'T KNOW IT COULD BE BLOOD

8185
05:14:47,400 --> 05:14:49,840
ENDOTHELIAL CELLS

8186
05:14:49,840 --> 05:14:52,880
DIFFERENTIATING TO LYMPHATIC

8187
05:14:52,880 --> 05:14:54,720
ENDOTHELIAL CELLS OR COULD BE

8188
05:14:54,720 --> 05:14:58,520
LYMPHATIC ENDOTHELIAL CELLS NRS

8189
05:14:58,520 --> 05:15:00,320
THAT CONTRIBUTE TO DISEASE.

8190
05:15:00,320 --> 05:15:01,040
GREAT QUESTION.

8191
05:15:01,040 --> 05:15:06,760
SECOND I HAD WAS FROM

8192
05:15:06,760 --> 05:15:08,320
(INDISCERNIBLE), HE ASKED

8193
05:15:08,320 --> 05:15:09,400
WHETHER WHAT KIND OF DRUGS COULD

8194
05:15:09,400 --> 05:15:13,000
BE USED FOR KLA PATIENTS WITH

8195
05:15:13,000 --> 05:15:17,000
THE NRAS 61QR MUTATION BASED ON

8196
05:15:17,000 --> 05:15:17,840
OUR WORK.

8197
05:15:17,840 --> 05:15:19,400
SO AGAIN GREAT QUESTION.

8198
05:15:19,400 --> 05:15:23,720
I KNOW THAT SOME PATIENTS ARE

8199
05:15:23,720 --> 05:15:27,040
BEING TREATED WITH TRANATNIB

8200
05:15:27,040 --> 05:15:29,120
FROM OUR STUDIES IS A MEK

8201
05:15:29,120 --> 05:15:30,480
INHIBITOR, I KNOW SIDE EFFECTS

8202
05:15:30,480 --> 05:15:37,240
CAN BE AN ISSUE.

8203
05:15:37,240 --> 05:15:38,760
SEROLAMU SARKS IS USED FOR A

8204
05:15:38,760 --> 05:15:41,400
NUMBER OF YEARS IN PATIENT AND

8205
05:15:41,400 --> 05:15:42,880
SHOWN SIGNIFICANT IMPROVEMENTS.

8206
05:15:42,880 --> 05:15:46,240
DR. ADAMS PUBLICATION IN JOURNAL

8207
05:15:46,240 --> 05:15:47,520
PEDIATRICS SHOWED THAT.

8208
05:15:47,520 --> 05:15:49,080
SO IT IS CERTAINLY EVOLVING

8209
05:15:49,080 --> 05:15:52,680
FIELD IN TERMS OF DRUG

8210
05:15:52,680 --> 05:15:53,720
TREATMENTS FOR PATIENTS. 

8211
05:15:53,720 --> 05:15:55,720
UNDERSTANDING MUTATIONS, SHOULD

8212
05:15:55,720 --> 05:15:59,080
BE VERY HELPFUL IN FUTURE AND

8213
05:15:59,080 --> 05:16:00,880
USING PRE-CLINICAL MODELS THAT

8214
05:16:00,880 --> 05:16:04,560
LIKE THE ONES WE HAVE BEEN

8215
05:16:04,560 --> 05:16:13,360
DEVELOPING.

8216
05:16:13,360 --> 05:16:16,000
MOVE TO QUESTIONS FOR DR.

8217
05:16:16,000 --> 05:16:16,680
DELLINGER NEXT.

8218
05:16:16,680 --> 05:16:20,560
I SEE A QUESTION FROM DR.

8219
05:16:20,560 --> 05:16:23,600
QUAGGIN THAT SHE ASKED ME.

8220
05:16:23,600 --> 05:16:28,680
>> I CAN ASK YOU, I'M
REALLY

8221
05:16:28,680 --> 05:16:30,120
INTERESTED IN SIGNALING SO

8222
05:16:30,120 --> 05:16:34,000
REALLY INTERESTED IN THE ANG 2

8223
05:16:34,000 --> 05:16:36,200
WORK AND WONDER IF YOU LOOKED AT

8224
05:16:36,200 --> 05:16:38,400
PHLOX L 1 EXPRESSION IN THE

8225
05:16:38,400 --> 05:16:40,000
ACTUAL LESIONS.

8226
05:16:40,000 --> 05:16:42,840
THE REASON BEING PHLOX L 1 IS A

8227
05:16:42,840 --> 05:16:44,760
POTENT TRANSCRIPTIONAL REGULATOR

8228
05:16:44,760 --> 05:16:46,560
AND CLEARLY INVOLVED IN SOME

8229
05:16:46,560 --> 05:16:50,840
VASCULAR MALFORMATIONS AS WELL.

8230
05:16:50,840 --> 05:16:52,360
>> THAT IS A GREAT
QUESTION,

8231
05:16:52,360 --> 05:16:52,920
SUE.

8232
05:16:52,920 --> 05:16:56,240
SO THE SHORT ANSWER IS WE HAVE

8233
05:16:56,240 --> 05:16:56,640
NOT.

8234
05:16:56,640 --> 05:16:59,720
BUT IT IS ON OUR LIST OF THINGS

8235
05:16:59,720 --> 05:17:00,520
TO DO.

8236
05:17:00,520 --> 05:17:02,840
THANKS TO NHLBI FUNDING WE ARE

8237
05:17:02,840 --> 05:17:05,520
ABLE TO DO THAT NOW.

8238
05:17:05,520 --> 05:17:06,240
GREAT QUESTION.

8239
05:17:06,240 --> 05:17:08,440
IT IS KNOWN TRANSCRIPTIONAL

8240
05:17:08,440 --> 05:17:11,720
REGULATOR OF ANGIOPOIETIN 2.

8241
05:17:11,720 --> 05:17:15,480
IN TERMS OF ROLE OF ANGIOPOIETIN

8242
05:17:15,480 --> 05:17:17,040
2, THAT IS AGAIN ANOTHER

8243
05:17:17,040 --> 05:17:20,280
QUESTION WE ARE ANSWERING.

8244
05:17:20,280 --> 05:17:23,840
GETTING NEUTRALIZING ANTIBODIES,

8245
05:17:23,840 --> 05:17:26,320
TO BLOCK ANG 2 IN OUR MODELS.

8246
05:17:26,320 --> 05:17:30,280
THAT IS AN EXCITING IF IT COULD

8247
05:17:30,280 --> 05:17:31,760
BE CONTRIBUTING TO THE DISEASE

8248
05:17:31,760 --> 05:17:34,400
PROCESS, THE PATHOPHYSIOLOGY

8249
05:17:34,400 --> 05:17:38,680
SINCE NEUTRALIZING ANTI-BOYS

8250
05:17:38,680 --> 05:17:40,920
HAVE BEEN DEVELOPED IN NUMBER OF

8251
05:17:40,920 --> 05:17:42,200
TUMORS AND SOME CLINICAL TRIALS

8252
05:17:42,200 --> 05:17:44,520
DONE WITH NEUTRALIZING ANN

8253
05:17:44,520 --> 05:17:45,160
ANGIOANTIBODIES.

8254
05:17:45,160 --> 05:17:46,560
SO SHORT ANSWER, WE DON'T KNOW

8255
05:17:46,560 --> 05:17:48,360
YET, WE HOPE WE CAN FIGURE IF

8256
05:17:48,360 --> 05:17:49,960
THIS COULD BE A POTENTIAL

8257
05:17:49,960 --> 05:17:50,360
TREATMENT.

8258
05:17:50,360 --> 05:17:52,600
GREAT QUESTION.

8259
05:17:52,600 --> 05:17:54,720
>> WHILE YOU ARE LOOKING
FOR

8260
05:17:54,720 --> 05:17:58,720
QUESTIONS I CAN ASK MICHAEL.

8261
05:17:58,720 --> 05:18:00,360
CLEARLY LIGAND IS A DOMINANT

8262
05:18:00,360 --> 05:18:03,560
FACTOR FOR OSTEOCLAST AND THE

8263
05:18:03,560 --> 05:18:07,000
SUCCESS OF LIGAND THERAPY IN

8264
05:18:07,000 --> 05:18:08,680
OSTEOPOROSIS TUMOR OSTEOLYSIS

8265
05:18:08,680 --> 05:18:11,880
AND OTHER OSTEOLYTIC DISEASES.

8266
05:18:11,880 --> 05:18:13,120
HAS BEEN EXTRAORDINARY.

8267
05:18:13,120 --> 05:18:16,040
HAVE PATIENTS BEEN TREATED WITH

8268
05:18:16,040 --> 05:18:16,600
DENASMIB?

8269
05:18:16,600 --> 05:18:19,200
>> I AM AWARE OF ONE CASE
REPORT

8270
05:18:19,200 --> 05:18:22,520
WHERE PATIENT HAS BEEN TREATED

8271
05:18:22,520 --> 05:18:24,640
WITH THAT AND THE OSTEOLYTIC

8272
05:18:24,640 --> 05:18:26,720
PROCESS WAS REPORTED TO NOT

8273
05:18:26,720 --> 05:18:29,320
PROGRESS WHILE PATIENT WAS ON

8274
05:18:29,320 --> 05:18:29,760
THE DRUG.

8275
05:18:29,760 --> 05:18:32,280
THANK YOU FOR YOUR QUESTION.

8276
05:18:32,280 --> 05:18:35,960
>> MIKE, I SEE TALK IN THE
CHAT

8277
05:18:35,960 --> 05:18:38,480
FROM DR. (INDISCERNIBLE) HE

8278
05:18:38,480 --> 05:18:40,600
ASKED IF YOU WAITED UNTIL MUTANT

8279
05:18:40,600 --> 05:18:42,400
MICE BECOME ADULTS BEFORE

8280
05:18:42,400 --> 05:18:44,560
TAMOXIFEN AND INDUCE THE MUTANT

8281
05:18:44,560 --> 05:18:46,400
KRAS.

8282
05:18:46,400 --> 05:18:47,080
>> WE HAVE.

8283
05:18:47,080 --> 05:18:48,760
WE ARE REALLY EXCITED BY THIS

8284
05:18:48,760 --> 05:18:49,120
RESULT.

8285
05:18:49,120 --> 05:18:51,560
THE LATEST WE HAVE LOOKED IS SIX

8286
05:18:51,560 --> 05:18:54,400
WEEKS AFTER GIVING MICE

8287
05:18:54,400 --> 05:18:56,520
TAMOXIFEN ADULT MICE TAMOXIFEN

8288
05:18:56,520 --> 05:18:58,320
AND LYMPHATICS LOOK COMPLETELY

8289
05:18:58,320 --> 05:18:59,000
NORMAL.

8290
05:18:59,000 --> 05:19:00,800
THERE APPEARS TO BE WINDOW OF

8291
05:19:00,800 --> 05:19:04,040
SENSITIVITY TO THE RAS MUTATION.

8292
05:19:04,040 --> 05:19:07,640
AND HYPOTHESIS IS IN ORDER

8293
05:19:07,640 --> 05:19:09,160
MUTATION TAB HAVE GREATEST

8294
05:19:09,160 --> 05:19:11,240
EFFECT NEEDS TO BE ACTIVELY

8295
05:19:11,240 --> 05:19:16,000
GROWING LYMPHATIC NETWORK.

8296
05:19:16,000 --> 05:19:26,520
THAT IS A HYPOTHESIS WE TEST NOW

8297
05:19:30,840 --> 05:19:35,600
LITTLE EFFECT IN ADULT MICE.

8298
05:19:35,600 --> 05:19:38,360
>> MIKE, I SEE ANOTHER
QUESTION

8299
05:19:38,360 --> 05:19:39,760
FROM NADA.

8300
05:19:39,760 --> 05:19:42,360
QUESTION DO YOU SEE CHANGES IN B

8301
05:19:42,360 --> 05:19:45,600
CAD HEREIN AT THE LEC FUNCTION

8302
05:19:45,600 --> 05:19:46,880
OR PI 3K PATHWAY?

8303
05:19:46,880 --> 05:19:50,480
>> WE HAVEN'T STAINED FOR
E CAD

8304
05:19:50,480 --> 05:19:51,520
HEREIN IN ANIMAL MODEL.

8305
05:19:51,520 --> 05:19:56,520
HOWEVER, IN TISSUE CULTURE, E

8306
05:19:56,520 --> 05:19:57,800
CAD HEREIN DOESN'T APPEAR TO BE

8307
05:19:57,800 --> 05:19:58,960
LOCALIZED TO THE CELL CELL

8308
05:19:58,960 --> 05:20:00,040
JUNCTIONS AND IT IS SOMETHING WE

8309
05:20:00,040 --> 05:20:02,160
ARE CURRENTLY EXPLORING IN

8310
05:20:02,160 --> 05:20:03,040
COLLABORATION WITH JOSH LOOKING

8311
05:20:03,040 --> 05:20:06,280
AT THE EFFECT OF RAS MUTATION ON

8312
05:20:06,280 --> 05:20:08,360
E CAD HEREIN AND HOW THAT COULD

8313
05:20:08,360 --> 05:20:10,560
IMPACT DEVELOPMENT AND

8314
05:20:10,560 --> 05:20:11,280
MAINTENANCE.

8315
05:20:11,280 --> 05:20:13,760
>> DO YOU SEE CHANGES IN
THE PI

8316
05:20:13,760 --> 05:20:15,760
3K PATHWAY?

8317
05:20:15,760 --> 05:20:16,040
BECAUSE --

8318
05:20:16,040 --> 05:20:19,600
>> WE ALSO -- WE DO SEE IN

8319
05:20:19,600 --> 05:20:21,480
TISSUE CULTURE WE HAVE DONE

8320
05:20:21,480 --> 05:20:24,040
WESTERN BLOT FOR PI 3 KINASE

8321
05:20:24,040 --> 05:20:25,280
PATHWAY AND INCREASED ACTIVATION

8322
05:20:25,280 --> 05:20:27,280
OF THAT PATHWAY IN OUR KRAS

8323
05:20:27,280 --> 05:20:29,680
MUTANT CELLS.

8324
05:20:29,680 --> 05:20:32,080
ONE THING WE ARE DOING IS

8325
05:20:32,080 --> 05:20:33,920
TREATING CELLS WITH EITHER PI 3

8326
05:20:33,920 --> 05:20:36,040
KINASE INHIBITORS OR MAP KINASE

8327
05:20:36,040 --> 05:20:39,360
INHIBITORS TO WEED OUT WHICH

8328
05:20:39,360 --> 05:20:41,160
PATHWAYS IS CONTROLLING THE

8329
05:20:41,160 --> 05:20:47,200
DIFFERENT PHENOTYPES WE OBSERVE.

8330
05:20:47,200 --> 05:20:49,520
>> I SEE YOU HAD A
QUESTION FOR

8331
05:20:49,520 --> 05:20:50,040
DR. SCHWARZ.

8332
05:20:50,040 --> 05:20:52,280
WOULD YOU LIKE TO INMUTE

8333
05:20:52,280 --> 05:20:53,920
YOURSELF AND ASK IT?

8334
05:20:53,920 --> 05:20:57,600
>> THANK YOU SO MUCH.

8335
05:20:57,600 --> 05:21:00,440
FANTASTIC TALK DR. SCHWARZ.

8336
05:21:00,440 --> 05:21:03,280
I WONDER IF YOU CAN SEE

8337
05:21:03,280 --> 05:21:05,920
CORRELATION IN TIME WHICH COMES

8338
05:21:05,920 --> 05:21:11,360
FOR EFFECT ON TNF ON THE B

8339
05:21:11,360 --> 05:21:12,120
CELLS.

8340
05:21:12,120 --> 05:21:13,760
CHICKEN OR EGG KIND OF SITUATION

8341
05:21:13,760 --> 05:21:16,280
AN WHETHER YOU CAN FIND ANY

8342
05:21:16,280 --> 05:21:19,040
DIFFERENT -- CELLS THAT YOU CAN

8343
05:21:19,040 --> 05:21:24,560
SEE SYNOVIAM OR AWAY FROM THE

8344
05:21:24,560 --> 05:21:25,720
POPLITEAL LYMPH NODE?

8345
05:21:25,720 --> 05:21:27,920
>> SIMPLE ANSWER, THERE
ARE

8346
05:21:27,920 --> 05:21:30,120
ECTOPIC B CELL FOLLICLES IN THE

8347
05:21:30,120 --> 05:21:31,480
TNF MICE AND IN PATIENTS WITH

8348
05:21:31,480 --> 05:21:33,280
RHEUMATOID ARTHRITIS.

8349
05:21:33,280 --> 05:21:35,720
SO THAT IS CERTAINLY EXISTS.

8350
05:21:35,720 --> 05:21:42,760
IN TERMS OF WHICH COMES FIRST

8351
05:21:42,760 --> 05:21:44,320
THERE'S HARD THE FINDS EFFECTS

8352
05:21:44,320 --> 05:21:49,560
IN OUR MODEL AND AN DRYIA HAS

8353
05:21:49,560 --> 05:21:52,600
ADOPTED TNF 1 AND 2 KNOCK OUT B

8354
05:21:52,600 --> 05:21:55,960
CELLS INTO TNF MICE IN THE

8355
05:21:55,960 --> 05:21:57,840
DISEASE AND THE DISEASE IS

8356
05:21:57,840 --> 05:21:58,440
UNCHANGED.

8357
05:21:58,440 --> 05:22:00,720
MOST RECENTLY I WAS ELUDED TO

8358
05:22:00,720 --> 05:22:03,880
SOME UNPUBLISHED PATIENT

8359
05:22:03,880 --> 05:22:04,720
TRANSCRIPTOMIC DATA.

8360
05:22:04,720 --> 05:22:06,800
REPEAT AGAIN WE CANNOT FIND

8361
05:22:06,800 --> 05:22:09,000
ANYTHING AT THE BULK LEVEL.

8362
05:22:09,000 --> 05:22:12,240
AT THE SPATIAL I CAN ONLY TELL

8363
05:22:12,240 --> 05:22:15,560
YOU THE MARK POSITIVE SPOTS

8364
05:22:15,560 --> 05:22:18,040
WHICH HAVE THESE ENDOTHELIAL

8365
05:22:18,040 --> 05:22:20,480
CELLS, ARE SHOWING SOME VERY

8366
05:22:20,480 --> 05:22:22,200
INTERESTING SIGNS.

8367
05:22:22,200 --> 05:22:25,040
I WOULD SAY THE STROMA OF TNF

8368
05:22:25,040 --> 05:22:28,240
EFFECTS ON STROMA HAPPEN FIRST,

8369
05:22:28,240 --> 05:22:30,240
THESE CELLS ARE LARGELY

8370
05:22:30,240 --> 05:22:32,200
UNCHANGED, I'M TOLD THEY

8371
05:22:32,200 --> 05:22:35,280
TRANSLOCATE FROM THE FOLLICLES

8372
05:22:35,280 --> 05:22:37,600
IN TO THE POSITIVE SINUSES

8373
05:22:37,600 --> 05:22:39,360
SPACES WHERE THEY INTERACT WITH

8374
05:22:39,360 --> 05:22:41,160
T-CELLS AND THEN THAT IS THE

8375
05:22:41,160 --> 05:22:43,720
FIRST TIME WE SEE CLASS

8376
05:22:43,720 --> 05:22:48,520
SWITCHING IN B CELL ACTIVATION.

8377
05:22:48,520 --> 05:22:52,840
GREAT I SEE ANOTHER QUESTION,

8378
05:22:52,840 --> 05:22:56,040
DR. SCHWARZ FROM DR. MARARRA.

8379
05:22:56,040 --> 05:22:57,760
WOULD YOU LIKE TO INMUTE AND ASK

8380
05:22:57,760 --> 05:22:58,200
YOUR QUESTION?

8381
05:22:58,200 --> 05:22:59,360
>> THANK YOU SO MUCH.

8382
05:22:59,360 --> 05:23:02,120
I WAS WONDERING IF YOU LOOKED AT

8383
05:23:02,120 --> 05:23:04,800
KRAS EXPRESSION IN THE

8384
05:23:04,800 --> 05:23:07,960
ENDOTHELIAL CELLS POPLITEAL

8385
05:23:07,960 --> 05:23:09,160
LYMPHODISSECTION.

8386
05:23:09,160 --> 05:23:11,360
MOSTLY CONCERNED WHAT HAPPENS

8387
05:23:11,360 --> 05:23:12,680
WITH LYMPHEDEMA BECAUSE WE HAVE

8388
05:23:12,680 --> 05:23:14,800
A LOT OF SAME PHENOTYPES IN THAT

8389
05:23:14,800 --> 05:23:16,880
SETTING.

8390
05:23:16,880 --> 05:23:19,920
>> WE HAVEN'T LOOKED AT
KRAS

8391
05:23:19,920 --> 05:23:23,160
ACTIVATION IN LYMPHATIC VESSELS

8392
05:23:23,160 --> 05:23:25,120
POST INJURY.

8393
05:23:25,120 --> 05:23:26,360
OR LYMPHEDEMA MODELS.

8394
05:23:26,360 --> 05:23:28,280
HOWEVER I WILL SAY COMPLEX

8395
05:23:28,280 --> 05:23:29,880
LYMPHATIC ANOMALY OF PATIENTS

8396
05:23:29,880 --> 05:23:30,840
HAVE LYMPHEDEMA.

8397
05:23:30,840 --> 05:23:33,760
THOUGH THE PATIENTS THAT -- THE

8398
05:23:33,760 --> 05:23:36,360
PATIENT THAT I DESCRIBED TODAY

8399
05:23:36,360 --> 05:23:38,480
DID NOT HAVE LYMPHEDEMA I

8400
05:23:38,480 --> 05:23:40,760
IMAGINE AS WE CONTINUE TO

8401
05:23:40,760 --> 05:23:42,240
SEQUENCE COMPLEX LYMPHATIC

8402
05:23:42,240 --> 05:23:44,920
ANOMALY SOME WHICH DO HAVE

8403
05:23:44,920 --> 05:23:46,480
LYMPHEDEMA MA WILL HAVE RAS

8404
05:23:46,480 --> 05:23:49,920
PATHWAY ACTIVATING PATIENTS.

8405
05:23:49,920 --> 05:23:51,040
>> THANKS.

8406
05:23:51,040 --> 05:23:53,920
>> SO NOW I SEE SOME
QUESTIONS

8407
05:23:53,920 --> 05:23:56,760
FOR DR. QUAGGIN.

8408
05:23:56,760 --> 05:23:59,320
I SEE A QUESTION HOW YOU

8409
05:23:59,320 --> 05:24:00,400
DISTINGUISH BETWEEN LIVE BORN

8410
05:24:00,400 --> 05:24:03,640
POSITIVE LECs AND LIVE BORN

8411
05:24:03,640 --> 05:24:05,920
POSITIVE MACROPHAGES?

8412
05:24:05,920 --> 05:24:07,440
ARE THEY ABUNDANT POPULATION

8413
05:24:07,440 --> 05:24:09,280
CERTAIN TISSUES THESE ARE

8414
05:24:09,280 --> 05:24:10,880
MARKERS IN MULTIPLEX IMAGING

8415
05:24:10,880 --> 05:24:13,040
ASSAYS AND MORPHOLOGY.

8416
05:24:13,040 --> 05:24:15,720
>> GREAT QUESTION.

8417
05:24:15,720 --> 05:24:19,680
MULTIPLE MARKERS AND THAT IN

8418
05:24:19,680 --> 05:24:22,080
PART THAT IS WHY SO GREAT TO

8419
05:24:22,080 --> 05:24:24,720
HAVE THESE DATA SETS WHERE WE

8420
05:24:24,720 --> 05:24:31,640
CAN TAKE IT BACK TO TISSUE.

8421
05:24:31,640 --> 05:24:44,400
AND DISTINGUISH.

8422
05:24:44,400 --> 05:24:47,160
>> MAYBE I HAVE ONE
QUESTION FOR

8423
05:24:47,160 --> 05:24:49,520
ALL THE PANELISTS.

8424
05:24:49,520 --> 05:24:51,760
AND MAYBE ANYBODY WHO STILL ON

8425
05:24:51,760 --> 05:24:52,600
FROM THIS MORNING.

8426
05:24:52,600 --> 05:24:55,000
I AM INTERESTED TO KNOW WHAT

8427
05:24:55,000 --> 05:24:58,200
PEOPLE'S THOUGHTS ARE ABOUT

8428
05:24:58,200 --> 05:25:00,920
ORGAN SPECIFIC LYMPHATICS AND

8429
05:25:00,920 --> 05:25:02,600
MICHAEL, I AM LOOKING AT YOU

8430
05:25:02,600 --> 05:25:04,200
ALSO ABOUT IN THE BONE WHEN YOU

8431
05:25:04,200 --> 05:25:08,200
ARE GROWING THESE, HOW DIFFERENT

8432
05:25:08,200 --> 05:25:11,040
ARE THOSE LACKS IN THAT SETTING

8433
05:25:11,040 --> 05:25:12,280
THAN -- AND IS THERE AN ISSUE

8434
05:25:12,280 --> 05:25:13,720
WHEN WE START TO THINK ABOUT

8435
05:25:13,720 --> 05:25:16,360
THESE EXPERIMENTAL MODELS WHERE

8436
05:25:16,360 --> 05:25:18,640
WE ARE BOOSTING LYMPHATIC

8437
05:25:18,640 --> 05:25:23,560
GROWTH, ARE THEY THE SAME AS

8438
05:25:23,560 --> 05:25:26,840
NATIVE LYMPHATIC OR ARE WE

8439
05:25:26,840 --> 05:25:28,640
ADDING A LEVEL OF ARTIFACT?

8440
05:25:28,640 --> 05:25:31,640
ANYONE CAN ANSWER.

8441
05:25:31,640 --> 05:25:34,240
I SEE MY ZOOM SCREEN.

8442
05:25:34,240 --> 05:25:36,000
>> SURE, I CAN START OFF.

8443
05:25:36,000 --> 05:25:37,320
THAT IS ONE THING WE ARE

8444
05:25:37,320 --> 05:25:39,440
INTERESTED IN, THE DIFFERENCES

8445
05:25:39,440 --> 05:25:40,840
BETWEEN LYMPHATIC VESSELS IN

8446
05:25:40,840 --> 05:25:44,320
BONE VERSUS OTHER TISSUES.

8447
05:25:44,320 --> 05:25:45,360
WE ACTUALLY SEE AMAZING

8448
05:25:45,360 --> 05:25:47,480
DIFFERENCES IN OUR VEGF C

8449
05:25:47,480 --> 05:25:50,040
TRANSGENIC MODEL, WHEREAS IF WE

8450
05:25:50,040 --> 05:25:52,920
INDUCE VEGF C EXPRESSION IN BONE

8451
05:25:52,920 --> 05:25:55,840
IT SIMULATES THE GROWTH OF

8452
05:25:55,840 --> 05:25:57,640
LYMPHATICS OUTSIDE OF BONE BUT

8453
05:25:57,640 --> 05:25:58,960
ALSO STIMULATES FOR MISSION OF

8454
05:25:58,960 --> 05:26:00,160
LYMPHATICS IN BONE.

8455
05:26:00,160 --> 05:26:02,480
THEN WE WITHDRAW VEGF C THE

8456
05:26:02,480 --> 05:26:04,280
LYMPHATICS IN BONE DISAPPEAR BUT

8457
05:26:04,280 --> 05:26:07,240
THE LYMPHATIC NEXT TO BONE STAY

8458
05:26:07,240 --> 05:26:08,600
ABNORMAL AND PERSIST SO THAT

8459
05:26:08,600 --> 05:26:10,000
SUGGESTS THERE ARE TISSUE

8460
05:26:10,000 --> 05:26:11,840
SPECIFIC DIFFERENCES AND IT CAN

8461
05:26:11,840 --> 05:26:13,720
BE DUE TO THE MICROENVIRONMENT

8462
05:26:13,720 --> 05:26:17,320
AND THAT CAN BE A COMBINATION OF

8463
05:26:17,320 --> 05:26:20,400
INHIBITORY FACTORS PRESENT IN

8464
05:26:20,400 --> 05:26:22,600
TISSUE, OR FACTORS THAT

8465
05:26:22,600 --> 05:26:24,160
STABILIZE THE LYMPHATIC NETWORK.

8466
05:26:24,160 --> 05:26:26,360
IN THE SETTING OF DISEASES WE

8467
05:26:26,360 --> 05:26:28,280
WORK ON, WE THINK THAT THIS

8468
05:26:28,280 --> 05:26:32,280
SOMATIC GENETIC MUTATION IS THAT

8469
05:26:32,280 --> 05:26:34,560
GAS PEDAL THAT CAN OVERCOME ANY

8470
05:26:34,560 --> 05:26:38,920
INHIBITOR FACTORS, AND PROMOTE

8471
05:26:38,920 --> 05:26:42,120
OR MAINTAIN LYMPHATIC VESSEL IN

8472
05:26:42,120 --> 05:26:43,840
ENVIRONMENT WHICH TYPICALLY

8473
05:26:43,840 --> 05:26:48,000
CANNOT BE IN.

8474
05:26:48,000 --> 05:26:51,280
>> DR. SCHWARZ DO YOU WANT
TO

8475
05:26:51,280 --> 05:26:51,520
COMMENT?

8476
05:26:51,520 --> 05:26:52,560
>> I WOULD SAY IT IS A

8477
05:26:52,560 --> 05:26:53,960
REMARKABLE FINDING BECAUSE BONE

8478
05:26:53,960 --> 05:26:55,680
DOESN'T HAVE LYMPHATICS.

8479
05:26:55,680 --> 05:27:00,160
SO THE BONE MARROW IS LYMPHATICS

8480
05:27:00,160 --> 05:27:02,960
AND USING SINUSOID.

8481
05:27:02,960 --> 05:27:04,760
THIS WOULD BE SPECIFIC, YEAH FOR

8482
05:27:04,760 --> 05:27:07,360
THIS DISEASE.

8483
05:27:07,360 --> 05:27:09,040
>> GREAT.

8484
05:27:09,040 --> 05:27:10,080
THANKS, THANK YOU EVERYBODY FOR

8485
05:27:10,080 --> 05:27:11,400
YOUR QUESTIONS, IT'S BEEN A

8486
05:27:11,400 --> 05:27:12,040
FANTASTIC SESSION.

8487
05:27:12,040 --> 05:27:14,320
WE APPRECIATE THE ORGANIZERS WHO

8488
05:27:14,320 --> 05:27:16,800
PUT ALL OF THIS TOGETHER.

8489
05:27:16,800 --> 05:27:21,400
AND THANKS FOR YOUR ATTENTION.

8490
05:27:21,400 --> 05:27:23,680
>> JUST I WOULD LIKE ON
BEHALF

8491
05:27:23,680 --> 05:27:25,320
OF NIH TO THANK YOU ALL FOR

8492
05:27:25,320 --> 05:27:27,520
TAKING THE TIME TO ATTEND AND

8493
05:27:27,520 --> 05:27:29,680
PARTICIPATE IN DAY ONE OF THIS

8494
05:27:29,680 --> 05:27:30,120
WORKSHOP.

8495
05:27:30,120 --> 05:27:31,920
FOR ALL THE SPEAKERS, THANK YOU

8496
05:27:31,920 --> 05:27:35,440
FOR YOUR WONDERFUL INSIGHTFUL

8497
05:27:35,440 --> 05:27:36,920
PRESENTATIONS.

8498
05:27:36,920 --> 05:27:38,600
TO ALL ATTENDANTS FOR Q4

8499
05:27:38,600 --> 05:27:39,920
QUESTIONS AND CONTRIBUTIONS.

8500
05:27:39,920 --> 05:27:42,360
WE HOPE YOU WILL JOIN US

8501
05:27:42,360 --> 05:27:44,640
TOMORROW FOR DAY TWO OF THIS

8502
05:27:44,640 --> 05:27:45,240
WORKSHOP.

8503
05:27:45,240 --> 05:27:47,120
WE HAVE AN EXCITING PROGRAM IN

8504
05:27:47,120 --> 05:27:49,640
THE WORKS, INCLUDES SOME OF

8505
05:27:49,640 --> 05:27:51,720
OTHERS KEYNOTE AND SPECIAL TALKS

8506
05:27:51,720 --> 05:27:56,880
BY DR. SALLY AND SARA AND THREE

8507
05:27:56,880 --> 05:27:59,760
EXCITING SESSIONS INCLUDING ONE

8508
05:27:59,760 --> 05:28:02,400
LYMPHEDEMA, ONE COMMUNITY

8509
05:28:02,400 --> 05:28:04,080
PERSPECTIVE AND ONE ON NEW

8510
05:28:04,080 --> 05:28:04,960
TECHNOLOGIES IN LYMPHATIC

8511
05:28:04,960 --> 05:28:07,320
IMAGING AND MAPPING.

8512
05:28:07,320 --> 05:28:08,960
LOOKING FORWARD TO SEEING Y'ALL

8513
05:28:08,960 --> 05:28:09,000
AGAIN TOMORROW AND THANK YOU

8514
05:28:09,000 --> 05:28:10,440
AGAIN.

8515
05:28:10,440 --> 00:00:00,000
GOOD EVENING.