LET'S GET STARTED. I'M JUN
HUH FROM THE EXPERIMENTAL
IMMUNOLOGY BRANCH OF THE NCI. IT
IS REALLY MY GREAT PLEASURE TO
WELCOME TODAY'S SPEAKER JUN HUH
FOR HARVARD MEDICAL SCHOOL AND
JUN RECEIVED HIS UNDERGRADUATE
AND MASTERS DEGREE FROM SOLE
NATIONAL UNIVERSITY IN KOREA. IN
MICROBIOLOGY. SEAOUL. AFTERWARDS
HE DECIDED TO MOVE EAST,
CROSSING THE PACIFIC OCEAN
LANDING IN CALIFORNIA AND DID
HIS Ph.D. INCAL TECH. STUDYING
DROSOPHILA AND THEN DECIDED TO
MOVE UP AND GO TO VERTEBRATE AND
LUCKILY FOR US IMMUNOLOGIST HE
DID POST-DOCTORAL WORK MOVING
AGAIN EAST IN NEW YORK AND DAN
(INAUDIBLE) LAB HE DID
PHENOMENAL WORK ON
INTERLEUKIN-17 PRODUCING CELLS
OR TH 17 CELLS. AND LOOKING AT
TRANSCRIPTION FACTOR GAMMA T AND
HOW IT IS REGULATED BY SMALL
MOLECULE LIKE DINGOXIN. THEN
DECIDED TO MOVE FURTHER EAST TO
U MASS WORCESTER WHERE HE BECAME
ASSISTANT PROFESSOR AND THEN GOT
A BREAK THROUGH IN IMMUNOLOGY
AND NEURAL DEVELOPMENT, THEY
FOUND MATURE IL 17 IS REGULATING
AUTISM, NEURAL DEVELOPMENT IN
MICE AND THEN FURTHER FOUND OUT
THE MICROBIOME TO INFLUENCE SIP
1. PHENOMENALLY SUCCESSFUL THEN
DECIDED TO MOVE EVEN MORE EAST
AND NORTH, ENDED UP IN HARVARD
WHERE HE IS NOW ASSOCIATE
PROFESSOR. AND I HOPE HE'S NOT
MOVING FURTHER BECAUSE THE ONLY
OTHER PLACE TO GO IS NOVA
SCONOVASCOTIA. SCIENTIFICALLY JS
JUST PHENOMENAL. HE IS A
FIELDIST AND PIONEERING AND
TRAIL BLAZING PERSON. HE'S ALSO
VERY SWEET AND NICE GUY AND I
LOVE TO LISTEN TO HIS TALK. I
LISTEN HIM LIKE A FEW TIMES AND
ALWAYS AMAZED HOW HE DEVELOPED
HIS STORY AND I HOPE YOU WILL
ENJOY IT AS MUCH AS I DO. AND
WITHOUT FURTHER ADIEU, WELCOME,
JUN, TO THE NIH.
>> THANK YOU VERY MUCH FOR THE
KIND INTRODUCTION. I THINK I
WILL MOVE EAST. THIS IS MY FIRST
TIME TO THE SEMINAR AT NIH SO I
THOUGHT BRIEFLY WHAT WE DO IN MY
LAB AND THEN INITIALLY TELL YOU
ABOUT PUBLISHED WORK SHOWING THE
ROLE OF MICROMETABOLITE OF
BIOLIPID, THIS IS ALL PUBLISHED
SO GIVE YOU A SUMMARY THEN MOVE
TO THE STORY TH 17 IN REGULATING
NEURAL ACTIVITY. I WANT SHARE
WITH YOU UNPUBLISHED WORK AS
WELL. SO MANY OF YOU KNOW THIS
IS A GRAPH BUT GRAPH ON YOUR
RIGHT, COVID IS THE FIRST STORY
BUT AS SOCIETY WE HAVEN'T DONE
GOOD JOB, THE RATE HAVE BEEN
OVER THE YEARS. LOOK AT GRAPH ON
YOUR RIGHT, THOSE ARE VERY
DIFFERENT IMAGE, THE PREVALENCE
RATE OF MANY IMMUNE RELATED
DISORDER AND FOR SOME REASON
NOBODY KNOW FOR SURE IT HAS BEEN
STUDIED ON THE STEADY RISE. I
WANT TO SHOW YOU ANOTHER GRAPH
WHICH IS PREVALENCE RATE OF
NEUROLOGICAL DISORDERS SUCH AS
AUTISM AND HERE YOU SEE DIRECTLY
THE STEADY INCREASE OVER THE
TRAINING YEAROR YEARS AND
ACCORDING TO RECENT DATA CDC ONE
OUT OF 36 CHILDREN BORN IN THE
STATES ARE DIAGNOSED WITH AUTISM
SPECTRUM DISORDER. SO
ESSENTIALLY 30% OF CHILDREN TEND
TO BE ON THIS SPECTRUM. WE CAN
SPEND HOURS DISCUSSING ONE MAY
UNDERLIE SUCH STEADY INCREASE
BUT ONE THING THAT IS ABUNDANTLY
CLEAR TO ME GENETIC MUTATION MAY
NOT EXPLAIN ALONE, DIFFICULT TO
IMAGINE MORE GENETIC MUTATION
OVER PAST 20 YEARS YEARS. IMPORT
ROLE OF THE ENVIRONMENTAL
FACTORS NON-GENETIC FACTORS BUT
WHAT THOSE FACTORS ARE ANOTHER
TOPIC FOR DISCUSSION. BUT YOU
MIGHT HAVE -- WE ARE FOCUSING ON
PERHAPS IN MY MIND TWO MOST
IMPORTANT NON-GENETIC FACTORS
THAT CAN INFLUENCE HUMAN HEALTH.
ONE IS MICROBIOME. AND WHAT
HAPPENED DURING PREGNANCY. THIS
IS A FACTOR THAT INFLUENCE FETUS
AND CAN HAVE LONG TERM EFFECT IN
OUR HEALTH. OVER THE YEARS MOST
FOCUSING ON TWO FACTOR TRYING TO
UNDERSTAND HOW THAT CAN
INFLUENCE ANIMAL HEALTH MOSTLY
MOUSE HEALTH. WE WILL BE FOCUS
ON THE ROLE HAVING A SYSTEM IN
THE MIDDLE. THIS IS THE SYSTEM
IN INTERMEDIATE SIGNAL FROM THE
MICROBIOME, REMEMBER WHAT
HAPPENED IN PREGNANCY AND THOSE
IMMUNE CELLS THAT INFLUENCE GUT
HEALTH, ALSO IN A BRAIN
FUNCTION. SO THAT'S WHAT TRUE
ORGAN THAT MY LAB AND MOSTLY
FOCUS ON. IN TERM OF CYTOKINE,
IL 17, I DON'T NEED TO GIVE THE
AUDIENCE INTERLEUKIN-17 IS
HISTOROCK ILY KNOWN TO HAVE
IMMUNE RELATED PROTECTING US
FROM INVADING PATHOGENESIS,
EXTRA CELL BACTERIA AND FUNGAL
INFECTION BUT IL 17 IS SHOWN TO
CONTRIBUTE TO DIFFERENT
AUTOIMMUNE INFLAMMATORY DISORDER
AND OUR WORK ALSO WORK FROM
(INAUDIBLE) LAB SHOW THAT
INTERLEUKIN 17 SHOW IMPACT ON
NEURAL DEVELOPMENT AND FUNCTION
AND NEURONAL REGENERATION OF
INJURY. IMMUNE FUNCTION CAN BE
INDUCED BY IL 17 AND PREVIOUSLY
SHOWN, I WAS ABLE TO IDENTIFY
MOLECULE WITH HORMONAL
DIFFERENTIATION OF THE MOLECULE
BUT BE SURE BY TRANSCRIPTION
FACTOR RECEPTOR THAT SIT IN THE
CONSERVATIVE'S SEAT AND CONTROL
TH 17 PROGRAM AND ALSO SHOW
(INAUDIBLE) CAN IMMUNOSUPPRESS
THE FUNCTION OF GAMMA T AND TH
17 CELLS. SO WE CAME IN
WONDERING WHETHER THERE'S
NATURAL LIGAND OR INHIBITOR OF
TH 17 CELL THAT MAY ALSO BIND TO
GAMMA T AND ALSO SUPPRESS
SUPPRESS GAMMA CELL. WE
HYPOTHESIZE WITH WACK TIERIA
GAVE THE ABILITY TO CONTROL
DEVELOPMENT OF FUNCTIONAL TH 17
CELL BY PRODUCING SUCH A SMALL
MOLECULE THAT CAN BIND TO GAMMA
T. TO MAKE LONG STORY SHORT
IDENTIFY METABOLITE WITH
MODULATORY ACTIVITY WE DECIDE TO
FOCUS ON BIOACIDACID. THE REASE
FOCUS ON BIOACID IS AT THE TIME
OTHER KNOWN GAMMA LIGAND WITH
AGONISTIC OR ANTAGONISTIC
ACTIVITY (INDISCERNIBLE) CORE
CHOLESTEROL DERIVATIVE AND SOME
OF YOU MAY KNOW DERIVED FROM
CHOLESTEROL AND TONS OF VIRUSES
ARE ABLE TO SEE IN OUR SYSTEM
AND THE BIAS ARE SUBJECT TO THE
MODIFICATION OF WHETHER THEY
HAVE ABILITY TO CONTROL TH 17
FUNCTION. THIS IS PUBLISHED
WORK. SO I'M GOING TO GIVE YOU
HIGHLIGHT OF THE STORY. WE
WANTED TO KNOW IN VITRO SCREEN
USING PRIMARY T-CELL CULTURE
READ OUT WE USE A TH 17
REGULATORY T-CELL, IDENTIFY TRUE
BIAS, ACID DERIVATIVE, TH 17
CELLS INHIBITED TH 17 CELL AND
ENHANCE REGULATORY T-CELL IN
VITRO. SO WHEN WE FIRST IDENTIFY
THE SCA WE CONFIRM BIND TO HUMAN
OLIGOBACTERIA IN VITRO WITH A
MICROMOLAR. AND SUPPRESS
TRANSCRIPTION ACTIVITY BECAUSE
WHEN WE USE (INAUDIBLE)
COEFFICIENT ACTIVITY AND
MOREOVER IT IS SUPPRESS TH 17
CELL DIFFERENTIATION WHEN WE ADD
INTO THE IN VITRO CULTURE.
RELATED TO THE CELLS ACID IN
SUCH A PHENOTYPE IN VIVO WHEN WE
ADMINISTER THE SINGLE MOUSE WITH
(INAUDIBLE) WE ARE ABLE TO
DETECT THIS, WE DO TH 17
CHILDRENIATION, THIS IS A
BACTERIA DEPENDENT TH 17
DIFFERENTIATION MODEL. HOWEVER
THE SAME (INAUDIBLE) REGULATORY
T-CELL PERCENTAGE. THEN THIS IS
THE FUN OF SCIENCE IN WAY WE
WANT TO IDENTIFY BACTERIA OR
BACTERIA ENZYME THAT PRODUCE TH
17 MODULATORY BIOACID, WE
COLLABORATED WITH OUR COLLEAGUE
AT HMS AND BASICALLY SCREEN
THOUSANDS OF HUMAN BACTERIA
INDIVIDUALLY USING LCMS. AND
BASED ON EACH WE INCLUDED THE
INOCULATE ONE BACTERIA AND IN
PREVIOUS AMINO ACID AS PRECURSOR
MOLECULE AND THEN WE ARE ABLE TO
IDENTIFY BACTERIA STRAIN THAT
CONVERT ACETYLCHOLINE ACID. THIS
IS THE TRUE FORCE SPEARHEADED BY
(INDISCERNIBLE) FORMER POST DOC,
WE ARE ABLE TO SUCCESSFULLY
IDENTIFY BACTERIA AND BACTERIA
ENZYME THAT CAN GENERATE THIS TH
77 MODULATORY OR INHIBITOR
BIOACID IN VITRO AND IN VIVO. IN
TERMS OF HUMAN RELEVANCE WE
COLLABORATED WITH (INAUDIBLE) IN
OUR LAB, WE LOOK AT THE CELL TH
INHIBITOR ASSAY, IN PATIENT WITH
IGG PATIENT VERSUS HEALTHY
CONTROL AND WE FOUND THIS IDD
PATIENT WITH IDD THEY HAVE
DEVELOP BACTERIA IN THEIR SYSTEM
CONTROL, THIS IS CORRELATION BUT
THAT DATA IS POSITIONED WITH OUR
HYPOTHESIS, BACTERIAL IN TH
FUNCTION AND PARTICIPATION, THEY
MAY BE EXPOSED TO INFLAMMATION
BECAUSE THEY DON'T HAVE AS MUCH
MATERIAL CELLS IN THEIR SYSTEM.
AND MOREOVER WHEN WE LOOK AT
GENE EXPRESSION CHANGES WE FOUND
IN CORRELATION BETWEEN LEVEL OF
HCA AND EXPRESSION OF TH 17 SUCH
AS IL 17 SO SUGGESTING EVEN IN
HUMAN THE LEVEL OF MATERIAL
CELLS MAY BE CORRELATED WITH TH
17 PROGRAM. SO FROM ALL THIS
DATA WE ARE ABLE TO FIND
PARTICULAR BIAS AND PARTICULAR
TYPES OF BACTERIA IN THE GUT,
THEY CAN CONVERT THIS BACTERIA
CAN CONVERT THE INKNOCK LOUSE
BIAS SUCH AS ACETYLCHOLINE ASHED
AND T-CELL INTO TH 17 OR T
MODULATORY BIOASSAY AND THIS
BACTERIA GENERATED SMALL
MOLECULE BIOACID CUP INFLUENCE
SYSTEM BY DIRECTLY INTERACTING
WITH IN THIS CASE IN VITRO HOST
TRANSCRIPTION FACTOR AND IN
DOING SO MAY IMMUNOSUPPRESS
INFLAMMATION. LIKEWISE,
DIFFERENT TYPES OF BIAS, I
DIDN'T HAVE TIME TO TALK ABOUT
THIS BUT ANOTHER BIAS REGULATORY
T-CELL DIFFERENTIATION MOSTLY IN
VIVO, IN THIS CASE RECEPTOR, WE
DO NOT CARE ABOUT -- THIS BIAS
WITHIN (INAUDIBLE) BUT SHOWING
AN EXAMPLE OF HOW BACTERIA
UTILIZE THE HOST BACTERIA
MODIFYING THEM AND CONTROLLING
IMMUNE RESPONSES. AROUND THE
SAME TIME (INDISCERNIBLE) IN
JAPAN, THEY COMPARED BIAS IN THE
CENTRAL AREA, PEOPLE WHO LIVE
OVER 100 YEARS OLD VERSUS
HEALTHY 80 YEARS OLD PEOPLE AND
FOUND WHY (INAUDIBLE) IS
COMPARABLE THEY FOUND OLDER
IMMUNE MODULATORY BIAS WE
IDENTIFY IN THE SENNARYIANS HAVE
HIGHER IMMUNOMODULATORY BIAS
THEIR GUT. THIS DATA DOESN'T
MEAN THIS BILE ACID CAN MAKE
THESE PEOPLE LIVE LONGER BUT
AGAIN, PERHAPS THERE'S SOME
CONNECTION CONTRIBUTION OF THIS
IMMUNE MODULATORY BIAS AND THEIR
HEALTH. JUST GOING TO GIVE YOU A
BRIEF OVERVIEW OF THE TYPE OF
WORK WE ARE DOING IN KIND OF
STUDYING THE RELATIVE
INTERESTING BETWEEN GUT BACTERIA
AND IMMUNE CELL IN THE PERIPHERY
AND THE CONTEXT OF GUT
INFLAMMATION. NOW I WANT TO
CHANGE GEAR AND TELL YOU
DIFFERENT STORY, BETWEEN IMMUNE
CELLS AND THE BRAIN. THE CELLS
IN THE BRAIN. FOR THIS WORK WE
DID COLLABORATE WITH GLORIA
NEUROSCIENTIST AT MIT. AND WE
DID HERE SO IF YOU HAVE A
DIFFICULT QUESTION JUST WAIT AND
ASK HER THOSE QUESTIONS, OKAY? I
WANT TO ALSO BEFORE I GET INTO
THIS, CANCER IMMUNOTHERAPY THIS
IS ONE FINDING THAT REALLY
CHANGED THE FIELD THE WAY WE
TREAT CANCER PATIENTS. AND THEN
BASICALLY THIS IS A WAY TO THIS
IS HARNESSING OUR OWN IMMUNE
SYSTEM AND IN DOING SO PEOPLE
ARE ABLE TO RESTORE RE-ESTABLISH
BALANCE, MAINTAIN THIS BALANCE.
SO THE REASON WHY I MENTION THIS
IS BECAUSE MY DREAM IS THAT
PERHAPS SOME DAY WE MAYBE ABLE
TO UTILIZE A SIMILAR APPROACH
BECAUSE THE SYSTEM SYSTEM
BASICALLY BALANCED, WHEN THINGS
GO AWRY THEY CAN GET DEPLOYED TO
DIFFERENT TISSUE. AND RESTORE
HOMEOPATHIC BALANCE, THAT IS HOW
WE ARE DOING IN THE SYSTEM TO
SOME DAY IN THE FUTURE I HOPE
THAT WE MAY BE ABLE TO SEE NOVEL
IMMUNOTHERAPY THAT CAN BE USED
TO TREAT AND TRAIN DISORDER,
THAT'S WHEY I INCLUDE THAT. LIKE
MANY OTHER GOOD IDEAS, YOU ARE
NOT FIRST ONE TO THINK ABOUT SO
THIS IS IMMUNOTHERAPY FOR
NEUROLOGICAL DISORDERS. IT HAS
BEEN USED BEFORE. SO SOMETIME
AGO PEOPLE WANTED TO TRANSFER
THIS AWESOME POWER OF
INFLAMMATION AND THEY WANT TO --
BY TRANSFERRING THIS
INFLAMMATION THEY WANT TO TREAT
PSYCHIATRIC PATIENTS AND
POTENTIALLY DRAWING PLOT IN A
PATIENT THAT INFECTD WITH
MALARIA AND BY TRANSFERRING THAT
BLOOD INTO (INAUDIBLE) PATIENT
THEY WANTED TO CURE THAT
SYMPTOM. APPARENTLY THIS
APPROACH WE EASILY TEND TO
IMAGINE GOOD PRESENCE OF
PATIENTS IN THIS NEW -- THE
ARTIFACT, IMMUNE ACTIVATION.
ALTERNATIVELY THIS APPROACH MUST
HAVE BEEN SUCCESSFUL TO SOME
DEGREE BECAUSE THE HISTORY 1927
NOBEL PRIZE WAS GIVEN FOR
THERAPY OF MALARIA INOCULATION
IN TREATING CERTAIN FORM OF
DEMENTIA. SO THIS IMMUNE --
NEURAL IMAGING, IS NOTHING NE N.
THE FAST FORWARD IF YOU LOOK AT
THIS PHENOMENON, I BRIEFLY
INTRODUCED INCREASING RATE
PREVALENCE RATE OF AUTISM BUT
AMONG THIS PARAMOUNT (INAUDIBLE)
CHILDREN THEY NOTED THAT WHEN
THEY ARE CHILDREN WERE EXPOSED
TO INFLAMMATION CERTAIN
PERCENTAGE OF CHILDREN WITH
AUTISM THEIR SYMPTOM, TALKING
ABOUT THEIR CORE SYMPTOM, WHICH
IS ASSOCIATED WITH (INAUDIBLE)
BEHAVIOR THEIR (INAUDIBLE)
IMPROVED. THIS IS IS SO CALLED
FEVER EFFECT. SO FEVER EFFECT
WHEN CHILDREN HAVE A FEVER THEIR
SYMPTOM GET (INDISCERNIBLE)
DRAMATICALLY IMPROVE. THIS IS AN
ARTICLE I BROUGHT HERE AND MORE
RECENT STUDY THEY LOOK AT MORE
THAN 200 CHILDREN WITH AUTISM
AND ACCORDING TO THIS STUDY 17%
OF THESE CHILDREN THEY SHOW
PEOPLE VISITATION OF AUTISM
RELATED SYMPTOM. THEY SAY
INTERESTING AND WEIRD. AUTISM IS
LIKE A NEURAL DEVELOPMENT
DISORDER BUT CORE SYMPTOM
IMPROVED WHEN THEY IMPROVED
INFLAMMATION. SO BASED ON THIS
STUDY, ANOTHER STUDY ARTICLE
SHOWING PEOPLE WITH BEHAVIOR
PROBLEM IN SOME CHILDREN WITH
AUTISM, AND SOME VARIATION STUDY
TO STUDY VARIATION. I THINK
SOMEWHERE BETWEEN 70% OF
CHILDREN WITH AUTISM SHOW FEVER
MITIGATION. ANOTHER STUDY WITH
6% OF CHILDREN, I THINK
SOMEWHERE BETWEEN LIKE 6 TO 17%,
NOBODY KNOW FOR SURE THE FACTOR
IN THE PHENOTYPE, MY LAB WE ARE
TRYING TO INITIATE HUMAN STUDY.
WE ARE COLLABORATING WITH
AUTISTIC -- WE ARE GOING TO
START TO IDENTIFY IMMUNE
CORRELATES POSITIVELY OR
NEGATIVELY ASSOCIATED WITH A
FEVER. SO HOPEFULLY IF THERE IS
A CHANCE IN A FEW YEARS I CAN
SHARE IT WITH YOU MORE EXCITING
FINDIFINDIFINDING. BASED ORANGEN
OBSERVATION WE DECIDED TO USE
MOUSE MODEL FOR AWETISM AND THEN
TRY TO UNDERSTAND AUTISM AND TRY
TO UNDERSTAND THE UNDERLYING
MECHANISM THAT IMPROVE I BELIEVE
FLAYMATION ASSOCIATED WITH --
THIS WAS PUBLISHED AWARD BUT IN
ORDER TO STUDY THAT WE FIRST
NEED TO USE A MOUSE MODEL IN
AUTISM THERE'S NO BIOMARKER
ESSENTIALLY A PHENOTYPIC BASIS
STUDY SCIENTISTS GENERATE MANY
REFER TO AUTISM MODEL, SOME
REQUIRE GENETIC MUTATION. OTHER
AUTISM MODEL DEPENDENT ON
ENVIRONMENTAL FACTOR AND ONE
MODEL THAT WE OFTEN USE IS HUMAN
ACTIVATION MODEL. THIS IS A VERY
-- THIS MODEL IS BASED ON HUMAN
EPIDEMIOLOGICAL STUDY. IN
RESPONSE TO SOME INFLAMMATION
DURING PREGNANCY. SECOND
TRIMESTER, LATE FIRST TRIMESTER
PREGNANCY. THEIR CHILDREN HAVE A
CHANCE TO DEVELOP
NEURODEVELOPMENTAL DISORDER
SIGNIFICANT INCREASE SO THIS IS
AN APPROVAL REPORTED AGAIN,
STUDY IN DENMARK, THEY HAD THIS
STUDY IN DENMARK SINCE 1980, A
WOMAN HOSPITALIZED DURING
PREGNANCY, CHILDREN -- A CHANCE
TO DEVELOP AUTISM SIGNIFICANTLY
INCREASE. SO WE UTILIZE THIS
MODEL IN MICE DURING PREGNANCY
WE GIVE THEM INFLAMMATION,
INJECT THEM WITH POLYIC AND
LIGAND AND COMPARABLE TO HUMAN
SECOND TRIMESTER OR LATE FIRST
TRIMESTER. AND THEN -- LED WAIT
TWO MONTHS, THEIR OFF SPRING
(INAUDIBLE) COMPARE TO OFFSPRING
PREVIOUS INJECTION TO THE MOTHER
THEY SHOW INCREASE BEHAVIOR,
SHOW (INAUDIBLE) SO OF COURSE
NOBODY KNOW FOR SURE WHETHER
THESE MICE ARE AUTISTIC BUT WE
CAN SAY THESE MICE DURING
PREGNANCY MANY MONTHS LATER
THERE'S BEHAVIOR CHANGES SO
USING THIS MOUSE MODEL WE WANT
TO TEST WHETHER THIS MICE MODEL,
WHEN THIS MOUSE SHOWING AUTISM
LIKE BEHAVIOR WHEN THEY REACH
(INAUDIBLE). WHAT HAPPEN IF WE
GIVE THEM TO ANOTHER IMMUNE
STIMULUS, RIGHT? SO COMPLICATED,
RIGHT? SO INFLAMMATION DURING
PREGNANCY CAN PROMOTE AUTISM
BEHAVIOR. WE ARE ASKING THAT
INFLAMMATION ONCE THE CIRCUIT IS
COMPLETELY ESTABLISHED WHETHER
THAT INFLAMMATION CAN MITIGATE
BEHAVIOR SYMPTOM THAT IS WHAT WE
DECIDED TO ASK. SOME MAY NOT BE
FAMILIAR WITH BEHAVIOR STUDY,
THIS IS A WIDELY ESTABLISHED
MODEL BY IMMUNE BIOLOGIST,
CONTROL MICE WAS GIVEN A CHOICE,
THIS MOUSE SPEND MORE TIME WITH
THEIR SOCIAL TARGET INSTEAD OF
SPENDING TIME (INAUDIBLE) FOR
DURATION OF 10 TO 15 MINUTES WE
SHIFT THE MOUSE AND BY
QUANTIFYING RELATIVE TIME SPENT
IN ASSOCIATED TARGETS IN TARGET
WE CAN QUANTIFY THE SOCIAL
OPPORTUNITY THERE. SO
ESTABLISHED STUDY, THAT IS WHAT
BUT YOU SEE FROM THE CONTROL
MICE. WHAT HAPPENED IF YOU DO
THE SAME EXPERIMENT WITH THE
MICE, P POSED TO INFLAMMATION IN
MICE DURING PREGNAN PREGNANCY. T
INTEREST IN SOCIAL TARGET. THEY
SPEND EQUAL AMOUNT BETWEEN TWO
TARGET BUT OVERALL THEY ARE
MOVING DISTANCE, THEY ARE
INVESTIGATION TIME ARE
COMPARABLE. NO MAJOR INHIBITORY
EFFECT SO JUST SPENDING TIME
WITH TARGET. THIS IS A
QUANTIFICATION I WANT TO SHOW
YOU. THIS IS CONTROL MICE, 70%
TIME SOCIAL TARGET AND MICE THEY
-- EVEN WITH OR WITHOUT -- THEY
SPEND SMALL MEDIAN AMOUNT OF
TIME WITH SOCIAL TARGET SO
SOCIAL DEFICIT BEHAVIOR
PHENOTYPE. WE GIVE ANOTHER
IMMUNE STIMULUS. WE DECIDED TO
USE APF BECAUSE WHEN YOU GIVE
NO, MA'AM MULTI-IT WILL -- WE
DECIDE TO GIVE A DIFFERENT
STIMULUS. WHAT HAPPENED IS WE
SAW SOCIAL ABILITY. WITH HIGHER
LEVEL OF MOUSE DEVELOP BEHAVIOR,
EVERYTHING COMES OUTS TO -- WE
GIVE PEERS THAT IS NOVEL, THEIR
OVERALL INDUCE PHENOTYPE WAS
STILL CELL TEMPORALLY ROBUST
RESCUE SOCIAL ABILITY PHENOTYPE.
THE SAME BEHAVIOR PHENOTYPE AS
WELL. SO WE ARE ABLE TO
RECAPITULATE WHAT IS SHOWN IN
HUMAN IN CERTAIN AUTISTIC
INDIVIDUAL CORE SYMPTOMS CAN
IMPROVE. NEXT QUESTION IS IS
PEOPLE OR IS IT OTHER NON-FEVER
RELATED IMMUNE MOLECULE? HOW DO
WE INDUCE FEVER? WE INDUCE
INFLAMMATION. NEURAL BALANCE
WITH ALL NEW TECHNIQUE AND THEN
BASICALLY BY INHIBITING NEURONAL
ACTIVITY IN CERTAIN BRAIN AREA,
HYPOTHALAMIC REGION. YOU DO
THAT, INFLUENCE PARTICULAR BRAIN
LOCUST YOU CAN INCREASE, IN THIS
CASE NO INFLAMMATION. SO WHAT WE
ASK IS INCREASE THE TEMPERATURE
AND THAT CAN HAPPEN, THE MOUSE
STILL SHOW REDUCE ASSOCIATED
PHENOTYPE SUGGESTING THAT IN
THIS CASE INCREASING TEMPERATURE
IS NOT SUFFICIENT OR MITIGATING
BEHAVIOR ABNORMALITY. SO FACING
A FEVER, FOR VARIOUS REASON WE
CYTOKINES MEASURE CYTOKINE WITH
OR WITHOUT INJECTION AND NOTICE
THAT FIRST COMPARE TO CONTROL
GROUP, (INAUDIBLE) APS INDUCE
MORE CYTOKINE PRODUCTION IN MIL
STRENGTH SO WE PUBLISHED A PAPER
IN IMMUNITY LAST YEAR SO MICE
IMMUNOSYSTEM REMEMBER WHAT
HAPPENED DURING PREGNANCY AND
IMMUNE SYSTEM WHEN THEY GET
(INAUDIBLE) THEY BECOME MORE
HYPERACTIVATED. SO PROMOTE
BEHAVIOR BY ACTING ON THE STRESS
PATHWAY. IN THIS CASE WE THOUGHT
MAYBE IL 17 HERE, SOME OTHER
REASON PLAY AN IMPORTANT ROLE
MITIGATING THE SOCIAL ABILITY
PHENOTYPE SO QUESTION WILL IL 17
LEAD TO BEHAVIOR RESCUE. FIRST
WE INTRODUCE WE INHIBITED IL 17
ACTIVITY IN THE BRAIN BY
INTRODUCING BELONGING ANTIBODY
TO CNS ALL PUBLISHED SO LET ME
MOVE A LITTLE QUICKLY BECAUSE I
WANT TO SHARE WITH YOU PUBLISHED
LITERATURE. SO IN THIS CASE
BLOCKING IL 17 ACTIVITY IN THE
BRAIN THEN WE NEURONAL DETECT
INCREASE SOCIAL ABILITY, IF WE
BLOCK INTERFERON GAMMA AND
(INAUDIBLE) SO IL 17 ACTIVITY IN
THE BRAIN MAY PLAY A ROLE IN
MITIGATING SOCIAL DEFICIT.
PREVIOUSLY (INAUDIBLE) IDENTIFY
IMPORTANT BRAIN AREA THAT WHERE
INCREASE NEURONAL ACTIVITY LED
TO BEHAVIOR ABNORMALITY AND THEN
SUPPRESS NEURAL ACTIVITY SHE WAS
ABLE TO TEMPORALLY RESCUE
BEHAVIOR ABNORMALITY. WE THOUGHT
MAYBE THIS INFLAMMATION CAN ALSO
INFLUENCE THIS NEURONAL
ACTIVITY, AUTOTISSIC MOUSE FOR
VARIOUS AUTISM MODEL HAVE
INCREASE BRAIN ACTIVITY NEURAL
ACTIVITY IN THIS PARTICULAR
BRAIN AREA. AND THEN WE THOUGHT
PERIPHERAL INFLAMMATION,
FOLLOWING THIS INJECTION NOT
ONLY RESCUE BUT BEHAVIOR
ABNORMALITY BUT MAY INFLUENCE
INCREASING NEURAL ACTIVITY, THAT
IS WHAT WE SEE AND HYPOTHESIZE
SO SUPPORT THAT BASED ON SHOWING
PERIPHERY REDUCE THIS
(INAUDIBLE) SURROGATE MICE
NEURONAL ACTIVITY AND THIS IS A
BRAIN SPECIFIC BECAUSE WHEN YOU
GET OTHER BRAIN REGION THERE IS
NO CHANGE EVEN WITH INCREASE
NEURONAL ACTIVITY. SO
INTERESTING TO SEE KEY BRAIN
AREA MEDIATED THAT IS IMPORTANT
FOR BEHAVIOR ABNORMALITY,
PERIPHERAL INFLAMMATION IS
INTRODUCED TO ESTABLISH BACK TO
BASELINE. THEN WE GOT THE SAME
WHEN WE DID THE (INAUDIBLE) IN
THIS CASE AS WELL INDUCE THE
DIGOXIN NEURAL ACTIVITY CAN BE
PREVENTED IF WE BLOCK ANTIBODY
SUGGESTING THAT THIS CHANGE IN
NEURAL ACTIVITY REQUIRES IL 17.
IN ORDER TO UNDERSTAND WHY
(INAUDIBLE) MORE TRAJECTORY WITH
IL 17 CAN MEDIATE THE BEHAVIOR
RESCUE, WE FIRST LOOK AT
EXPRESSION OF IL 17 RECEPTOR,
THIS IS IL 17A SUB UNIT USING
RNA SCOPE. THIS IS RNA. THEN WE
SAW THERE THERE IS EXPRESSION OF
RNA INTO (INAUDIBLE) OF THE
CORTEX. WHEN WE MOVE THAT IL 17
RECEPTOR EXPRESSION USING
(INAUDIBLE) ONE THING TO MENTION
FOR IMMUNO-- PEOPLE WITH
IMMUNOBACKGROUND, IN THE SYSTEM
BRAIN IS STEADY, SO YOU CAN
DELIVER THE CRE PROTEIN IN
LOCALIZED BRAIN AREA, IN DOING
SO YOU CAN INFECT THAT PERSON
NOT THE NEIGHBORING REGION. ONLY
THAT PART. SO THAT'S WHAT WE
DID. THIS BRAIN AREA WE GET RID
OF REACCEPT EXPRESSION AND THAT
BRINGS BACK RESCUE. SO YOU KNEE
IL 17 RECEPTOR A SUB UNIT
CORTICAL BRAIN AREA. AT THAT
TIME WE ALSO DID A EXPERIMENT IN
THIS CASE WE INCLUDE PROTEIN
DIRECTLY INTO THIS -- ON TOP OF
THIS CRITICAL AREA BY DELIVERING
WHOLE IN THE CANNELLA AND IL 17
INTRODUCTION OF IL 17 RAY LOAN
IS SUFFICIENT FOR SOCIAL
BEHAVIOR SUGGESTING IL 17
RECEPTOR IS NECESSARY IL 17
PROTEIN IS SUFFICIENT TO INDUCE
BEHAVIOR ABNORMALITY. THEN LATER
WE ALSO ACHIEVE THE SAME GOAL,
SOCIAL ABILITY, THIS IS GENETIC
MOUSE MODEL OF AUTISM, THIS IS
ONE OF THE MUTATION THAT ARE
FOUND FOR HUMAN AUTISTIC
PATIEPATIENT. IN THIS CASE THOUH
THEY HAVE THE SAME GENETIC
MUTATION WHEN WE INCREASE IL 17
IN PERIPHERY IT IS SUFFICIENT TO
PROMOTE PHENOTYPE BASICALLY MICE
SPEND MUCH TIME EACH OTHER BUT
IN THIS CASE FOUR HOURS AFTER WE
INCREASE IL 17 LEVEL IN
PERIPHERY, THE MOUSE SPEND MORE
TIME WITH EACH OTHER AND THIS
RESCUE PHENOTYPE LAST AROUND A
FEW DAYS. THIS APPROACH IS NOT
RESTRICTED TO MIA. BUT WHEN --
OR SHANK 3 BUT WHEN WE BRING IN
MULTIPLE OTHER PROTEIN MOUSE
MODEL FOR AUTISM, WE ARE ABLE TO
(INAUDIBLE) GENETIC MUTATION AS
WELL AS WE INCREASE IL 17 IN
PERIPHERY, BEHAVIOR SYMPTOM IS
SIGNIFICANT WAS SIGNIFICANTLY
IMPROVED. SO SO FAR I TOLD YOU
THAT IL 17 WHETHER THIS LAB
INCREASE MANY THE BRAIN OR IN
THE PERIPHERY, THEN YOU HAVE
THIS MITIGATION OF BEHAVIOR
PHENOTYPE WHICH IS INCLUDE
SOCIAL ABILITY. SO THE QUESTION
IS, WHY IL 17? WHAT IS SPECIFIC
ABOUT IL 17? I GAVE A LOT OF
THOUGHT ABOUT THIS FROM THE NEXT
FEW SLIDES I WANT TO SHOW YOU
ANOTHER DATA FROM MY OWN
PERSONAL THOUGHTS. SO I WANT
HEAR YOUR (INAUDIBLE). SO WHEN I
FIRST THINK ABOUT IL 17 THIS IS
INTERLEUKIN-17. i, I BEGIN TO
WONDER OF COURSE WHENEVER I WANT
TO SEEK ANSWER THE FIRST THING I
DO IS RELY ON GOOGLE SO I WONDER
WHAT INTERLEUKIN IS. I CHECK
THIS DEFINITION AND IT SAYS A
GROUP OF CYTOKINES EXPRESSED AND
SECRETED BY WHITE BLOOD CELLS.
AND THEN THE QUESTION IS, OKAY
WHAT ARE THE CYTOKINES? I CHECK
AGAIN THE GLOSSARY AND CYTOKINE
IS ANY FORM OF SUBSTANCES SUCH
AS INTERLEUKIN AND GROWTH FACTOR
SECRETED BY CERTAIN CELLS OF THE
IMMUNE SYSTE SYSTEM. SO INTERLES
CYTOKINE AND CYTOKINE IS
INTERLEUKIN. SO I WONDER
CYTOKINE KIND OF UNDERSTANDING
WHERE IT CAME FROM BUT WHAT
ABOUT INTERLEUKIN? COULD BE
CULTURAL BARRIER, SO PLEASE
EXCUSE ME. I FOUND ON GOOGLE AN
ARGUE SAYING THAT WILL IS A
SWITCH AROUND, SOME OF YOU MAY
HAVE BEEN THERE, I NEVER HEARD
THE TERM. EXCUSE MY POOR
PRONUNCIATION. THE CITY, AND I
GUESS THIS IS LIKE A LAKE. YOU
SEE A CITY BETWEEN TWO LAKES.
THAT IS WHY IT IS CALLED THE
INTERLAKEN. APPARENTLY THE
INTERLEUKIN FAMILY IS NAMED
AFTER LOCATION ENCOMPASSING
(INAUDIBLE) 1973. HOW WE START
TO CALL IMMUNE SECRETED IN SIGHT
COIN INTERLEUKIN ACCORDING TO
THIS. SO AGAIN, I'M OPEN TO
CORRECTION ON PRONUNCIATION.
YESTERDAY, OUR LAB -- MY THOUGHT
PROCESS, WHENEVER I THINK ABOUT
INTERLEUKIN YOU THINK
INTERLEUKIN-17 SO IMMUNE RELATED
RIGHT? SO I NEXT THING YOU KNOW
I WENT TO TEST, THE STRUCTURE,
FAMOUS CYTOKINE, STRUCTURE THEN
LIKE A PIONEER HERE SITTING
THROUGH BUT THESE CELL SIGH COIN
RECEPTOR, WITH THE RECEPTOR
CASCADE THROUGH LEAD TO
ACTIVATION OF JAK STAT PATHWAY.
SO THIS IS A REALLY -- THAT'S
KIND OF CYTOKINE. RIGHT? SO THEN
(INAUDIBLE) STRUCTURE PROCESS
DIMER SOME MONOMER, SOME
CYTOKINE DIMER BUT IF YOU LOOK
AT IL 17 THIS IS JUST IL 17.
DIMER, STRUCTURE AND THE
STRUCTURE I CHECK THIS EARLIER
WORK. BY THE WAY THIS DOWN
SIGNALING NF KAPPA B. THEN WHEN
I LOOK AT THE OLD LITERATURE,
CHILDREN AND OTHER GROUP SHOW
THE STRUCTURE IS OFTEN FOUND IN
PROTEIN FAMILY CALLED NEURAL
GROWTH FACTOR KNEW TROPHIN. I
DON'T HAVE BACKGROUND IN
STRUCTURAL BIOLOGY BUT USE FROM
OTHER CYTOKINE AND DOWNSTREAM
SIGNALING FROM OTHER CYTOKINES.
SO THIS IS OUR PAPER. THAT
ACCORDING TO IL 17 SOCIAL
ABILITY IN MOUSE MODEL FOR
AUTISM. THEN SO LIKE AROUND THE
SAME -- LIKE A YEAR, TWO YEAR
LATER, THE GROUP AT CORNELL --
WEILL CORNELL UNIVERSITY, HE
FOUND IL 17 INCREASE SOCIAL
ABILITY IN WILD TYPE MICE. SO
THIS CONFIRMED EARLIER WORK. BUT
THERE IS ALSO A GROUP THAT EVEN
OLDER THAN US, SO IN 2017, GROUP
IN UK, THEY STUDY C ELEGANS.
THEY DID FOUR GENETIC SCREEN TO
IDENTIFY MOLECULE THAT INHIBIT
-- DUE TO NATURE OF THIS THE
LEVEL OF OXIDANT AVAILABLE --
PHOTO AVAILABILITY C ELEGANS
SOMETIMES KIND OF GROUPED
TOGETHER, SOMETIMES INDIVIDUAL
MOVE AROUND. RIGHT? SO THEY DID
UNBIASED FOUR GENETIC SCREEN AND
THEY WERE ABLE TO IDENTIFY IL 17
AND IL 17 CENTER OF A KEY
MOLECULE THAT INCREASE
(INAUDIBLE) IN C ELEGANS. THEY
SHOW IL 17 REACC RECEPTOR EXPREG
IN NEURONS THAT PROMOTE
AGGREGATION BEHAVIOR. THEY SHOW
THAT IL 17 LIGAND CAN PROMOTE
PHENOTYPE AS WELL. SO VERY
EXCITING, OTHER GROUP
(INAUDIBLE) MORE REASON TO ME
WAS THAT IF YOU THINK ABOUT IT C
ELEGANS THEY DON'T HAVE
(INAUDIBLE). SO WHEN WE THINK OF
IL 17 INTERLEUKIN 17, IT IS THE
CYTOKINE THAT PRODUCED BY
T-CELL, T 77 TH 3 IL 17. THOSE
CELLS DON'T (INAUDIBLE) C
ELEGANS BUT EVEN SO C ELEGANS
NOT ONLY HAVE IL 17 BUT USING
NEURAL MODULATOR. AND IL 17 IS
ONE THOSE AGING CYTOKINE MUCH
EARLIER IN DEVELOPMENT THAN
INTERFERON GAMMA. SO THIS DATA
TO MANY E SUGGESTS THAT IL 17
COULD HAVE EVOLVED AS A NEURAL
MODULATOR THAT REGULATORS
AGGREGATION BEHAVIOR SOCIAL
BEHAVIOR PHENOTYPE, (INAUDIBLE)
FOR WHATEVER REASON IMMUNE CELLS
FOR OTHER PURPOSES SO JUST MY
IDEA. SO THIS IS GOING BACK TO
SOME DATA, RIGHT? SO WE THEN
BEGAN WONDERING HOW IL 17
ENHANCE SOCIAL ABILITY? IN ORDER
(INAUDIBLE) ON THIS INVASIVE
TECHNIQUE, WHERE TO TREAT THE
WHOLE BRAIN WE HAVE TO INTRODUCE
(INAUDIBLE) TO THE BRAIN, SO
MANY INVASIVE -- SO IT IS NOT
EASY TO DO THAT, VERY ROUTINE SO
WE WANTS TO TEST AND UNDERSTAND
THIS ROLE MECHANISM WHICH
(INAUDIBLE) SOCIAL ABILITY, WE
NEED TO COME UP WITH DIFFERENT
METHOD TO ACHIEVE THE SAME GOAL,
INCREASE (INAUDIBLE) IN THE
BRAIN BASICALLY. SO MY
(INAUDIBLE) CAME UP WITH THIS
IDEA. WHAT IF WE JUST
(INAUDIBLE) ITALY? THERE'S
(INDISCERNIBLE) TO THE BRAIN,
MANY SMALL MOLECULE AND ANTIBODY
PRETTY SURE THOSE ARE
(INAUDIBLE) GET TO CNS.
INITIALLY SHE TOLD ME THAT, I
SAID NO, DON'T DO THAT, IT IS
NOT GOING TO WORK. BUT LIKE MANY
OTHER GOOD POST DOC SHE DIDN'T
LISTEN TO ME. INTRODUCE THE IL
17 SHE SHOWED ME THE BIAS IN IL
17 SAID COME ON SHE WASN'T
DISCOURAGING I (INAUDIBLE) BACK
ON MICE AND IL 17 AND EVEN IN
THE CASE OF (INDISCERNIBLE) IN A
CORE TEST THERE IS INCREASE OF
(INAUDIBLE) IN THE CORTICAL
ASSAY. AND THEN WHAT TYPE OF IN
VITRO, THAT IS JUAN WAY TO MAKE
SOCIAL ABILITY, ANOTHER WAY IS
DOING THE SOCIAL INTERACTION.
PUTTING TUMORS -- MEASURING TIME
SPENT WITH EACH OTHER QUANTIFY
SOCIAL BEHAVIOR PHENOTYPE.
CONTROL MICE GOOD ITERATION, MY
MICE NOT SO GOOD INTERACTION.
THEN WHEN (INDISCERNIBLE) GIVE
INCREASE INTRANASALLY SHE WAS
ABLE TO DETECT INCREASE SOCIAL
-- THIS INCREASE FOUR TO EIGHT
HOURS AND THEN THEY WENT BACK TO
THIS BASELINE. SO NOW FINALLY WE
HAVE A SYSTEM THAT ALLOW US TO
INTRODUCE IL 17 OR INCREASE INTO
THE BRAIN. WHAT DO WE DO NEXT?
SO THEN WE DECIDE TO ASK, OKAY,
HAVING IL 17 THERE, PEOPLE TALK
ABOUT A AN F, MOST CASES BUT YOU
CAN GET THE LITERATURE THEY ARE
LIKE (INAUDIBLE) LIGAND. FIVE
DIFFERENT IL 17 SUB UNIT. EACH
SUB UNIT IN THE FORM MULTI-LAYER
COMPLEX, TWO DIFFERENT SUB UNIT
THE MOST FAMOUS IL 17 IS 17A
COMPLEX INITIAL SIGNAL BUT THERE
ARE MANY OTHER LIGANDS. SO WE
DECIDE TO TEST THEM ALL. WHICH
ASSAY ENHANCE SOCIAL ABILITY? SO
TO MAKE LONG STORY SHORT WE CAN
DETECT IL A, B, F RESCUE SOCIAL
ABILITY DEFICIT. NOT ONLY SO,
THIS ABEF SOCIAL ABILITY GOES TO
MITIGATE THE BEHAVIOR PHENOTYPE
SO TWO COURSE ALTERNATIVE CAN BE
WITH OR -- ADDITION OF FOUR
DIFFERENT LIGANDS OF BIAS
(INAUDIBLE) SO I JUST TOLD YOU
RESCUE SOCIAL ABILITY STEP ONE,
IF YOU LOOK AT THAT, THEY ARE --
YOU CAN ESSENTIALLY DETECT
DIFFERENT RECEPTOR SUB UNIT, RA
RC AND RB. SO THEN WE NEXT ASK
WE WANTED TO ASK WHERE ARE THESE
RECEPTORS EXPRESSED IN THE
BRAIN? AS SOME OF YOU MAY KNOW,
THE CYTOKINE EXPRESSION
(INAUDIBLE) SO THERE ARE
ANTIBODIES ARE TERRIBLE. DON'T
BUY THOSE ANTIBODIES. THEY
DIDN'T WORK. WE BASICALLY TESTED
THEM ALL. SO THEN IF YOU DO
BASICALLY SPATIAL TRANSCRIPTOME,
YOU GET ALL THE INFORMATION YOU
NEED. THERE'S SO MANY TO
INVOLVE, WE COULDN'T GET THE
RESOLUTION WE WANTED TO ACHIEVE
SO WE DECIDE TO THROUGH THE
PANDEMIC WE SAID OKAY, LET'S
MAKE MICE, JUST USE GENETICS TO
IDENTIFY WHERE THEY THEY ARE
LOCATED SO WE BASED GENETICS ON
(INDISCERNIBLE) BY TRANSFERRING
THE CRE DEPENDENTS BIOSAY TO THE
BRAIN WE BASICALLY ARE ABLE TO
MAP OUT AND KNOW WHERE THEY ARE
LOCATED. SO IF YOU ASK WHERE IS
CYTOKINE EXPRESSED, BEFORE WE DO
THIS EXPERIMENT, THE TRUE
GENERAL ANSWER IS I DON'T KNOW
OR EVERYWHERE. WE START TO LOOK
AT THIS, WELL -- THAT IS NOT THE
CASE. EVERY SINGLE BRAIN,
DIFFERENT EXPRESSION PATTERN.
RA, THERE IS A HIGH EXPRESSION
RB SO SOME THROUGHOUT THE CORTEX
BUT RC WHICH IS LIKE RECEPTORS
IN INCH 90%, THIS IS ALL
NEURONS. ONLY WE JUST TESTED
NEURONAL EXPRESSION. AND REA IS
MORE SPARSE. SO WE THOUGHT THAT
BASED ON THIS DATA, I TOLD YOU
THAT RA RB RC RESCUE, TO
SEPARATE PHENOTYPE BASED ON THIS
LIGAND, SPACING. BASED ON THIS
DATA WE KNOW THE CORTICAL AREA
AROUND HERE IS IMPORTANT FOR THE
SOCIAL RESCUE, BASED ON THIS
DATA WE THOUGHT RA AND RD PLAY A
ROLE BUT NOT RC. THEN WE TOOK
GENETIC -- BEFORE THAT WE
SEQUENCE THAT'S WHY IT IS GREEN,
WE PUT THE DIFFERENT EXPRESSION
NEURONS ARE DISTANT SO THEY HAVE
A DIFFERENT PROGRAM. THEN SO
NEXT WE ASK WHAT HAPPENED WHICH
GENETICALLY REMOVING -- COULD RB
RC RA PREVIOUS ISSUE THAT RA IS
CRITICAL. SO WE HAVE TO
(INAUDIBLE) RC USING, THIS IS
THE MOST NEURONAL CELL WHEN YOU
REMOVE 17A AND 17E DEPENDENT
RESCUE WERE NOT AFFECTED. SO
THIS DATA IS RC IS DISPENSABLE
AND AT LEAST FOR THIS SOCIAL
RESCUE. WHAT ABOUT RB, WHEN HE
YOU REMOVE RB LIGAND RESCUE THIS
PHENOTYPE. THIS DATA SUGGESTS
THAT (INAUDIBLE) RA RB PLAY A
CRITICAL ROLE IN RESCUE, THEN WE
GENERATED ANOTHER MOUSE LINE, IN
DOING SO WE ARE ABLE TO IDENTIFY
(INAUDIBLE) RC -- RB AND RA AND
THEN USING RA CRE MICE ANOTHER
MOUSE WE GENERATED WE CAN INDUCE
RB BASED ON DOUBLE POSITIVE
CELLS, THE RB EXPRESSION WE NO
LONGER SEE RESCUE PHENOTYPE
SUGGESTING THAT THESE CELLS THAT
EXPRESS -- THEY NEED TO EXPRESS
BOTH RA AND RB. TO THIS LIGAND.
AND PRODUCE SOCIAL RESCUE
PHENOTYPE. SO THE QUESTION WE
ARE ASKING SO OKAY RB AND RA ARE
IMPORTANT. BUT HERE WE HAVE A
PROBLEM. I ALREADY TOLD YOU 17A
AND THEN A F E RESCUE THE
PHENOTYPE, RIGHT? CONTAIN THE
SOCIAL ABILITY INDUCE SOCIAL
ABILITY ESTIMATE BUT WE FOUND RB
IS IMPORTANT, NOT RC IMPORTANT
BUT ALL THE DATA OUT THERE
SUGGEST THAT YOU NEED RA AND RC
FOR 17A. SO I TOLD YOU 17A LEADS
TO SOCIAL RESCUE BUT THAT YOU
NEED EXPRESSION OF RC AND
NEURONAL CELL, YOU DON'T NEED RC
-- HOW DOES THIS WORK? HOW DOES
THE RESCUE BECAUSE RC IS NOT
REQUIRED? SO WE HIGH BOTH SIZE
THAT PERHAPS -- HYPOTHESIZE 17A
FUNCTION BASED ON 17E, BASED ON
EVERYTHING I TRY TO SHARE WITH
YOU WE INTRODUCE 17A
INTRANASALLY AND FOUND THAT 17E
ADMINISTRATION LEAD TO
EXPRESSION OF 17E BY mRNA AND
ALSO PROTEIN AS WELL. SO 17A CAN
INCREASE IL 17E AND IL 17E CAN
FUNCTION THROUGH RA RB. SO NEXT
PERSON, OKAY, IF REALLY THE CASE
17A CAN MODULATE NEURAL
ACTIVITY, SO WE DID THE -- WE
MEASURED THE NEURAL ACTIVITY
FROM THE BRAIN AREA IMPORTANT
FOR THIS SOCIAL ABILITY
PHENOTYPE THEN APPLY 17A
COMPARED TO -- THIS IS IMMEDIATE
RESPONSE. WHEN WE ADD 17A OPT
PETRI DISHES WE MEASURE THIS
NEURAL ACTIVITY FROM 17RB
POSITIVE CELL WE CAN SEE IMAGE
OF THIS NEURAL ACTIVITY, FROM
POSITION OF 17A SUGGESTING THAT
17E CAN FUNCTION AS NEURAL
MODULATOR. IN THIS CASE. SO NEXT
QUESTION WE ASKED, OKAY, EVEN IF
THAT IS THE CASE 17A REQUIRES
17A WE PERFORMED AN EPISTATIC
EXPERIMENT. SO IN THIS CASE WE
GENERATED 17A AND THIS
BACKGROUND WHEN WE GIVE 17A OR E
WE ARE ABLE TO SEE SOCIAL
ABILITY PHENOTYPE. HOWEVER THE
SAME EXPERIMENT WITH 17E ON
MICE, 17E WHILE CAN ENHANCE
SOCIAL ABILITY 17 A NO LONGER
DOES THAT. SO THIS DATA
SUGGESTING THAT 17E IS
(INAUDIBLE) TO 17A AND I ALREADY
TOLD YOU 17A CAN ENHANCE 17E.
SO ALL THIS DATA TOGETHER IS
JUST A MODEL THAT 17A
POTENTIALLY ACT IN NON-NEURONAL
CELL WE DON'T KNOW NATURE OF THE
CELL AND LEAD TO INCREASE 17E
AND THIS 17E IN -- RECEPTOR A
AND RECEPTOR B COMPLEX AND IN
DOING SO BRING DOWN INCREASE
HYPERNEURAL ACTIVITY BACK TO
BASELINE, THEN BASICALLY ENHANCE
SOCIAL ABILITY IN THIS ANIMAL
MODEL. THEN WE FOUND THAT
(INAUDIBLE) IL 17A AND E CAN
ENHANCE SOCIAL ABILITY
PHENOTYPE, NOT ONLY SO THIS THIS
CAN BE APPLICABLE TO
DIFFERENTIATED MOUSE MODEL OF
AUTISM, NOT JUST -- DIFFERENT
MOUSE WITH AUTISM, ADDITIONAL
17A OR E SUFFICIENT TO ENHANCE
PHENOTYPE. SO I HOPE THAT I WAS
ABLE TO CONVINCE YOU THAT THIS
PATHWAY TO REGULATORY MECHANISM
CYTOKINE OR IN THIS LIGAND HAD
ABILITY TO CONTROL NEURAL
ACTIVITY, MAY HAVE MORE ANCIENT
FUNCTION. SO BASICALLY WE THINK
AHEAD. WE ARE THINKING ABOUT
IMMUNOTHERAPY FOR THE DISORDER.
CAN WE COME UP WITH A WAY TO
EDUCATE IN CELLS FROM THE GUT IN
VITRO, CAN WE -- IT IS NOT CLEAR
WHETHER (INAUDIBLE) CAN
INFLUENCE CELL BRAIN NEURAL
ACTIVITY ACTUALLY BUT CAN WE
UTILIZE THE (INAUDIBLE) CELL AS
A VEHICLE TO PRODUCE -- TO
IMPACT NEURAL ACTIVITY IN THE
BRAIN AND THEN IN DOING SO
VENOUS CELL CAN ACT AS A SEARCH
BY ENGAGING IN CYTOKINE RECEPTOR
ACTIVITY. SO WE THINK THIS
PATHWAY IS IMMUNE TOE BRAIN
CIRCUIT IS REALLY IMPORTANT AND
I HOPE I'M SURE GLORIA WILL
SHARE WITH YOU SOME OTHER DATA
FOCUSED ON DIFFERENT CYTOKINE
RECEPTORS, TO ATEN THE TALK. SO
BASICALLY SUMMARY. I HAVE
(INAUDIBLE) CYTOKINE MODULATED
BY NEURAL ACTIVITY. WE IDENTIFY
POTENTIAL LIGANDS THAT HAVE SUCH
ACTIVITY, WE MAP OUT THE BRAIN
AREA, THAT EXPRESS DIFFERENT
RECEPTOR SUB UNIT AND THEN WE
ARE ABLE TO SHOW GENETICALLY WE
CHALLENGE RECEPTOR TO PLAY A
ROLE IN MODULATING THE SOCIAL
ABILITY OF PHENOTYPE.
SOCIOIBILITY OF PHENOTYPE. THIS
WORK ESSENTIALLY IS DONE BY --
THROUGH COLLABORATION BY
(INAUDIBLE) IN MY LAB AND --
PUBLISHED THE WORK I SHOW YOU,
THIS IS PEOPLE I WANT TO END, MY
FUNDING SOURCES. THANK YOU VERY
MUCH FOR YOUR ATTENTION. HAPPY
TO TAKE ANY QUESTIONS.
>> THANK YOU VERY MUCH, THAT WAS
REALLY A LOVELY TALK. I DIDN'T
KNOW THAT IL 17 IS A HAPPY HOUR
CYTOKINE. BUT I THINK TIME FOR
QUESTIONS.
>> VERY NICE TALK. THANK YOU. I
WAS WONDERING MAYBE I MISSED
THIS POINT. WHICH SOURCE OR
WHICH SOURCES MIGHT BE FOR IL
17E? BECAUSE IF I REMEMBER
CORRECTLY, I'M MAINLY FOCUSING
ON THE SKIN AND THERE IT IS NOT
HEMATOPOIETIC CELLS.
>> I DIDN'T CARRY THAT BUT
NEURONAL CELL AND NON-NEURONAL
CELLS PRODUCE, THEY ARE
PRODUCING IL 17E IN THE BRAIN
EVEN AT STEADY STATE AND UPON
(INAUDIBLE)
>> THANK YOU.
>> GREAT TALK. THAT WAS REALLY
-- SO IN YOUR AUTISM MODELS, DO
WE SEE DECREASING IL 17A OR
EXPRESSION FOR RECEPTORS AND ANY
IDEA HOW IT CAN BE RELATED?
>> IT IS COMPLICATED OBVIOUSLY.
IL 17 AS MENTIONED I DIDN'T TALK
ABOUT THAT EARLIER WORK BUT IL
17 IN THE MODEL DURING PREGNANCY
CAN PROMOTE PHENOTYPE IN THE
OFFSPRING. THEN THAT IS LIKE A
STRESS PATHWAY WE SHOW THAT IT
IS ENGAGE INDUCE UPR PATHWAY, SO
GETTING BACK TO YOUR QUESTION,
YEAH, I (INAUDIBLE) THE QUESTION
WHETHER LIGANDS PLAY -- HAVE A
PHYSIOLOGICAL FUNCTION TO
MODULATE SOCIABILITY. I WAS ABLE
TO CONVINCE (INAUDIBLE) TO
GENERATE KNOCK ON MICE, REMOVE
ALL LIGAND. SO CAN WE SHOW THAT
A, B, E, PLAY A ROLE AND MOVE
ONLY ONE LIGAND SUFFICIENT TO
INDUCE THE PHENOTYPE, BASED ON
(INAUDIBLE) DATA WE MAY HAVE TO
SEE SOME EFFECT SO SHE IS DOING
MOUSE CROSS -- BUT IT IS MANY
THAT DIFFICULT BECAUSE A AND F
ARE MANY THE SAME LOCI SO IT IS
A TRUE KNOCK OUT. HOPEFULLY I
DON'T KNOW BUT I'M JUST -- MY
GUESS IS MAYBE SEE SOME
PHENOTYPE THERE. HAPPY TO TALK
WITH YOU MORE ABOUT THAT.
>> THANK YOU.
>> VERY INTERESTING TALK. SO MY
QUESTION IS I'M THINKING THE
MECHANISM TO HOW INTERLEUKIN 17
IS GOING TO INCREASE THE
SOCIOIBILITY RATE. DO YOU KNOW
BY CHANCE WHEN YOU KNOCK OUT IL
17 OR RECEPTOR, THERE HAVE BEEN
SOME CHANGES IN THE TRANSMISSION
ACTIVITY? SOME CHANGES IN THE
NEURAL TRANSMISSION ACTIVITY
LIKE SOME NEURONS ESPECIALLY FOR
EXAMPLE SEROTONIN LEVELS SOME
PEOPLE THEY THINK SEROTONIN
LEVELS THAT WHEN THEY BECOME
KNOCK DOWN (INAUDIBLE) ANY OTHER
STUFF. AND I WAS WONDERING IL 17
THAT ALSO WHEN YOU INCREASE IL
17 THAT ALSO INCREASE OR CHANGE
THE LEVELS INTO THE SEROTONIN
ACTIVITY OR RECEPTORS OF
SEROTONIN CHANGED IN YOUR MODEL,
HOW THESE HAS BEEN CHANGED.
>> YEAH. SO WE THINK IL 17 A AND
E FUNCTION AS NEURAL MODULATOR
AND THEN AS TO -- VERY IMPORTANT
HOW THIS NEURAL MODULATOR WORK
BY INFLUENCING NEURAL TRANSM
TRANSMITTER IT IS NOT WELL UN.
SO WE DON'T KNOW BUT IF YOU -- I
OFTEN USE THIS (INAUDIBLE)
OXYTOCIN AS AN EXAMPLE, THOUGH
OXYTOCIN HAS BEEN STUDIED MANY,
MANY YEARS, THEY ARE -- CRITICAL
NEURAL MODULATOR BUT HOW THEY
WORK IS STILL NOT CLEAR SO TELL
YOU THAT UNDERSTANDING THE
MOLECULAR MECHANISM BY WHICH
NEURAL MODULATOR WORKS.
>> THEY DIDN'T CHECK THE LEVELS
IN THE KNOCK OUT MODELS? YOU
MENTION SOMETHING ABOUT THE
ACTUAL POTENTIAL HOW THAT IS
IMPROVED SO THAT TELL YOU HOW
MANY (INAUDIBLE) IS GOING ON.
>> COULD BE -- SO MANY, SO MANY
CANDIDATES WE HAVEN'T CHECKED
THEM.
>> THANK YOU.
>> THANK YOU VERY MUCH FOR THE
INTERESTING TALK. SO I HAVE A
QUESTION, THE SMALL MOLECULE
IDENTIFY FOR INHIBITING R GAMMA
P FUNCTION. R GAMMA P IS NOT THE
ONLY PH 17 SO I HAVE TWO
QUESTIONS BUT BASED ON THIS. THE
FIRST ONE IS (INAUDIBLE) LIKE RC
3 IL 17 IS ALSO INHIBITED AND
THE SECOND ONE IS R GAMMA T IS
ALSO EXPRESSED IN (INAUDIBLE)
FOR SURVIVAL OF THE CELLS SO
WONDERING IF YOU GIVE MORE
INHIBITOR MOLECULAR IF CYTOKINE
ALSO AFFECTED?
>> HAVING THE SYSTEM OURSELVES
PREVIOUSLY SHOW R GAMMA
INHIBITOR CAN ALSO SUPPRESS ILC
3 FUNCTION AND THEN MANY
(INAUDIBLE) STARTED A CLINICAL
TRIAL WITH INHIBITOR AND THEY
STOPPED THE TRIAL BECAUSE OF THE
DEVELOPMENT OF MELANOMA, ABOUT
DOUBLE IN -- THAT HAPPEN DURING
THE TIME SITE DEVELOPMENT SO FOR
R GAMMA INHIBITOR, POST DOC
APPOINTED CELL IN ILC 3 SEEM TO
BE AFFECTED BUT WHETHER OR NOT
THE BIAS (INAUDIBLE) INFLUENCE
THE SAME WE HAVEN'T TESTED THAT.
>> THANK YOU.
>> HI. SO AUTISM IS CORRELATED
WITH A NUMBER OF AUTOIMMUNE AND
ALLERGIC DISEASE INCLUDING
PSORIASIS WHICH IS 17 MEDIATED.
I'M WONDERING YOUR THOUGHTS ONE
ON POSSIBLE CAUSATION IN TERMS
OF WHY THESE MIGHT COME TOGETHER
BUT ALSO THIS MIGHT LIMIT
UTILITY OF THIS AS THERAPEUTIC.
IF YOU HAVE PEOPLE ALREADY
EXCESSIVE 17 PATHWAY.
>> RIGHT. I THINK PARTICULARLY
DURING PREGNANCY, ALLERGIC
RESPONSE THERE IS A PAPER
SHOWING THAT'S SOME CORRELATION
AND THEN SOME PSORIATIC PATIENT
HAVE DEVELOPED AWE TIM SYMPTOMS
SO WHETHER OR NOT -- SO WE DON'T
KNOW, SHORT ANSWER WE DON'T KNOW
BUT IN TERMS THERAPEUTICS,
(INAUDIBLE) INDICATED AND OTHERS
SHOW THAT INCREASE IL 17 ALONE
IS NOT -- NOT REALLY
INFLAMMATORY. NOT INFLAMMATORY.
WHEN I PRESENT WAY OTHER
CYTOKINES INTERFERON GAMMA
(INAUDIBLE) INFLAMMATION. SO I
THINK YOUR QUESTION THERE ARE
(INAUDIBLE) FIRST I DON'T KNOW,
SECOND MAYBE.
>> THANK YOU.
>> THAT WAS A GREAT TALK. SO THE
IL 17 IN RESPONSE TO INFECTION
OR PRESUMABLY THAT'S PERIPHERAL
IL 17. THAT HAS TO GO INTO THE
BRAIN. DOES THAT PASS THROUGH
BLOOD BRAIN BARRIER EASILY?
>> WHEN THE CYTOKINES GET
INDUCED IN THE CONTEXT OF
INFLAMMATION, THIS IS LIKE ONE
THING THAT FIELD PEOPLE NOTICE
FOR MANY, MANY YEARS BUT STILL
IS NOT CLEAR NOBODY UNDERSTAND
MOLECULAR MECHANISM WHICH IS
WHEN YOU GIVE MICE WITH APS
EXPOSE MICE WITH VIRAL INFECTION
THERE IS TEMPORALLY INCREASE
PERMEABILITY IN THE BBB. SO YOU
ARE INDUCING INFLAMMATION, GIVE
SOME TIME THEN YOUR BRAIN MOUSE
BRAIN IS TURN BLUE. SO THIS
INFLAMMATION HAS AN AMAZING
ABILITY TO INCREASE
PERMEABILITY. THAT IS A GOOD
REASON FOR THAT. BECAUSE THAT IS
WHAT THAT NEED TO HAPPEN DURING
INFLAMMATION WHEN INUNDATED BY
INFECTION. SO IN THAT CONTEXT,
INFLAMMATORY CONTEXT I
ABSOLUTELY (INAUDIBLE) IN THE
BRAIN MECHANISM.
>> LAST QUESTION. THANK YOU FOR
THAT TALK. THAT WAS AWESOME. SO
I JUST HAD A QUESTION ON THE
MATERNAL IMMUNE ACTIVATION
MODEL. WHEN YOU CHALLENGE WITH
POLYIC AND THEN LATER SEE AUTISM
PHENOTYPE MANY THE OFFSPRING, DO
YOU THINK THERE'S ANY
COMMONALITY TO THE ANTIGEN
RESTRICTION TO THE TH 17 CELLS
GENERATED IN THE OFFSPRING?
PERHAPS LIKE TWO POLYIC BECAUSE
I KNOW REACH TOUT LPSO, ANY
CORRELATION FOR THE ANTIGEN
RESEARCH OF THOSE T-CELLS?
>> WE DON'T KNOW. SO I MEAN, WE
CAN INDUCE SIMILAR PHENOTYPE BY
TRANSPORTING T-CELL MICE DURING
PREGNANCY. SO TCL NOT
NECESSARILY (INAUDIBLE) BUT
WHETHER -- WE ALSO DETECT --
OFFSPRING SIDE THERE ARE SECOND
CHALLENGE IT BUT WHETHER OR NOT
THIS -- CHANGE IN TISSUE THAT
PUTS FORWARD -- AND THIS ISSUE
DIFFERENCE IMMUNE (INAUDIBLE)
DURING PREGNANCY CAN INDUCE
CHANGES IN OFF SPRIEST MT.
SYSTEM. SO I THINK DOSE
DEPENDENT ON PATHOGEN, LIKE
ANTIGENS, IT IT IS NOT --
>> THANK YOU VERY MUCH. SO I SAW
THAT STORY GOT PRESENTED AS
SUBMITTED SO MAYBE WE CAN SEND
SOME FLOWERS FOR IL 17,
CHOCOLATE COATED WITH IL 17.
GOOD LUCK WITH YOUR STORY. THANK
YOU, EVERYONE FOR COMIN COMING
[APPLAUSE]