>> GOOD MORNING, EVERYONE.
IT'S PAST 1:00 P.M. SO DR. KOOB
WILL CALL THE MEETING TO ORDER.
>> SO, GOOD AFTERNOON, EVERYONE.
I WOULD LIKE TO WELCOME YOU ALL
TO THE 169TH MEETING OF THE
NATIONAL ADVISORY COUNCIL ON
ALCOHOL ABUSE AND ALCOHOLISM.
I'M GOING TO CALL ON EACH
COUNCIL MEMBER.
NANCY GONZALEZ IS NOT ABLE TO
JOIN US.
LEY
LEYDEN.
DAVID.
>> INDIANA UNIVERSITY SCHOOL OF
MEDICINE DEPARTMENT OF NEUROLOGY
AND DIRECTOR OF OUR ALCOHOL
RESEARCH CENTER HERE.
>> DAVID SENT ME AN E-MAIL NOT
TOO LONG AGO ABOUT A WEEK OR SO
AGO AND HE HAS BEEN AWARDED A
FULL RIDE FELLOWSHIP TO STUDY IN
FRANCE, ALCOHOL.
HE'LL BE WORKING WITH LAURA
HASAN AT THE UNIVERSITY OF
STRASBURG AND FLORENCE WARSPA IN
PARIS.
>> CONGRATULATIONS.
>> THANK YOU.
>> FRANCIS, ARE YOU ON?
>> YES, I AM.
HOW ARE YOU?
FRANCIS LEVIN AT THE NEW YORK
STATE PSYCHIATRIC INSTITUTE AND
ALSO COLUMBIA UNIVERSITY MEDICAL
CENTER AND CHIEF OF THE DIVISION
ON SUBSTANCE USE DISORDERS AND
GLAD WE'RE MEETING.
>> WE ARE TOO, FRANCES.
GREAT TO SEE YOU.
MICHAEL.
>> I'M MICHAEL LEWIS PROFESSOR
OF PSYCHOLOGY AT HUNTER COLLEGE
AND THE GRADUATE SCHOOL OF CITY
UNIVERSITY OF NEW YORK.
>> THANKS, MICHAEL.
DAYNE.
>> I'M ALSO GLAD YEAR ABLE TO
MEET.
I'M AT THE UNIVERSITY OF TEXAS
AT AUSTIN AND WITH THE WAGNER
CENTER FOR ALCOHOL AND ADDICTION
RESEARCH AND THE DEPARTMENT OF
NEUROSCIENCE.
>> THANKS.
I'M THE DIRECTOR GEORGE KOOB OF
THE NATIONAL INSTITUTE ON
ALCOHOL ABUSE AND ALCOHOLISM.
I'LL GO THIS DIRECTION.
SO TRISHA IS NEXT.
>> DEPUTY DIRECTOR OF NIAAA.
GLAD TO SEE EVERYONE.
>> GOOD AFTERNOON, EVERYONE I'M
KATHY YOUNG THE DIRECTOR OF
DIVISION OF METABOLISM AND
HEALTH S IN NIAA.
>> I'M REPRESENTING THE DIVISION
OF NEUROSCIENCE AND BEHAVIOR,
MARK EGLI, NIAAA.
>> I'M ACTING CHIEF OF THYROID
DISORDERS AT THE NIAAA.
>> I'M LAURA CHIEF OF THE
RECOVERY BRANCH AND ACTING
DIVISION DIRECTOR OF TREATMENT
AND RECOVERY AT NIAAA.
>> I DIRECT EPIDEMIOLOGY AND
PREVENTION RESEARCH AT NIAAA.
>> GOOD AFTERNOON.
I'M PHILIPPE MARMILLOT DIRECTOR
OF EXTRAMURAL ACTIVITIES AT
>> OKAY.
SO THIS IS GOING TO BE MY
DIRECTOR'S RECORD OF REPORT FOR
THE 169th MEETING OF THE NIAAA
NATIONAL ADVISORY COUNCIL.
WE HAVE SOME SAD NEWS AND A
LITTLE BIT MORE SAD NEWS BECAUSE
I'M GOING TO TALK ABOUT A NUMBER
OF PROMINENT PEOPLE WHO'VE
PASSED TO THE OTHER SIDE AND THE
NUMBER OF PEOPLE THAT RETIRED
THIS YEAR.
SO WE'RE GOING TO GO THROUGH
THAT FIRST AND THEN I'LL TELL
YOU ABOUT SOME EXCITING RESEARCH
AT THE END.
SO WE LOST WARREN BICKELL.
MANY KNEW OR KNOW OF WARREN.
HIS CAREER WAS CHARACTERIZED BY
A WONDERFUL BLEND OF
PRODUCTIVITY AND INNOVATION IN
THE FIELD OF ADDICTION AND HELD
POSITIONS AT THE ALBERT EINSTEIN
COLLEGE OF MEDICINE AND
UNIVERSITY OF VERMONT AND
VIRGINIA TECH.
HIS RESEARCH ACCOMPLISHMENTS
INCLUDING DEVELOPING
BUPRENORPHINE AS THE MEDICATION
FOR THE TREATMENT OF OPIOID USE,
APPLYING BEHAVIORAL ECONOMICS TO
THE STUDY OF ADDICTION AND
STARTING A SEMINOLE ADDICTION
RECOVERY REGISTRY.
HE WAS A GREAT RESEARCHER AND
CONTRIBUTOR TO THE FIELD AND THE
ALCOHOL FIELD AS WELL.
WE ALSO LOST FLOYD BLOOM.
HE HAD A LONG AND DISTINGUISHED
CAREER INCLUDING MAJOR ADVANCES
IN THE FIELD OF NEUROSCIENCE.
HE WAS ONE OF THE FIRST TO
PROVIDE EVIDENCE THAT SIGNALLING
IN THE BRAIN MAY BE CHEMICAL AS
WELL AS ELECTRICAL AND
IDENTIFIED CIRCUITS IN THE BRAIN
AND DIRECTOR OF THE ARTHUR
VINING CENTERS AT THE SALK AND
AT SCRIPPS RESEARCH INSTITUTE
LOOKING AT WHERE DRUGS PRODUCES
ITS EFFECTS AT THE CELLULAR AND
SYSTEMS LEVEL.
HE WAS MY BOSS FOR 40 YEARS.
HE RECRUITED ME TO THE SALK
INSTITUTE AND MOVED WITH HIM TO
SCRIPPS RESEARCH.
FLOYD WAS ONE OF THE MOST
PREEMINENT NEUROSCIENCE -- NEURO
SCIENTIST AND FORMER PRESIDENT
OF THE SOCIETY FOR NEUROSCIENCE
EARLY ON AND CO-FOUNDER OF A BIO
TECHNOLOGY COMPANY THAT ,
MANUFACTURES AND COMMERCIALIZES
MEDICINES FOR THE TREATMENT OF
CHRONIC DISEASES AND THAT
COMPANY PRODUCED MANY LONG
ACTING DRUGS INCLUDING THE
MALTREXONE USED FOR TREATMENT
DISORDER AND WE ALSO LOST
CHARLO
CHARLOTTE BOETTIGER.
SHE WAS THE PROFESSOR OF
NEUROSCIENCE AT THE ALCOHOL
RESEARCH CENTER AND SHE USED A
VARIETY OF APPROACHES TO EXAMINE
ASSISTIVE LEARN AND SELECTION
BIAS FOR IMMEDIATE AWARDS AND
RETENTION TOWARDS
ALCOHOL-RELATED INFORMATION.
SHE WAS A HIGHLY PRODUCTIVE
RESEARCHER AND STRONG ADVOCATE
FOR ALCOHOL RESEARCH.
WHERE HE ALSO LOST JAN FROEHLICH
A PROFESSOR OF THE INDIANA
UNIVER
UNIVERSITY.
AND SERVED AS THE SCIENTIFIC
CO-DIRECTOR OF THE ALCOHOL
RESEARCH CENTER IN INDIANA
UNIVERSITY SCHOOL OF MEDICINE.
SHE DEDICATED HER CAREER TO
UNDERSTANDING HOW ALCOHOL AFFECT
THE BRAIN AND HOW ADDICTION AND
ALCOHOL USE DISORDER DEVELOP.
SHE STUDIED THESE QUESTIONS
THROUGH THE LENS OF HORMONAL,
NEUROCHEMICAL AND GENETIC
FACTORS AND WORKED TOWARDS THE
DEVELOPMENT OF PHARMACO
THERAPIES FOR ALCOHOL USE
DISORDER.
I KNEW JAN QUITE WELL.
SHE WAS A REMARKABLE PERSON
BECAUSE SHE ALWAYS TOLD YOU WHAT
SHE THOUGHT AND YOU COULD DEPEND
ON HER FOR THOSE OPINIONS.
AND MARTIN KENT TRUSTY WAS
BEFORE MY TIME, I KNOW THAT'S
HARD TO BELIEVE.
HE WAS NIAAA'S EXECUTIVE OFFICER
FOR 29 YEARS GUIDING THE
ADMINISTRATIVE AND MANAGEMENT
AFFAIRS UNTIL HE RETIRED IN
1999.
AFTER RETIRING, NIAAA
ESTABLISHED AN ANNUAL
MERITORIOUS AWARD IN HIS NAME
HONORING HIS LEADERSHIP AND
CONTRIBUTIONS.
IT'S GIVEN EACH YEAR TO A STAFF
MEMBER IN RECOGNITION OF THE
OUTSTANDING COMMITMENT TO AND
EXCELLENCE IN MANAGEMENT OF
NIAAA.
IT'S ONE OF MY FAVORITE AWARDS
BECAUSE IT AWARDS INDIVIDUALS
WHO DON'T NECESSARILY GET THAT
KIND OF RECOGNITION IN OUR
ENTERPRISE.
RETIREMENTS.
RAYE LITTEN RETIRED AFTER ALMOST
40 YEARS OF FEDERAL SERVICE WITH
THE LAST 36 YEARS SPENT AT
NIAAA.
HE HAD MAJOR IMPACT ON THE
MEDICATIONS DEVELOPMENT FIELD
INCLUDING THE CREATION OF THE
NIAAA CLINICAL INVESTIGATIONS
GROUP.
A HIGHLY SUCCESSFUL PROGRAM
DESIGN TO TEST THE SAFETY AND
EFFECTIVENESS OF PROMISING
COMPOUNDS TO TREAT ALCOHOL USE
DISORDER AND PROOF OF CONCEPT
PHASE 2 CLINICAL TRIALS.
HE SPEARHEADED THE ADVANCEMENT
OF TWO U.S. FOOD AND DRUG
ADMINISTRATION APPROVED OUTCOME
MEASURES, USED IN MEDICATION
DEVELOPMENT TRIALS.
DR. LITTEN WAS ALSO INSTRUMENTAL
IN THE DEVELOPMENT OF NIAAA'S
RECOVERY, DEFINITIONS AND
DEVELOPMENT OF NIAAA HEALTH CARE
PROFESSIONALS CORE RESOURCE ON
ALCOHOL.
IN ADDITION TO HIS MANY
ACCOLADES AND ACHIEVEMENTS HE'LL
BE TRULY MISSED AS ABLE
EXTRAORDINARY MENTOR, LEADER,
SCHOLAR AND COLLEAGUE.
WE WISH HIM ALL THE BEST UP HIS
RETIREMENT.
ANTONIO NURONA RETIRED AS THE
DIRECTOR OF NEUROSCIENCE AND
BEHAVIOR.
HE HAD 35 YEARS OF FEDERAL
SERVICE.
DURING HIS TENURE AT NIAAA HE
TRANSFORMED NEUROSCIENCE
RESEARCH BY INTRODUCING NEW
DOMAINS OF RESEARCH THAT OPENED
THE DOOR FOR NEUROSCIENCE FOR
DIAGNOSIS, PREVENTION AND
TREATMENT OF ALCOHOL MISUSE AND
ALCOHOL USE DISORDER.
THESE EFFORTS CULMINATED IN A
WIDE RANGE OF ADVANCEMENTS IN
ALCOHOL RESEARCH AND TRAINING
PROGRAMS AND INITIATIVES
INCLUDING THE COLLABORATIVE
STUDIES ON THE GENETICS OF
ALCOHOLISM.
THE INTEGRATIVE NEUROSCIENCE
INITIATIVE AND THE NATIONAL
CONSORTIUM ON ALCOHOL, NEURO
DEVELOPMENT AND ADOLESCENCE AND
ADULTHOOD AND THE CONSORTIUM ON
THE NEUROBIOLOGY OF ADOLESCENT
DRINKING AND ADULTHOOD, AND THE
ADOLESCENT BRAIN COGNITIVE
DEVELOPMENT STUDY, THE ABCD
STUDY PART OF OUR EFFORT.
WE'LL BE TALKING ABOUT THAT
TOMORROW.
SO WE WISH HIM ALL THE BEST FOR
HIS RETIREMENT.
THE LIST GOES ON QUITE A LONG
WAYS AS MANY OF YOU PROBABLY
FIGURED OUT.
SO SO I'M GOING TO GO THROUGH
THESE LISTS BECAUSE I'D LIKE TO
HONOR THE THAT DID WORK AND
SERVE WITH US AT NIAAA.
GREGORY BLOS WAS A PUBLIC HEALTH
ANALYST AND PROGRAM OFFICER IN
THE DIVISION OF EPIDEMIOLOGY AND
PREVENTION RESEARCH.
HE RETIRED AFTER ALMOST 33 YEARS
OF FEDERAL SERVICE.
HE OVERSAW PROJECTS THAT
EVALUATED HOW ALCOHOL POLICY
IMPLEMENTATION INFLUENCE ALCOHOL
DRINKING AT THE STATE AND LOCAL
LEVEL AND LED EFFORTS ON THE
ALCOHOL POLICY INFORMATION
SYSTEM.
A VALUABLE TOOL TO EVALUATE THE
IMPACT OF STATE POLICIES ON
ALCOHOL MISUSE AND RELATED
CONSEQUENCES.
AN INVENTORY SPECIALIST AFTER 27
YEARS WITH THE CLINICAL AND
BIOLOGICAL RESEARCH AND
ADMINISTRATIVE SERVICES BRANCH.
A COMPUTER SPECIALIST IN THE
LAST YEARS WE HAD RESEARCH
PROGRAMS.
AN ADMINISTRATIVE OFFICER IN THE
ADMINISTRATIVE SERVICES BRANCH
RETIRED AFTER 30 YEARS OF
SERVICE AT NIAAA.
SHE SERVED IN MULTIPLE ROLES
WITHIN THE BRANCH.
A TRAVEL SPECIALIST IN THE NIAAA
OFFICE OF THE DIRECTOR RETIRED
AFTER 19 YEARS OF FEDERAL
SERVICE.
SHE JOINED NIAAA IN 2014.
SHE TOOK CARE OF ALL MY TRAVEL
IN ALL THESE 11 YEARS I'VE BEEN
AT NIAAA AND NEVER ONCE LEFT ME
STRANDED OR WITHOUT A HOTEL ROOM
AND I DON'T THINK I EVEN HAD A
DELAYED FLIGHT SO BLESS YOU.
MICHAEL TODD KING IN THE OFFICE
OF INTEGRATIVE NEUROSCIENCE IN
THE DIVISION OF INTRAMURAL
CLINICAL AND BIOLOGICAL RESEARCH
RETIRED AFTER ALMOST 33 YEARS OF
FEDERAL SERVICE.
HE PREVIOUSLY WORKED WITH
DR. BEACH IN THE LABORATORY ON
METABOLIC CONTROL.
KIMBERLY MARTIN, A TECHNICAL
WRITER AND EDITOR IN THE OFFICE
OF SCIENCE POLICY AND
COMMUNICATIONS IS RETIRING AFTER
18 YEARS TO NIH OVER ALL AND
WROTE AND EDITED NIAAA
RESOURCES, SOCIAL MEDIA CONTENT
AND OTHER MATERIALS AND WAS THE
LEAD FOR DEVELOPING NIAAA SHORT
TAKE VIDEO SERIES.
A COMPUTER SCIENTIST WESTBOUND
THE INFORMATION TECHNOLOGY
BRANCH IN THE DIVISION OF
INTRAMURAL AND CLINICAL
BIOLOGICAL RESEARCH RETIRED
AFTER ALMOST 33 YEARS OF FEDERAL
SERVICE.
SHE PERFORMED DATA ANALYSIS FOR
THE NIAAA CLINICAL PROGRAM AND
PREVIOUSLY WORKED AT NIAAA
INTRAMURAL LABORATORIES AND WE
HAVE ANOTHER RETIREE AFTER 16
YEARS AND COORDINATED NIAAA
GREEN BANK ACTIVITIES AND SERVED
IN THE JOINT ADDICTION AND
MENTAL AGING DATA ACCESS
COMMITTEE.
WE HAVE ANOTHER RETIREE.
FOLLOWING HER TIME AS A STAFF
SCIENTIST IN THE SECTION ON
LIVER BIOLOGY SHE JOINED THE
DIVISION IN 2006.
AND SHAPED A ROLE IN THE
ASSOCIATED HEPATITIS NETWORK
WHICH HAS HAD AND CONTINUES TO
HAVE BROAD IMPACTS ON THE FIELD
OF LIVER DISEASE AND CLINICAL
PRACTICE.
GREGORY ROA IN THE OFFICE OF
SCIENCE POLICY AND
COMMUNICATIONS RETIRED AFTER
MORE THAN 18 YEARS WITH NIAAA
AND ORGANIZED OUTREACH EFFORTS
AND KEY TO A WIDE RANGE OF NIAAA
COMMUNICATION ACTIVITIES
INCLUDING WEBSITES, THE ALCOHOL
TREATMENT NAVIGATOR, SPECTRUM
AND THE NIH RECORD.
BRENDA ROBERTSON A PROGRAM
SPECIALIST IN THE DIVISION OF
INTRAMURAL CLINICAL AND
BIOLOGICAL RESEARCH RETIRED
AFTER 33 YEARS IN FEDERAL
SERVICE.
SHE SERVED MANY ROLES FOR THE
INTRAMURAL RESEARCH PROGRAM
THROUGHOUT HER CAREER RECENTLY
IN PROCUREMENT.
AND A STATISTICIAN IN BIO METRIC
IN THE DIVISION OF INTRAMURAL
CLINICAL AND BIO MEDICAL
RESEARCH RETIRED AFTER 33 YEARS
OF FEDERAL SERVICE.
AND MARY ELLIS SHIRLEY RETIRED
FROM FEDERAL SERVICE AFTER
JOINING NIAAA IN 2022 AND NIH IN
2022 AND NIAAA IN 2006 AND
OVERSAW GRANTS ON YOUNG ADULTS,
OLDER POPULATIONS AND
TRANSLATIONAL SCIENCE WITHIN THE
DIVISION OF TREATMENT AND
RECOVERY.
DR. SHIRLEY WAS CO-CHAIR OF THE
NIAAA CENTERS AND TRAINING
COMMITTEE.
A CHEMIST IN THE DIVISION OF
INTRAMURAL AND CLINICAL AND
BIOLOGICAL RESEARCH RETIRED
AFTER 33 YEARS OF FEDERAL
SERVICE HE WAS AN ESSENTIAL
MEMBER OF THE CLINICAL CORPS
TEAM AND AN ANALYST INVEST
OFFICE OF POLICY AND
COMMUNICATIONS RETIRED AFTER 25
YEARS OF FEDERAL SERVICE.
HE COORDINATED THE COMPLIANCE
WITH THE POLICY OF INCLUSION OF
WOMEN AND MINORITIES AND ENSURED
NIAAA MATERIALS WERE ACCESSIBLE
TO THOSE WITH DISABILITIES.
AND A SENIOR RESEARCH PHYSICIAN
IN THE LABORATORY OF
NEUROIMAGING IN THE DIVISION OF
INTRAMURAL CLINICAL AND
BIOLOGICAL RESEARCH RETIRED
AFTER 11 YEARS OF FEDERAL
SERVICE.
HE STUDIED THE NEURO PSYCHIATRIC
MECHANISMS AND MANIFESTATIONS OF
ALCOHOL AND DISORDER AND HYPER
ACTIVITY DISORDER AND A
BIOLOGIST WITH THE DIVISION OF
INTRAMURAL CLINICAL AND
BIOLOGICAL RESEARCH RETIRED
AFTER 24 YEARS OF FEDERAL
SERVICE.
RECENT REDUCTIONS IN FORCE
IMPACTED SIX MEMBERS IN THE
NIAAA OFFICE OF SCIENCE POLICY
AND COMMUNICATIONS AND FOUR
STAFF MEMBERS AT NIAAA'S ETHICS
AND MANAGEMENT ANALYSIS BRANCH.
IN ADDITION FOUR STAFF MEMBERS
WERE AFFECTED BY DISMISSALS.
I HOPE BY GOING THROUGH THE
LISTS AND HONORING THE PEOPLE
WHO SERVED WITH US YOU REALIZE
WE LOST MANY CONTRIBUTORS TO OUR
PROGRAM OVER THE LAST 10 YEARS
AND LONGER SECOND, THE REMAINING
STAFF HAVE A LOT OF WORK TO DO
AS A RESULT.
I WANT YOU TO UNDERSTAND HOW
MUCH WORK EVERYONE IS DOING AT
NIAAA TO KEEP OUR MISSION ON
TARGET.
SO I WANT TO CONGRATULATE
EVERYONE AT NIAAA PART OF OUR
TEAM FOR ALL YOUR HARD WORK.
THE TRANSITION IS CHALLENGING
FOR EVERYONE AND WE'RE ALL
WORKING HARD TO KEEP OURSELVES
FOCUSED ON OUR MISSION.
I THOUGHT IT WAS IMPORTANT TO
LET YOU ALL KNOW ABOUT THOSE OF
US WHO HAVE GONE ON TO WHAT I
HOPE IS A VERY HAPPY RETIREMENT.
INSTITUTE UPDATES ON MARCH 15
THE PRESIDENT SIGNED A FULL YEAR
CONTINUING RESOLUTION EXTENDING
FUNDING AT THE FISCAL 2024
LEVELS TO SEPTEMBER 30, 2025.
THE FISCAL YEAR 2026
APPROPRIATION FOR NIH AND NIAAA
HAS NOT BEEN FINALIZED AND I
WILL SAY NOTHING ELSE AT THE
BUDGET AT THIS POINT BECAUSE
WE'RE SIMPLY WAITING FOR
CONGRESS TO DO WHAT CONGRESS
ALWAYS DOES WHICH IS COME UP
WITH A BUDGET BEFORE THE END OF
THE FISCAL YEAR.
WE DID PROMOTE THE BENEFITS OF
JANUARY AND WE HELD A MEDIA TOUR
WHERE I SPOKE TO 19TV AND RADIO
OUTLETS HOW PEOPLE CAN ASSESS
THEIR DRINKING.
THE EVENT ALLEGEDLY REACH 21
MILLION PEOPLE.
IT'S SOMETHING WE'VE BEEN DOING
FOR FIVE OR SIX YEARS NOW AND
EVER YEAR THERE SEEMS TO BE MORE
ACCEPTANCE AND ENTHUSIASM AND
WANTING TO HEAR THE WORD ABOUT
HOW AN INDIVIDUAL CAN ENGAGE IN
RE-EVALUATING THEIR RELATIONSHIP
WITH ALCOHOL.
WE DID IT AGAIN THIS YEAR.
WE RECOGNIZED DRY JANUARY ON
SOCIAL MEDIA WITH INFLUENCERS TO
RECOGNIZE THE IMPORTANCE OF
TAKING A BREAK FROM ALCOHOL.
AND IF YOU DON'T CARE ANY
PARTICULAR PROGRAM, IT COULD BE
SOBER OCTOBER, IT CAN BE
MOCKTAILS AND DRY BARS IF YOU
CAN RE-EVALUATE YOUR
RELATIONSHIP WITH ALCOHOL IT CAN
REDUCE THE BEHAVIOR AND MOVES
THE GROUP THAT MOVES TO THE
OTHER CATEGORY OF DRINKING
EXCESSIVELY.
SO WHAT'S AHEAD IS THE ANNUAL
MEETING THAT WILL TAKE PLACE IN
SEATTLE WASHINGTON ON THE
EMPHASIS OF PREVENTION SCIENCE
FOR ACTION LEVERAGE AND IN THE
48th ANNUAL RESEARCH SCIENTIFIC
MEETING WILL BE OCTOBER 24 TO
25.
AND JOIN THE ADVANCES IN SCIENCE
AND HOPE TO EFFECT IN THE
FUTURE.
SO I PICKED OUT ONLY FOUR
PRESENTATIONS TO TALK ABOUT
TODAY.
TWO ARE FROM OUR INTRAMURAL
PROGRAM.
I PICKED THEM BECAUSE THEY'RE
AREAS WE DON'T PAY AS MUCH
ATTENTION TO AND HOPE WE WILL
WHERE WE'RE GOING IN THE FUTURE
WHICH IS WITH A FOCUS ON ALCOHOL
IT'S A CHRONIC DISEASE AND IS
THE AFFECT ON LONGEVITY WHICH IS
DR. BHATTACHARYA EMPHASIS.
THE UPWARD OF TRAJECTORY OF LIFE
EXPECTANCY EXPERIENCED A DECLINE
IN THE UNITED STATES AND IT
SCREENS FOR ALCOHOL USE TO
EXAMINE CARDIOVASCULAR OUTCOMES
OVER A FOUR-YEAR PERIOD.
CONDUCTED BY A GROUP AND KAISER
PERMANENTE IN NORTHERN
CALIFORNIA.
THE SAMPLING INCLUDED 42,000
YOUNG AND MIDDLE AGED ADULT.
AT THE FOUR-YEAR FOLLOW-UP THE
RESEARCHERS FOUND AN INCREASED
RISK FOR CORONARY HEART DISEASE
AMONG MEN AND WOMEN WHO CONSUMED
ALCOHOL ABOVE THE GUIDELINE
RECOMMENDED LIMITS VERSUS AT OR
ABOVE THE LIMITS.
THE HIGHEST RISK WAS FOR MIDDLE
AGE WOMEN.
A COUPLE THINGS TO NOTE WEEKLY
ALCOHOL OF THE LIMITS WAS
ASSOCIATED WITH 26% HIGHER RISK
OVER ALL FOR CORONARY HEART
DISEASE.
THERE WAS A 19% AND 43% MEN
VERSUS WOMEN RISK OF CORONARY
HEART DISEASE.
SO SOMETHING WE'VE BEEN SEEING
NOW OVER THE LAST FEW YEARS IS
WOMEN ARE MORE ADVERSELY
AFFECTED THAN MEN.
YOU KNOW WHAT THE DIETARY
GUIDELINES ARE BUT THEY'RE ON
THE SLIDE IN THE PANEL.
YOU CAN SEE IT WITHIN THE
DIETARY GUIDELINES IS ONE TO 14
WEEKS PER WEEK AND 1 TO 7 FOR
WOMEN.
HIGHER INCIDENTS FOR MEN ABOVE
THE LIMITS AND WOMEN ABOVE THE
LIMITS IS BIGGER THAN THE MEN'S.
THEN ON THE BOTTOM PANEL WHILE
THERE WAS A SIGNIFICANT
ASSOCIATION BETWEEN HEAVY
EPISODIC DRINKING AND CORONARY
HEART DISEASE IN THE OVER ALL
STUDY POPULATION IT WASN'T
SIGNIFICANT BUT IF THEY DID A
STRATIFIED ANALYSIS OF HEAVY
EPISODIC DRINKING THERE WAS A
HIGHER BUT STATISTICALLY
NON-SIGNIFICANT EFFECT OF
CORONARY HEART DISEASE AMONG MEN
AND WOMEN.
COMPARED TO THE NON-HEAVY
EPISODIC DRINKING INDIVIDUALS.
IF YOU LOOK AT THE BOTTOM PANEL
WHEN PEOPLE WERE INVOLVED IN
HEAVY EPISODIC DRINKING IN
ADDITION TO THE WEEKLY LIMITS,
THERE WAS AN INCREASE.
IT WASN'T STATISTICALLY
SIGNIFICANT BUT A STRONG HINT I
THINK .054.
WHILE MORE RESEARCH IS NEEDED TO
UNDERSTAND CAUSALITY THEY CAN
HELP IDENTIFY POPULATIONS THAT
MAY HAVE THE HIGHEST RISK FOR
DEVELOPING CORONARY HEART
DISEASE BASED ON THE ALCOHOL
CONSUMPTION PATTERNS.
AND INTERESTINGLY ENOUGH,
PARTHAT IN TISSUE INJURY DID A
STUDY IN CHRONIC ALCOHOL
CONSUMPTION ACCELERATING AGING.
THE STUDY SUGGESTS HEAVY ALCOHOL
USE MAY ACCELERATE BIOLOGICAL
AGING UNDERSTANDING THE HEALTH
SPAN OF GROWING ADULTS 8-65 IS
IMPORTANT AND THE STUDY WAS TO
IDENTIFIED SIX MONTHS OF ALCOHOL
CONSUMPTION ON HEMODYNAMIC AND
CARDIOVASCULAR MEASURES.
TO GIVE A BRIEF VIEW.
THESE ARE YOUNG AND AGING RATS,
LESS THAN THREE MONTHS OLD AND
ONES THAT WERE FISHER RATS, 24
TO 26 MONTHS OLD.
THAT'S THE STRAIN USUALLY USED
FOR STUDYING AGING IN RATS AND
DIVED
DIVIDED AND THEY GOT A 5% PER
VOLUME LIQUID DIET AND OBTAINED
ALCOHOL LEVEL OF PEAK OVER 130,
140 MILLIGRMILLIGRAMS PER DECILD
ACCELERATED AGING BY IMPAIRING
MITOCHONDRIAL FUNCTION,
INCREASING OXIDATIVE STRESS,
TRIGGERING, INFLAMMATION AND
FIBROSIS AND APOPTOSIS
PARTICULARLY IN AN AGING ANIMAL
VERSUS A YOUNG ANIMAL.
ALL THE THINGS MENTIONED ON THE
DIAGRAM ARE SEPARATE SECTIONS IN
THE PAPER WITH DATA AND GRAPHS
THAT ARE SIGNIFICANT RELATIVE TO
THE MEASURES.
SO IT'S REALLY QUITE AN
EXTRAORDINARY THOROUGH STUDY OF
CHRONIC ALCOHOL AND
CARDIOVASCULAR MEASURES IN BOTH
YOUNG AND OLDER ANIMALS.
IT ALSO SUGGESTS THE LONG-TERM
USE CAN AFFECT CARDIOVASCULAR
AGING AND DIMINISH THE FUNCTIONS
ASSOCIATED WITH AGING.
YOU CAN SEE IN THE DIAGRAM, THIS
INTERACTION BETWEEN HEMODYNAMIC
ALTERATION AND HYPERTENSION IS
SOMETHING KATHY YOUNG AND I
TALKED A LOT ABOUT AND MANY
HEARD ME SAY THIS BEFORE BUT AT
MAYO CLINIC LAST YEAR I HAD A
CLINICIAN TELL ME NOW WHEN HE
HAS A NEW PATIENT THAT COMES IN
WITH HYPERTENSION HE ASKS ABOUT
ALCOHOL AND THAT'S THE FIRST
LINE OF TREATMENT TO CUT BACK ON
ALCOHOL INTAKE AND THE
INFLAMMATION AND ACTIVATION AND
YOU END UP WITH SEVERE
CARDIOVASCULAR EVENTS.
I'M REALLY GLAD THE GROUP AT THE
INTRAMURAL GROUP IS WORKING ON
THE SUBJECT MATTER.
THIS IS A COOL PAPER BY HOLLY
JOSEPH AND KASHUBU DID THIS WORK
IN INDIA BUT WAS ALSO DONE IN
NORAH VOLKOW'S LABORATORY AND IT
WAS A COLLABORATIVE EFFORT AND
THE STUDY AIMED TO LOOKED AT THE
HUMAN CONNECTOME PROJECT DATA
FOR IMAGING AND THE ALCOHOL
MEASURES.
TASTE AND SMELL CAN PLAY A ROLE
IN ALCOHOL CRAVING WHICH IS
ALREADY ESTABLISHED USING
RESTING STATE FUNCTIONAL MRI AND
THE RESEARCHERS IDENTIFIED
SPECIFIC FUNCTIONAL NETWORKS
ASSOCIATED WITH SMELL AND TASTE
ING WITH DIFFERENT DRINKING
PATTERNS.
ON THE LEFT HAND PANEL YOU CAN
SEE FOR EXAMPLE WITHIN THE
OLFACTORY NETWORK, THERE WAS A
POSITIVE ASSOCIATION BETWEEN
TOTAL PAST WEEK WINE CONSUMPTION
AND THE VISUAL CONNECTION AND
TOTAL INTAKE SHOWED AN AFFECT
WITH THE PARIETAL NUCLEUS
CONNECTIVITY.
THAT'S A MOUTHFUL BUT NATS THE
CONNECTIVITY ESTABLISHED.
YOU SEE THE DARK BLUE LINE WITH
THE OLLI -- OLFACTORY CONNECTION
NETWORK AND IT HAD PREDICTIVE
VALUE FOR WINE CONSUMPTION AND
THE VENTRAL ATTENTION NETWORK
FRONTAL PARIETAL NUCLEUS TASTE
NETWORK HAD PREDICTIVE VALUE FOR
ALCOHOL CONSUMPTION.
THOSE ARE ILLUSTRATED ON THE TWO
BOTTOM GRAPHS.
FUTURE STUDIES ARE NEEDED TO
EXPLORE THE RESULTS FOR
BIOLOGICALLY INFORMED
INTERVENTION AND TREATMENT
STRATEGIES BUT ALSO IT'S WORTH
NOTING THE CONNECTIONS
IDENTIFIED WITHIN THE OLFACTORY
AND OTHER NETWORKS ARE
CONSISTENT WITH THE PREMISE THAT
THE CHEMO SENSORY SYSTEMS AFFECT
ALSO SENSORY FUNCTION LIKE
ATTENTION AND IT HAS PROPOSITION
FOR LEADING US AND WHO WILL
PROGRESS IN WHAT DIRECTION WITH
THEIR ALCOHOL USE PROBLEM.
IT'S NOVEL AND INNOVATIVE.
THE LAST ONE IS IMPORTANT TO ME
BECAUSE FOR MANY YEARS WE'VE
BEEN SUPPORTING RESEARCH ON THE
AFFECTS OF LOOKING AT AROUND
TESTING THE HYPOTHESIS THAT
CHOLINE MAY BE ABLE TO HELP
BECAUSE MUCH IT'S ANTI-OXIDANT
REACTIVE PROPERTIES AND MAY HELP
IN TREATMENT OF FETAL ALCOHOL
SPECTRUM DISORDER AND THERE WAS
RESEARCH THE SUPPLEMENTATION MAY
HAVE POSITIVE MEMORY AFFECTS AND
THIS COMBINES DATA IN THREE
DOUBLE BLINDED RANDOMIZED
TREATMENT IN PRE-AGED CHILDREN.
THIS WAS DONE AT THE MAYO CLINIC
IN WISCONSIN AND THE
PARTICIPANTS WERE RECRUITED FROM
FASD INCLUDING THE MINNESOTA
CLINIC AND SUPPORT GROUPS FOR
FAMILIES RAISING CHILDREN WITH
FETAL ALCOHOL SPECTRUM DISORDER.
THOUGH IT WAS NOT REQUIRED FOR
INCLUSION, ALL PARTICIPANTS WERE
LIVING WITH ADOPTIVE FAMILIES OR
IN PERMANENT PLACEMENTS.
THERE WERE NONE IN FOSTER
TRANSITIONAL CARE.
DIAGNOSES WERE MADE USING
CRITERION AND INFORMATION FROM
THE CHILD'S MEDICAL RECORDS AND
DYSMORPHOLOGY CONDUCTED BY A
STUDY PHYSICIAN.
IN ADDITION BECAUSE THE
INSTITUTE OF MEDICINE CRITERIA
DO NOT SPECIFICALLY CHARACTERIZE
COGNITIVE FUNCTION THEY APPLIED
THE CENTERS FOR DISEASE CONTROL
AND CENTRAL NERVOUS SYSTEM FOR
FETAL ALCOHOL DISORDER.
IN THE END THEY IDENTIFIED
APPROXIMATELY 104 INDIVIDUALS
WITH HIGHLY PROBABLE FETAL
ALCOHOL SPECTRUM DISORDER.
YOU REMEMBER THAT FETAL ALCOHOL
SPECTRUM DISORDER INCLUDES
DEVELOPMENTAL DISORDER AND
PARTIAL SYNDROME AND FETAL
ALCOHOL SYNDROME AMONG OTHERS.
WE DON'T REALLY HAVE A CONCRETE
DEFINITION YET OF FETAL ALCOHOL
SPECTRUM DISORDER BUT THE FIELD
IS WORKING ON A CONSENSUS
DEFINITION.
AFTER THE NINE-MONTH FOLLOW-UP
VISIT CHOLINE VISIT IMPROVED
EARLY NON-VERBAL MEMORIES
ELICITED WITH THE TASK COMPARED
WITH PLACEBO.
SO REMEMBER, THESE WERE 2 TO
6-YEAR-OLDS.
THE AVERAGE AGE WAS SOMEWHERE
AROUND 4 --.
THIS WAS NOT VERBAL.
THERE WERE GIVEN TOYS TO PLAY
WITH AND GIVEN AN ORDER AND THEY
WERE SUPPOSED TO REMEMBER THE
ORDER.
IF THEY PAIRED THE TOYS PROPERLY
AS SEEN BEFORE, THAT IS WHAT WAS
MEASURED.
I DON'T KNOW.
LAURA MAY BE ABLE TO TELL ME
MORE ABOUT THE TASK BUT IT
SOUNDS COMPLICATED BUT I'D LIKE
TO SEE IT IN ACTION BUT THESE
WERE FOR 4-YEAR-OLDS.
YOU CAN SEE THE INCREASE AT THE
NINE MONTH TEST, VISIT IN THE
CHOLINE GROUP THAT WAS QUITE
DRAMATIC.
THE GRAPH ON THE RIGHT AND THE
YOUNGER CHILDREN SHOWED A
GREATER IMPROVEMENT WITH THE
FULLY ADJUSTED MODEL TOOK IT
INTO ACCOUNT AND THAT WAS ALSO
SIGNIFICANT.
OVER
OVER ALL CHOLINE SHOWED NO
AFFECT ON INTELLIGENCE QUOTIENT.
THERE WAS NO ADVERSE EFFECT FROM
CHOLINE SUPPLEMENTATION AND
THERE WAS A FISHY BODY ORDER AND
IT WAS DOSE DEPENDENT.
I GUESS IF THE BODY ORDER GOT
TOO STRONG, THEN MAYBE CHILDREN
HAVE TO MODERATE THEIR DOSE BUT
IN ANY EVENT THE AUTHORS SAID
THERE'S LONG-TERM BENEFITS TO
MODIFY TRAJECTORY IN EARLY
CHILDHOOD AND EVEN A COURSE AT
THE CRITICAL MOMENTS IN THE
DEVELOPMENT OF THE INDIVIDUALS
CAN LEAD TO EFFECTS THAT CAN
SNOWBALL IN A POSITIVE AWAY
LATER ON.
DID I SCREW IT UP OR IS THAT A
FAIR ARGUMENT?
PHIL IS THE COORDINATOR OF OUR
FETAL ALCOHOL SPECTRUM DISORDER
EXTRAMURAL PROGRAM.
AND THIS HELPS UNDERSTAND THE
TREATMENT OPTIONS AND YOU CAN
LEARN ALCOHOL USE DISORDER IS A
SPECTRUM DISORDER AND THEN
HEALTH CARE PROFESSIONAL CORE
RESOURCE COVERS THE BASICS OF
WHAT EVERY HEALTH CARE
PROFESSIONAL NEEDS TO KNOW ABOUT
ALCOHOL KWLUGDP INCLUDING
STRATEGIES FOR INTERVENTION.
I WANTED TO ADVERTISE THE NATIVE
COMMUNITIES ALCOHOL AND
PREVENTION REVIEW THAT WE PUT UP
IN NOVEMBER AND EDUCATE IN
IDENTIFYING EFFECTIVE
SCIENTIFICALLY ALCOHOL
INTERVENTIONS FOR COMMUNITIES.
IT WAS IN PARTNERSHIP WITH
SCIENTIFIC EXPERTS HAVING
EXTENSIVE EXPERIENCE CONDUCTING
RESEARCH WITH NATIVE COMMUNITIES
AND EVALUATING NEARLY 40
INTERVENTIONS INCLUDING NATIVE
POPULATIONS FROM PUBLISHED
PEER-REVIEWED RESEARCH.
THERE'S INFORMATION THERE ON
PREVENTION OF ALCOHOL MISUSE AND
TREATMENT OF DISORDER AND
PREVENTION OF FETAL ALCOHOL
SPECTRUM DISORDER.
WE WANT TO BE YOUR CREDIBLE
SOURCE FOR ALCOHOL INFORMATION
AND HEALTH AND HOPE IT CONTINUE
TO BE AND UPDATE THESE
RESOURCES.
I WANT TO GIVE A SPECIAL THANKS
TO EVERYBODY THAT CONTRIBUTED TO
THESE SLIDES AND A LOT OF WORK
BY DEVIN PLOT AND LAURA AND
LAUREN AND TRISH POWELL.
THANK YOU VERY MUCH AND -- AM I
SUPPOSED TO TAKE QUESTIONS OR AM
I OVER?
WHERE ARE WE?
>> WE HAVE PLENTY OF TIME FOR
DISCUSSION.
>> DOES ANYBODY HAVE QUESTIONS
THAT I CAN ACTUALLY ANSWER?
>> WE HAVE A QUESTION.
>> THANK YOU FOR SHARING THE
BIOS OF ALL THE FOLKS WHO WORKED
FOR SUCH A LONG TIME AT NIAAA.
IT WAS WONDERFUL TO LEARN MORE
ABOUT THEM AND FOR YOU TO
RECOGNIZE THEM SO THANK YOU.
>> YOU'RE WELCOME.
IF YOU LOOK AT THE DIRECTOR'S
REPORT YOU'LL SEE EVERYTHING I
TALKED ABOUT IS IN THE
DIRECTOR'S REPORT AND EVEN
EXPANDED A BIT IN THERE.
OTHER COMMENTS OR QUESTIONS?
WE'LL HAVE TIME FOR DISCUSSION
LATER AFTER WE GO THROUGH SOME
OF THE TALKS.
>> THEY'RE ROBUST IN THEIR
ABILITY TO MEASURE MEMORY.
>> I WONDERED IF YOU HEARD OF
THAT ONE.
I HAD NEVER HEARD OF IT BEFORE
BUT APPARENTLY THEY HAVE TOYS
THEY HAVE TO ARRANGE IN A
SEQUENCE OF THEME.
LIKE CATCHING A BALL OR
SOMETHING LIKE THAT.
THERE'S A LOT OF MANIPULATIVES
INVOLVES WHEN TESTING LITTLE
KIDS.
YOU HAVE TO PRESENT THEM IN
ORDER.
OBVIOUSLY WE'VE NEVER TESTED
KIDS.
OTHER QUESTIONS OR COMMENTS?
WHERE ARE WE AT IN THE SCHEDULE?
>> WE HAVE A COMMENT OR
QUESTION.
AFTER NOTING THE OLFACTORY
SYSTEM DOES MORE THAN OLFACTION
AND PARTICIPATES IN MOTOR
BEHAVIOR GOES TO SHOW YOU THE
BRAIN DOES MORE THAN ONE THING
AND IT'S A VERY INTEGRATED
CIRCUIT.
IT WAS GREAT TO SEE.
>> IN DROSOPHILA NOW THEY KNOW
MOST THE CONNECTIONS.
I BELIEVE THAT'S CORRECT.
KNOWING THEY INVADE MY FRUIT
TREES I CAN TELL YOU THEY HAVE A
WELL DEVELOPED OLFACTORY SYSTEM.
ANY OTHER THOUGHTS OR COMMENTS?
WELL, WE CAN TAKE A 15 MINUTE
BREAK AND BE 15 MINUTES AHEAD OF
TIME.
IS THAT OKAY OR DO I WANT TO
KEEP GOING, PHILIPPE?
>> YES, A 15-MINUTE BREAK AND
THE NEXT PRESENTATION IS
SCHEDULED AT 2:30 BUT I THINK --
>> LET'S STAY ON SCHEDULE.
PEOPLE AT INTRAMURAL PROBABLY
WANT TO HEAR HIM.
MAYBE WE'LL JUST TAKE A LONGER
BREAK.
>> I THINK THAT'S A GOOD IDEA.
>> LET'S DO IT THAT WAY.
SO YOU'RE ON AT 2:30.
IS THAT CORRECT?
OKAY TELL EVERYBODY AT FISHER'S
LANE YOU'RE ON AT 2:30.
I KNOW YOU WON'T BUT MAYBE
SOMEBODY WILL. WE'LL SEE EVERYBODY AT 2:30.
>> WE FORGOT TO INTRODUCE TWO
KEY MEMBERS OF NIAAA.
OUR TWO DAVIDS, DAVID GOLDMAN
AND DAVID LOVINGER.
DO YOU WANT TO SAY SOMETHING?
>> HELLO, GLAD YEAR ABLE TO GET
TOGETHER FOR COUNCIL.
I'M THE SCIENTIFIC OF THE
DIVISION OF INTRAMURAL CLINICAL
AND BIOLOGICAL RESEARCH AT
NIAAA.
GOOD TO SEE, Y'ALL.
>> THANKS, DAVE.
AND DAVID GOLDMAN AND THANK YOU
FOR REMINDING ME TO TELL
EVERYBODY THE DIRECTOR'S REPORT
IS ON THE WEBSITE.
DAVID.
IT'S A REAL PLEASURE FOR ME TO
INTRODUCE DR. RESAT CINAR FROM
FIBROTIC DISORDERS AT NIAAA
SINCE JANUARY 2021.
HE TRAINED AS A PHARMACIST AND
PHARMACOLOGIST IN TURKEY.
HE OBTAINED HIS Ph.D. BY
STUDYING MOLECULAR PHARMACOLOGY
OF THE CV1 RECEPTORS AND OPIOID
RECEPTOR SIGNALLING.
AFTER COMPLETING HIS Ph.D. HE
JOINED THE LAB AT NIAAA AS A
POSTDOCTORAL FELLOW AND THEN
BECAME A STAFF SCIENTIST AND
CURRENTLY A TENURE TRACK
INVESTIGATOR AT NIAAA.
HIS RESEARCH HAS DEMONSTRATED
GOALS OF THE CANNABINOID SYSTEM
IN DISORDERS SUCH AS LUNG AND
LIVER.
HE'S CONTRIBUTED IN
MULTI-TARGETED STRATEGICS TO
DEVELOP MORE EFFICIENT AND SAFER
MODALITIES FOR COMPLEX,
PROGRESSIVE DISORDERS.
HIS RESEARCH IDENTIFIED DUAL
INHIBITION OF RE -- RECEPTORS
AND INVOLVED IN NOVEL
PERIPHERALLY RESTRICTED HYBRID
COMPOUNDS, CB1 RESTRICTER AND
AMP K AS THIRD GENERATION CV1
RECEPTOR ANTAGONIST.
THIS NOVEL CLASS HAS THERAPEUTIC
POTENTIAL IN OBESITY, DIABETES,
ALCOHOL USE DISORDER AND
FIBROTIC DISORDER AND TWO OF THE
LEAD COMPOUNDS.
HAVE BEEN TRANSLATED TO CLINICAL
TESTING.
HIS RESEARCH FOCUSES ON
UNDERSTAN
UNDERSTANDING PATH LOGIC
MECHANISMS AND ALCOHOL INDUCED
INJURY AND IDENTIFIED
THERAPEUTIC TARGETS AND DEVELOP
EFFECTIVE PHARMACO THERAPIES.
THERE'S ALWAYS A WARM SPOT FOR
RESEARCHERS WHO TRAINED IN
PHARMACY.
ANOTHER WARM SPOT IN MY HEART
FOR SOMEONE WHO STUDIES THE
LIVER.
YOU'LL YOURS, RESAT.
>> THANK YOU FOR THE
INTRODUCTION AND INVITATION.
I'M HERE TO SHARE IN OUR
RESEARCH THE INTERNAL PROGRAM OF
THE NIAAA.
MY TITLE IS UNDERSTANDING THE
AFFECT OF ALCOHOL MISUSING IN
WOUND HEALING AND WE CAN TRY TO
FOCUS ON THERAPEUTIC TARGETS.
THIS IS ALSO ONE OF THE LESS
STUDIES INTERACTION WITH
ALCOHOL.
WE HAVE AN ESTABLISHED MECHANISM
AND FOCUSSING ON LUNG DISEASE
AND I WILL TRY TO OF GIVE
EVIDENCE HOW THE TWO DISEASE MAY
INFORM EACH OTHER OR SHED
PATHOLOGICAL MECHANISMS AND
SHARE SOME RECENT RESEARCH WITH
A POSTDOC IN MY LAB.
NOW MANY MAY KNOW THE LATEST
EVIDENCE AND PREVALENCE OF
ALCOHOL DRINKING INCREASED BASED
ON THE DATA AND AN IMPORTANT
POINT IS BASED ON THE SURVEY,
MORE THAN HALF THE UNITED STATES
POPULATION AGE 18 AND OLDER HAS
DRINKING AND A QUARTER OF THE
POPULATION ALMOST A QUARTER HAS
BINGE DRINKING EXPERIENCE AND
ABOUT 10% OF THE POPULATION HAVE
ALCOHOL USE DISORDER.
IS THIS IS CONCERNING IF YOU
CONSIDER THE NEGATIVE HEALTH
IMPACT OF ALCOHOL IN DIFFERENT
ORGANS.
MY FOCUS IS ON LUNG BUT I WILL
FOCUS ON MY TALK AND THE
PSYCHIATRIST WHO ALSO ONE OF THE
PERSONS INTRODUCED THE ALCOHOL
USE DISORDER CONCEPT DESCRIBED
THE ALCOHOL LUNG DISEASE AS
FATAL MORE THAN 200 YEARS AGO.
THE LAST 200 YEARS THERE'S A
REMARKABLE ADVANCEMENT OF THE
MEDICAL PRACTICE WITH THE MOST
IMPORTANT IS THE ANTIBIOTICS AND
THE RULES HAVE CHANGED IN THE
LAST 200 YEARS BUT STILL ALCOHOL
PREDISPOSED THE ALCOHOL WITH THE
PNEUMONIA AND SEPSIS AND THIS IS
ALL CAUSE MORTALITY.
BASED ON THE CAN CLINICAL
EVIDENCE, INDIVIDUALS WITH
ALCOHOL MISUSE HAVE ALMOST
DOU
DOUBLED INCIDENTS ADDRESSING THE
SYNDROME AND IT'S OFTEN
RESULTING IN MORTALITY.
IF YOU CHECK THE PUBLISHED
EVIDENCE WE CAN CONCLUDE OR SEE
EVIDENCE THAT HEAVY ALCOHOL
DRINKING PROMOTES WHAT IS
HAPPENING IN LUNGS AND THERE'S
OXIDATIVE STRESS AND ALCOHOL
CAUSES REPETIVE INJURIES.
AND LINING THE LUNGS FOR SECOND
INJURY.
THERE'S MULTIPLE EVIDENCE IT
AFFECTS THE IMMUNE SYSTEM.
I WANT TO EMPHASIZE THE UNIQUE
ROLE OF LUNG.
LUNG IS EXPOSED TO VIRUS,
BACTERIA, AIR POLLUTION.
THIS ORGAN HAS A LOT OF EXTERNAL
FACTOR CAN CAUSE MULTIPLE INJURY
AND INFLAMMATION AND WHY
INTEGRITY OF THE LUNG IMMUNITY
IS CRITICAL FOR HEALTHY
PHYSIOLOGICAL FUNCTION OF LUNG.
CONSIDERING THIS ONE OF THE
IMPORTANT QUESTIONS IS HOW DOES
THE ALCOHOL AFFECT THE LUNG THAT
BECOMES IMPORTANT QUESTION.
TO ADDRESS THIS WE TRIED TO
ANALYZE TRANSCRIPTOMICS DATA
WHICH IS POPULATION BASED LUNG
TRANSCRIPTOME DATA AVAILABLE
THROUGH THE DATABASE AND WE
IDENTIFIED 328 ALCOHOL DRINKERS
AND THEIR AGE WAS SIMILAR.
IN THIS POPULATION WE ALSO FOUND
DIFFERENT LEVELS OF ALCOHOL
DRINKING.
FROM LESS THAN ONE OR MORE THAN
FOUR OR IN BETWEEN.
S FIRST WE CZECHED THE EFFECT
AND HERE WE FOUND REGARDLESS OF
THE SEX OR ALCOHOL DOSE THE
GENES SIGNIFICANTLY ALTERED WITH
ALCOHOL DRINKING.
THAT WAS QUITE SURPRISING
BECAUSE THE LOWER LEVEL OF
ALCOHOL CAN DO SOMETHING IN THE
LUNG BUT WINCE ONCE WE CHECK THE
DOSE RESPONSE INCREASE ALCOHOL
CONSUMPTION AND INCREASING THE
GENES ONLY IN MEN BUT NOT WOMEN.
THAT SUGGESTED MEN ARE MORE
SENSITIVE TO ALCOHOL AFFECT TO
DYSREGULATING THE LUNG IMMUNITY.
AS A NEXT STEP WE WANT TO CHECK
THE HEAVY ALCOHOL DRINKER'S LUNG
AND SEE WHAT PATHWAYS ARE
ALTERED.
.
WE FOUND THESE WERE
SIGNIFICANTLY DOWN RELATED.
AND THIS IS ALSO HAPPENING OR
APPEARED IN MALE OR MEN NOT
WOMEN.
AND THESE PATHWAYS ARE NATURAL
KILLER CELLS MAYBE WITH
CYTOTOXICITY AND SIGNALLING AND
THESE ARE BASICALLY ALL
INVOLVING THE MOST EVENTS AND
INFLAMMATION INJURY PROCESS.
THAT SOMEHOW SET GROUND FOR US
FROM THE HUMAN DATA BUT WE NEED
TO UNDERSTAND THE FUNCTIONAL AND
TRANSLATI
TRANSLATIONAL RELEVANCE USING
ANIMAL STUDIES AND DECIDED TO
TRY FIRST CHRONIC DRINKING WHICH
WAS INTRODUCED BY DR. BENGOL AND
THIS MODEL WE BASICALLY CHECKED
THE IMMUNE CELLS BY FLOW
CYTOMETRY AND LEVELS DECREASE IN
MALE ANIMALS NINE HOURS AFTER
BUT RESTORING BACK AND
MACROPHAGE WAS DECREASED
PREDOMINANTLY IN MALE AND
SHOWING THE UP REGULATION.
THIS WAS MYELOID CELLS.
THIS IS THE INNATE IMMUNE CELLS.
WE ALSO CHECKED THE ADAPTIVE
IMMUNE CELLS WHICH ARE LYMPHOIDS
AND FOUND MULTIPLE LYMPHOID
CELLS LIKE TC17 CELLS OR NATURAL
KILLER CELLS ARE DOWN REGULATED.
THERE'S A RATE RESPONSE MUCH
MORE DOMINANT THAN THE 24 HOURS
BUT THIS IS ALSO PREDOMINANTLY
SEEN IN THE MALE SUBJECTS.
WE FOUND THE 17 T CELLS AND TOLD
MAYBE THE MODEL IS GOOD TO
ESTABLISH OR SEE THE TRANSLATION
BUT IN THE MORTALITY CAUSES IS
THE ALCOHOL RELATED LIVER
DISEASE.
THE NEXT QUESTION IS MAYBE IT
CAUSES THE UNIVERSAL INJURY IN
ALL ORGANS AND NOWADAYS WE HAVE
A SYSTEM BIOLOGY APPROACH WE CAN
SEE MORE SYSTEM IC INFORMATION F
THE TISSUE ON DIFFERENT ORDERS
AND DECIDED TO COMPARE SIDE BY
SIDE, LUNG AND LIVER FROM SAME
ANIMAL AND HERE WE USED THE SAME
ANIMAL MODEL IS WE ALSO WANT TO
SEE CHRONIC EFFECT.
AND HERE WE CHECKED THE
DIFFERENTIALLY EXPRESSED GENES.
THERE'S MORE SIGNIFICANT AT
RATION BUT IF YOU CHECK THE
LIVER -- ALTERATION BUT IF YOU
CHECK THE LIVER HAS MORE
EXPRESSED GENES COMPARED TO THE
LUNG BUT THE CHANGE WE CAN PRO
LONG DOWN REGULATE TO THE
PATHWAYS DOWN REGULATED AND
REMAIN DOWN REGULATED AFTER 14
DAYS.
ON THE OTHER HAND, LIVER HAS
ONLY FIVE PERSONS AF NINE HOURS
AND THERE'S A DELAYED DOWN
REGULATION BUT THEN IT'S
RESTORED.
14 DAYS EVEN SOME PATHWAYS ARE
UP REGULATED.
IT WAS SURPRISING SUGGESTING THE
ORGAN-SPECIFIC EFFECT OF ALCOHOL
AND THIS IS ACTUALLY SUPPORTING
OUR FINDING THAT LUNG MAY BE
MORE SENSITIVE FOR
ALCOHOL-REGULATED DYSREGULATION
AND WE WERE FORTUNATE TO SEE
WITH THE GTEX DATA WE IDENTIFIED
A PATIENT AND TRIED TO MATCH THE
LUNG AND LIVER SAMPLES FROM THE
SAME PATIENT AND THIS IS THE
SAME AND WE FOUND HUMAN LUNG
TRANSCRIPTOME AND THE MOUSE
TRANSCRIPTOME.
YOU SEE HERE THE PATHWAYS ARE
SIMILAR WE ALREADY IDENTIFIED T
CELLS AND K CELLS.
IT ALSO CONVINCED US MAYBE THE
MODEL IS RECAPITULATING THE
SIMILAR ALTERATIONS IN THE HUMAN
LUNG.
THEN TO IDENTIFY THE MOST
SIGNIFICANT CHANGE OR WHAT MAY
BE UPREGULATED FOR ALL THE
CHANGE WE WANT TO USE THE
SYSTEMIC BIOLOGY APPROACH.
HERE WE TRIED TO SEE WHAT IS
ALTERED IN HUMAN LUNG AND MOUSE
LUNG.
HERE WE DECIDED TO CHECK ALL THE
TIME POINTS WHETHER WE SEE
SIMILAR ALTERATIONS IN HUMAN AND
THEY'RE HAPPENING IN AND SOME
ARE IN IMMUNE REGULATED
PATHWAYS.
WE GENERATED THE EXPRESSION AND
TRIED TO SEE THE MAJOR DRIVERS
AND IDENTIFIED G1.
G1 NETWORK IS UP REGULATED WHICH
CONSISTS OF METABOLIC PATHWAYS
AND G3 IS DOWN REGULATED WHICH
IS IMMUNE REGULATED PATHWAYS.
CHECKING THE DATA SHOWED THE
DRIVERS OF THE ALTERATION IN
LUNGS WITH CHRONIC ALCOHOL
INTAKE IN HUMAN.
WE TRIED TO EXPLORE IN DETAILS
THE PATHWAYS AND IT NOTICED
CHECK ALCOHOL HAS MULTIPLE
METABOLIC CHANGE IN ORGAN AND
THERE'S SIGNIFICANT ALTERATIONS
AND WE DID TARGETED METABOLOMICS
TO SEE HOW IT'S ALTERED BUT WE
ALSO WANT TO SEE IF WE CAN
IDENTIFY A DIFFERENCE BETWEEN
THE JUST SINGLE ACUTE PINCH
VERSUS THE CHRONIC PLUS SINGLE
AND HERE YOU CAN SEE SINGLE
SHOWS THE SINGLE PINCH AND
OTHERS NOTICE HERE IT INCREASES
AMINO ACID LEVELS.
THAT ALSO ASK IS EVIDENT AND SEE
THE MOST SIGNIFICANTLY AT RATED
PATHWAY.
WE THOUGHT MAYBE WE NEED TO
FOLLOW THE EVIDENCE TO FURTHER
EXPLORATION.
AND BRANCH AMINO ACIDS WE TAKE
THEM BY DIET OR BY DEGRADATION
OF THE PROTEINS WE TAKE THIS ONE
HOUR BEFORE TISSUE COLLECTION
AND WE SEE THE LEUCINE LEVELS IN
SERUM.
THEY'RE TRANSPORTED TO THE LUNG
BY AMINO TRANSPORTERS THEIR
EXPRESSION WAS TWO TO FOUR FOLD
INCREASE AND WE COULD ONLY SEE
FOURFOLD INCREASE IN THE LUNG
AND THAT SUGGESTED THERE ARE
HIGHER CLEARANCE OF THIS IN THE
LUNG AND THE DEGRADATION
INCREASED.
ONCE WE CHECKED IN HUMAN AND
MOUSE LUNG INDIVIDUALS ENZYMES
IN THE DEGRADATION PATHWAY, WE
CAN SEE IN MOUSE AND HUMAN
SIGNIFICANT UPREGULATION OF THE
ENZYME.
OUR STUDY DEMONSTRATED IT
INCREASED DEGRADATION IN MOUSE
AND HUMAN.
HOW WE FOUND THIS AMINO ACID
QUITE INTERESTING SINCE THEY'RE
ESSENTIALLY WHAT OUR BODY NEEDS
AND WE WANT TO SEE WHAT PATHWAYS
THEY MAY BE INVOLVING.
ONE OF THE CRITICAL PATHWAYS IS
MTOR SIGNALLING BUT IT'S A
MASTER REGULATOR OF METABOLISM
AND CRITICAL FOR MITOCHONDRIAL
GENESIS.
AS THE FIRST STEP WE CHECKED THE
MTOR SIGNALLING AND CHRONIC
ALCOHOL IS REDUCING THE MTOR
ACTIVATION.
THEN WE WANT TO SEE A
PHARMACOLOGIC INTERVENTION TO
SEE HOW IT INVOLVES THE DE
REGULATION.
WE HAVE A SELECTIVE MTOR
INHIBITOR AND FDA APPROVED USED
BUT HERE AS YOU SEE WE DON'T
REDUCE FURTHER LIPOCYTE
REDUCTION BUT SOME OF THE IMMUNE
CELLS ARE FURTHER DOWN REGULATED
BUT THIS SUGGEST ED IT'S DOWN
REGULATED THE MTOR SIGNALLING
AND THEY MAY BE UPSTREAM
REGULATOR OF THE IMMUNE
REGULATION.
KNOW IF YOU PUT THE EVIDENCE
TOGETHER IT SUGGESTS THE CHANGE
IN THE LUNG AND SWITCH DOING
DOWN REGULATION AND IT'S AN
INTERESTING APPROACH AND MAY BE
WE CAN SUPPLEMENT THEM.
MAYBE SUPPLEMENTING THE AMINO
ACID SIMPLY RESTORES THE MTOR
ACTIVITY AND MAYBE WE CAN ALSO
RESTORE THE DYSREGULATION AND WE
FOUND PROTOCOL AND WE TRIED ONE
AND WE WERE ABLE TO INCREASE THE
BRANCHING AMINO ACID THREEFOLD
COMPARED TO THE UNTREATED GROUP
BUT COULD NOT RESTORE MTOR
ACTIVITY OR IMMUNE CELLS.
NOW, TO SUMMARIZE THIS PART WE
FOUND WE CHECKED THE BASAL
ALCOHOL AFFECT WITHOUT ANY
SECONDARY CHALLENGE BUT CHRONIC
ALCOHOL DRINKING AS A SEXUALLY
DYSMORPHIC EFFECT AND MALES ARE
MORE PRONE TO THE ALCOHOL AND
LUNG IS MORE SENSITIVE TO
ALCOHOL EFFECT THAN LIVER FOR
IMMUNE DYSREGULATION.
ALCOHOL AFFECTS CHANGE IN THE
HUMAN AND MOUSE LUNG AND IN THE
MTOR SIGNALLING MIGHT BE ONE OF
THE UP STREAM REGULATOR OF
ALCOHOL INDUCED DYSREGULATION.
BUT IT SEEMS MTOR MAY NOT BE
IDEAL TARGETS TO ACTIVATE TO
CORRECTING THIS IMMUNE
DYSREGULATION BECAUSE IT MAY
ALSO INVOLVE PROMOTING THE
CARCINOGENESIS.
WE NEED TO FIND MORE UP STREAM
MORE SELECTIVE TARGETS AND NEED
TO UNDERSTAND BETTER UP STREAM
PATHWAYS REGULATING THIS.
AND WE'LL SWITCH GEARS BUT WE
ALSO FOUND ALCOHOL CRIN DUCING
MACROPHAGE POLYMERIZATION AND
OBSERVED THE MACROPHAGES
ACQUIRING THE PHENOTYPE AND
ACTIVATE THE MARKER.
WHY THIS IS IMPORTANT?
LET ME EXPLAIN WITH THE
MACROPHAGE POLYMERIZATION.
WITH HEALTHY PEOPLE IF YOU HAVE
INFECTION OR INJURY, THE HOST
DEFENSE MECHANISM REQUIRE OF THE
PHENOTYPE.
THESE ARE GENERALLY PRO
INFLAMMATORY AND ONCE THEY'RE
ACTIVATED AFTER THE THREAT IS
ELIMINATED THEY'RE DOWN
REGULATED AND THE INFLAMMATORY
RESPONSE IS REQUIRED FOR HEALTHY
WOUND HEALING.
THIS SYSTEM REMAINS ELEVATED BUT
IT BECOMES PROFIBROTIC.
THERE'S MULTIPLE EVIDENCE THAT A
MONOCYTE DRIVE AND CONTRIBUTE TO
FIBROSIS.
CAN WE UNDERSTAND PATHOGENIC
MECHANISMS AND ALCOHOL INDUCED
LUNG INJURY?
THAT CAN BE BOLD QUESTION BUT WE
WANT TO TRY TO USE THE SYSTEMS
BIOLOGY APPROACH.
NOW, I WANT TO BRIEFLY MENTIONED
WHAT ARE THE FIBROTIC LUNG
DISEASES?
WE KNOW LUNG PLAYS A CRITICAL
ROLE FOR OXYGEN SUPPLY AND IT'S
HAPPENING IN ALVEOLI AND THE
WHITE SPACE IS AIR SACKS AND THE
OXYGEN EXCHANGE HERE BUT IN THE
FIBROTIC OR FIBROPROLIFERATION
ALVEOLI GETS THICKER OR SCARRING
AND YOU CAN SEE THIS HISTOLOGY
OR PATHOLOGY.
BLUE IS THE EXTRA CELLULAR
MATRIX DEPOSITION.
AS A RESULT OF THE CHANGE YOU
CAN APPRECIATE THE INDIVIDUALS
CAN LOSE THE LUNG CAPACITY AND
THE DECLINE AFTER THREE TO FIVE
YEARS MORE TRALT CAN OCCUR.
WHY THIS IS IMPORTANT BECAUSE
ALSO PREVALENCE AND MORTALITY
LUNG DISEASE INCREASED AND ONE
OF THE RECENT EVIDENCE BASED ON
THE GLOBAL BURDEN OF THIS
DISEASE DATA PUBLISHED IN 2019
CHRONIC RESPIRATORY DISEASE IN
THE FIRST TIME IN HISTORY IS THE
LEADING CAUSE OF DEATH WITH $4
MILLION DEATHS.
ONE OF THE DATA COMPARED THE 20
YEAR TREND AND THE REF LANCE HAS
HIGHER MORTALITY THERE'S LESS
DEATH BECAUSE OF THE ASTHMA
MEDICATIONS OR ANTIBIOTICS.
IT SHOWS UNMET MEDICAL NEED FOR
FIBROTIC LUNG DISEASE AS
EVIDENCE FROM INCREASED
PREVALENCE AND REMARKABLE
MORTALITY.
WHAT ARE THE MECHANISMS IN
LUNGS?
THIS IS IMPORTANT TO UNDERSTAND
DISEASE AND ALSO DEVELOPING
TARGETS AND STRATEGY.
IN MY LAB WE TRIES TO ALSO DO AN
APPROACH TO THE MULTI-OMICS
APPROACH USING THE FIBROSIS
ANIMAL MODEL AND HUMAN LUNG
PATIEN
PATIENTS AND HEALTHY LUNG
SAMPLES AND THE PARAMETERS
INCLUDING PULMONARY FUNCTION
TEST.
IT'S IMPORTANT BECAUSE IN CLINIC
IT'S THE ONLY MARKER TO MONITOR
THE PROGRESSION OF THE DISEASE.
IF YOU WANT TO DESIGN A CLINICAL
TRIAL THEY'LL ASK YOU TO SHOW
THE DECLINE OR MONITOR THE
CAPACITY.
WE INTEGRATED MORE THAN 13,000
GENES PULMONARY FUNCTION
PARAMETERS AND 200,000 LINKS AND
IDENTIFIED 5G NETWORKS.
AND AGAIN IT WAS IMPORTANT.
ONCE WE TRIED TO SEE THE 10 MOST
SIGNIFICANT GENES CO-REGULATED
WITH THE FUNCTION.
THE NI VH1 AND 2 WERE THERE AND
WE WERE NOT EXPECTING TO SEE
THEM.
BUT THIN ANOTHER STUDY WITH THE
SEQUENCING STUDY FOUND IN THE
HUMAN LUNG FIBROBLAST AND DURING
FIBROSIS THE LEVELS WERE DOWN
RELTHED AND IF THERE IS A
FIBROSIS RESOLUTION, ALDH HAS TO
BE A RISK AND ALSO THIS STUDY
HIGHLIGHTS THE IMPORTANCE OF
ALCOHOL METABOLISM AND WOUND
HEALING RESPONSE.
IN OTHER FOLLOW-UP STUDY
CONFIRMED IF YOU DELETE IT
AGGREGATED LUNG FIBROSIS THROUGH
MITOCHONDRIAL DYSFUNCTION AND
AGING FIBROBLASTS.
BASED ON THE EVIDENCE WE THINK
HEAVY ALCOHOL DRINKING MAY CAUSE
WOUND HEALING RESPONSE IN LUNGS.
AND THERE'S A THOUSAND REASONS
WHY THE ALCOHOL IS CAUSING
INJURIES WITH PERTURBATION IN
THE WOUND HEALING RESPONSE.
WITH THE HYPOTHESIZED DRIVEN
APPROACH INFORMED US SHARED
MECHANISMS IN ALCOHOL-RELATED
LUNG DISEASE AND FIBROTIC LUNG
DISEASE MAY EXIST.
IT MEANS WE NEED TO LOOK FOR
INTERACTION OF THE TWO
PATHOLOGIES.
WE TAKE THE INTEGRATIVE OMICS
APPROACH AND WE IDENTIFY OR
DEVELOP A FRAMEWORK FOR
IDENTIFYING TARGETS BECAUSE OUR
AIM IS IDEAL TARGETS THEY SHOULD
CAUSE CHANGE AT THE SAME TIME.
HERE WE FOUND THE THERAPEUTIC
TARGET FOR PULMONARY FIBROSIS
BECAUSE IT EARLIER WE SHOWED CV1
COMPARED TO THE HEALTHY LUNG
THERE'S A REMARKABLE INCREASE OF
C1 EXPRESSION.
AND THE ACTIVATOR NAMED AND
INCREA
INCREASED IN PATIENTS AND THE
INCREASE WAS NEGATIVELY
CORRELATED WITH PULMONARY
FUNCTION DECLINE.
IT MAY HAVE A BIOMARKER THE LAST
COUPLE YEARS WE ALSO TRIED TO
UNDERSTAND THE SPECIFIC OF CV1
IN THE PATHOLOGY.
WE IDENTIFIED THE CC1 RECEPTOR
IS RESPONSIBLE FOR THE ALVEOLI
AND RESPONSIBLE FOR CD2O6
EXPRESSION WHICH MAKES
FIBROBLASTS FIBROTIC SORRY,
MACROPHAGES PROFIBROTIC AND
CONTRIBUT
CONTRIBUTING WITH THE MARKERS
AND WE THOUGHT WE SHOULD
INVESTIGATE THE ROLE IN ALCOHOL
INDUCED LUNG INJURY.
THE SAME ANIMAL MODELS WE FOUND
IT INCREASED IN THE LUNG AND
ONLY INCREASED NINE HOURS, 24
HOURS RETURNING BACK BUT THE
GENE EXPRESSION WAS HIGHLY
ELEVATED.
NOW IN THE PREVIOUS SLIDE I WAS
TALKING ABOUT MACROPHAGE AND YOU
CAN ASK ABOUT THE STATUS OR
EXCREMENTAL MODEL.
WE CHECKED WITH THE FLOW
CYTOMETRY.
YOU SEE THE CD 1 LUNG EXPRESSION
INCREASED WITH FIBROSIS.
SIMILARLY ALCOHOL INCREASES THE
CD 1 EXPRESSION AND THAT'S
RETURNING BACK 24 HOURS.
WE WANT TO EXPLORE MORE THE V1.
I THINK ONE OF THE IDEAL MODELS
OR GROUP IS VOLUNTARY DRINK
MODELS IN NON-HUMAN PRIORITIES
AND ILD PATIENTS.
WE WERE FORTUNATE TO ESTABLISH
COLLABORA
COLLABORATION AND DEVELOPED A
DRINKING MODEL IN NON-HUMAN
PRIMATES AND THEY COLLECTED THE
LAVAGE AT THE BASELINE AND THE
ESCALATED THE DOSE AND AT THE
END THEY LET THE MONKEYS GO I
THINK 22 HOURS A DAY.
AT THE END IT COLLECTED AND WHAT
WE FOUND INCREASE IN THE LAVAGE.
THIS WAS THE SAME OBSERVATION WE
FOUND WITH THE MOUSE MODEL BUT
ONCE WE CHECKED LONG-TERM
VOLUNTARY DRINKING THERE'S
REMARKABLE ALMOST 22 INCREASE WE
WERE INTERESTED IN THE STATUS OF
THE HUMAN WE WERE FORTUNATE TO
ESTABLISH COLLABORATION FROM THE
COLORADO PULMONARY ALCOHOL
RESEARCH COLLABORATIVE AND
ASSESSED SAMPLES BUT DESIGN A
STUDY TO SELECT SAMPLES OF 40
HEALTHY INDIVIDUALS AND HAVE
BLOOD ALCOHOL -DRINKERS AND HAVE
AUD PATIENTS EITHER SMOKERS OR
NON-SMOKERS BUT WE WERE ALSO
DISCUSSING OBVIOUSLY THEY'RE NOT
DRINKING ALCOHOL AND THOUGHT
MAYBE THOUGHT IT MAY BE A MATTER
FOR OUR MEASUREMENT.
THAT'S WHY WE STRATIFIED THE
GROUPS SELECTING PATIENTS FROM
THE FOUND NON-SMOKERS AND WITH
ALCOHOL PATIENTS THERE'S A
SIGNIFICANT INCREASE OF A BR
BRONCHIAL LAVAGE AND ALL THIS
SUGGES
SUGGESTED THE CHRONIC ALCOHOL
DRINKING IN LUNGS AND WE'RE
WORKING ON THE ACTIVATION MAY
CONTRIBUTE INJURY PROCESS IN THE
LUNG AND IT REQUIRES FURTHER
INVESTIGATION BUT WE'RE WORKING
ON THIS.
I'D LIKE TO THANK MY LAB MEMBERS
INVOLVED IN THE STUDIES AND
COLLABORATIONS AND JUDY IS
INSTRUMENTAL IN HELPING WITH THE
MASS SPEC MEASUREMENTS AND NIAAA
LEADERSHIP AND THE CONTINUOUS
SUPPORT IN THE INTRAMURAL
PROGRAM AND AND HELP WITH
RESEARCH AND COLLABORATORS.
THANKS.
I'LL BE ABLE TO ADDRESS IF YOU
HAVE QUESTIONS.
>> GREAT TALK.
I ALWAYS HAVE A HUNDRED
QUESTIONS.
IS POLLUTION ACTIVATED?
WHAT ABOUT CIGARETTE SMOKING, IS
THERE A VIRAL OR BACTERIAL
COMPONENT.
YOU DIDN'T TELL US WHAT CAUSES
LUNG FIBROSIS AND THEN ALCOHOL
CLEARLY INTERACTS I'M ASSUMING.
THERE'S SOME EVIDENCE AND ARDS
IS CAUSING A SOMEWHAT OF A
FIBROTIC CONDITION BUT IT'S
RESOLVED.
AND COVID WE LOST PATIENTS DUE
TO THE REMARKABLE FIBROTIC
PROCESS IN A SHORT TIME AND
BASICALLY THE LUNG CANNOT GO
WITH THAT AMOUNT OF FIBROTIC
PROCESS.
PEOPLE DIED BECAUSE LUNG
FIBROTIC PROCESS PEOPLE CALL IT
LUNG FIBROSIS.
MOST DIE BECAUSE OF THE SAME
REASON BECAUSE OF A RESPIRATORY
INFECTION AND WERE HOSPITALIZED
BUT THEY DIE OF THE SITUATION.
AND CIGARETTE IS ASSOCIATED AND
PEOPLE ARE TRADING IT WITH SOME
OF THE AREA PEOPLE LIVE WITH THE
AIR POLLUTION HAVE SIGNIFICANT
DECLINE.
I TRIED TO TAKE EVIDENCE THAT
MAKES SENSE.
>> DOES ANYONE ONLINE HAVE A
QUESTION?
>> IT'S A VERY INTERESTING TALK.
THANK YOU.
>> IS THERE INFORMATION ON THE
ALCOHOL-RELATED FIBROTIC DISEASE
ON ATHLETIC PERFORMANCE.
FROM A PREVENTION POINT OF VIEW
IT SEEMS IF THERE'S SOME
RELATIONSHIP THAT WOULD BE A
POWERFUL PREVENTION TOOL BECAUSE
PEOPLE PARTICULARLY YOUNG PEOPLE
WANT TO INCREASE THEIR ATHLETIC
PERFORMANCE.
SO IS THERE A RELATIONSHIP COULD
THERE BE A RELATIONSHIP BETWEEN
SAY HOW FAST AND HOW LONG PEOPLE
CAN RUN.
ARE THERE PEOPLE WHO ARE RUNNERS
A MILE, HALF MILE, QUARTER MILE,
WHATEVER, CROSS COUNTRY.
AND THE OTHER THING THAT STRUCK
ME IS WHETHER OR NOT SMOKING
WHETHER THE SMOKING AND ALCOHOL
FIBROSIS WHEN YOU PUT THE TWO
TOGETHER WHETHER THE IMPACT IS
ADDITIVE OR LESS THAN ADDITIVE?
>> I'LL START WITH THE SECOND
QUESTION.
EXCELLENT QUESTION.
WE'LL START BUT THE DATA THE
SMOKING MAY HAVE A CONTRIBUTORY
ROLE AND MAY TAKE THE
EXPERIMENTAL MODEL AND LOOK AT
THE DATA TO UNDERSTAND I
MENTIONED THE LUNG DECLINE.
THE LUNG CAPACITY IS CRITICAL
FOR THIS -- IT'S ONE CAPACITY.
ONE THING IS BASED ON THE
CURRENT EVIDENCE, IF IT HAS A
VITAL INFECTION OR SOMETHING
GOING ON AS THE SECONDARY
INJURY, I THINK ALCOHOL
CONSUMPTION BECAUSE IT CAUSE
DELAY OR PERTURBATION THEY'LL
NOT BE READY FOR THE EVENT
BECAUSE THE RECOVERY TIME CAN BE
DELAYED.
I DON'T -- I CANNOT RECALL ANY
EPIDEMIOLOGICAL DATA BECAUSE
THESE ARE YOUNG PEOPLE BUT I GOT
INTERESTED AND WAS LOOKING AT
THE DATA PARTICULARLY FOR THE
BRANCHING AMINO ACID PART
BECAUSE MANY BODY BUILD ARE
USING THE BRANCH CHAIN AMINO
ACIDS AS A SUPPLEMENT.
AND MANY COLLEGE STUDENTS CAN
HAVE A BINGE DRINKING AND BEFORE
OR AFTER THEY CAN HAVE A
PHYSICAL ACTIVITY.
THEY CAN HAVE BRANCH AMINO ACID
SO WE WERE THINKING SINCE WE
FOUND THE UTILIZATION IS
IMPORTANT IN THE LUNG, WHETHER
IT MAY HAVE SOME ASSOCIATION OR
NOT AND IT COULD BE INTERESTING
TO INFORMING US AS AN EVIDENCE.
AT OUR DATA SHOWED IT'S CRITICAL
BUT WE CANNOT RESTORE ANYTHING
BUT THEY'RE ALL GREAT QUESTIONS
AND PEOPLE CAN INFORM US IN THE
PICTURE.
>> THERE'S A QUESTION FROM
FRANCES LEVIN FROM COLUMBIA.
>> THIS IS A GREAT TALK.
I THINK YOU SAID THE CB1
ANTAGONIST MAY HAVE SOME UTILITY
AND IF I GOT THAT WRONG YOU CAN
CORRECT ME BUT THE PROBLEM WITH
SUICIDAL IDEATION WITH THE
ANTAGONIST BUT WONDERING IF
THERE'S A FORM THAT DOESN'T
ACROSS THE BLOOD BRAIN BARRIER
AND I'VE LOOKED AT SIGNALLING
SPECIFIC NEGATIVE MODULATOR THE
CB1 RECEPTOR AND WHETHER THAT
MIGHT HAVE UTILITY.
YOU ARE ALWAYS THINKING ABOUT
OKAY WHAT DO YOU DO ABOUT THIS
PROBLEM.
CERTAINLY DRINKING LESS IS ONE
OPTION BUT HOW CAN YOU HELP THEM
BUT I THOUGHT THE TALK WAS
GREAT.
THANK YOU.
>> THE ANTAGONIST IS NOW IN THE
PHRASE II TRIALS BUT WE'LL SEE
THE SAFETY AND EFFICACY.
WE'RE TRYING TO LOOK AT THE
BIOLOGY IN THE EXACT CELL TYPES
BUT WE ALSO DEVELOP A STRATEGY
AND CAN INHALE TO THE LUNG
ALVEOLI AND RETAINED IN THE LUNG
AND HAVE A STRATEGY TO ENSURE
THE SYSTEMIC SAFETY.
THAT COULD BE AN APPROACH WE CAN
PURSUE.
>> YOU CAN FIND IT EASILY BY
SENDING AN E-MAIL.
>> THE FIRST IS THE GUT THEN
LIVER AND WHATEVER WE HAVE SEEN
IN THE STUDIES ARE SECONDARY
EFFECTS OF ALCOHOL AND CHRONIC
CONDITIONS.
SO IF YOU WANT TO TREAT ALCOHOL
USE DISORDERS SO WE WILL TREAT
FIRST OR GO FOR GUT-LIVER DAMAGE
TO SEE FIRST HERE AND THEN GO TO
LUNG, RIGHT?
AND I DON'T KNOW IF YOU LOOKED
AT THE EFFECT OF ALCOHOL ON
LUNG.
>> NICE BIG PICTURE QUESTION.
BASICALLY, ANY MEDICATION
REDUCING ALCOHOL INTAKE
ALLEVIATES THE SECONDARY
COMPLICATIONS.
ALSO SOME OF THE INDIVIDUALS
DEVELOPING THE LUNG DISEASE
DON'T HAVE ANOTHER COMPLICATIONS
AND TARGETED THERAPIES
>> DO YOU THINK ACUTE ALCOHOL
CONDITION AFFECTS LUNGS?
>> I TALKED ABOUT ACUTE EFFECT
BUT RIGHT NOW WE ARE TRYING TO
ESTABLISH THE MODEL AND THEN
BRIDGING THE TRANSLATION.
I THINK THAT WILL BE INTERESTING
TO FOLLOW ACUTE OR CHRONIC
INTERVENTION AND CHALLENGE WITH
THE SECONDARY INJURIES.
THANK YOU.
>> THAT WAS SUPER.
WE'LL MOVE ON TO OUR NEXT TALK
FROM DAYNE MAYFIELD.
ARE YOU ON?
DO YOU WANT TO LOAD YOUR SLIDES.
HE'S A PROFESSOR IN THE
DEPARTMENT OF NEUROSCIENCE AND
FOUNDING MEMBER OF THE WAGNER
CENTER FOR ALCOHOL AND ADDICTION
AND PART OF THE INITIATIVE ON
ALCOHOLISM NEURO IMMUNE A
MULTI-DISCIPLINARY EFFORT
STUDYING BRAIN MECHANISMS THAT
UNDER LIE ALCOHOL MISUSE AND
STRESS AND ANXIETY.
HE BRINGS DEEP KNOWLEDGE OF THE
MOLECULAR AND CELLULAR
MECHANISMS IN THE CENTRAL
NERVOUS SYSTEM AND MAY
CONTRIBUTE TO OTHER SUBSTANCES.
HIS WORK HAS LED TO NEW DRUG
TARGETS AND BIOMARKERS OF
ALCOHOL AND OTHER SUBSTANCE
MISUSE.
THIS IS A HUMBLE DESCRIPTION SO
I ACTUALLY WENT TO LOOK AT THE
MORE SEM NAL PAPERS AND
MOLECULAR PSYCHOLOGY AND ALCOHOL
USE IN THE HUMAN BRAIN.
IN THE JOURNAL OF NEUROSCIENCE
HE LOOKED AT EPIDEMIOLOGIC
MODIFICATIONS AND LOOKED AT
SINGLE CELL TRANSCRIPTOME
PROFILING OF THE HUMAN ALCOHOL
DEPENDENT BRAIN.
HE'S ALWAYS BEEN AT THE CUTTING
EDGE OF WHERE MOLECULAR BIOLOGY
MEETS ALCOHOL NEUROSCIENCE AND I
HOPE THE TOPIC IS GLIAL CELL
DIVERSITY IN ANIMAL MODELS AND
MOVED BEYOND NEURONS.
IT'S ALWAYS YOURS.
>> HOPEFULLY YOU CAN HEAR ME.
I'LL TALK ABOUT WORK WE'RE DOING
IN BRAIN SINCE WE HAVE A GLIAL
FOCUS AND IMMUNE SYSTEMS ARE THE
MAJOR TOPIC HERE, ONE OF THE
THINGS WE DON'T KNOW IS HOW DO
IMMUNE SIGNALS GET FROM THE
PERIPHERY TO THE BRAIN.
DO THEY ORIGINATE IN THE BRAIN?
THERE'S A LOT OF UNANSWERED
QUESTIONS AND THE DISCUSSION WE
PREVIOUSLY HAD REALLY POINT TO
THE QUESTIONS.
I WANT TO POINT OUT WHAT REALLY
DRIVES THE WORK THAT WE'RE ALL
TALKING ABOUT THAT WE'RE ALL
DOING AND THAT IS HERE IN THE
FUNDING.
AND NOTHING WOULD ROLL WITHOUT
THIS SO I WANT TO MAKE SURE TO
GET THE PLUG IN NOW.
AS GEORGE MENTION ED I WANT TO
TALK ABOUT THE LARGE COLLECTIVE
EFFORT AND THIS IS A GROUP OF
INVESTIGATORS ACROSS THE COUNTRY
WITH ALL KINDS OF EXPERTS AND
COLLABORATORS ARE PART OF THE
WORK I DO AT THE INDIANA SCHOOL
OF MEDICINE AND ALLISON GOAD AT
THE MOUNT SINAI SCHOOL OF
MEDICINE.
IN THE WAGNER CENTER WAS
DIRECTED WITH A RICH
ENENVIRONMENT THAT ALLOWS US TO
DO A LOT OF WORK THAT WOULD BE
HARD TO DO ELSEWHERE.
GRADUATE STUDENTS AND
TECHNICIANS HAVE ALL BEEN GREAT
AND THEY'RE TO THE ONES THAT DO
THE WORK AND I JUST GET TO TAKE
CREDIT FOR IT.
I APPRECIATE THE HARD WORK AND
THEY APPRECIATED PHARMACY AND
PHARMACOLOGY.
I WILL SAY THAT I WAS TRAINED IN
THE '80s AS A PHARMACOLOGIST.
MOST OF WHAT I WAS DOING BACK IN
THOSE DAYS WAS INVESTIGATING
SINGLE MOLECULES WHETHER IT'S AT
A GENE LEVEL OR PROTEIN LEVEL
AND HAMMERING TO UNDERSTAND HOW
ALCOHOL MIGHT IMPACT THOSE
PARTICULAR MOLECULES.
AFTER 10 OR 15 YEARS I GOT
INTERESTED IN MORE SYSTEMS LEVEL
APPROACHES AT THE TIME THE
GENOMICS FIELD WERE STARTING TO
EXPLODE AND STARTED TO
APPRECIATE COMPLEX DISEASE
STATES LIKE ALCOHOL USE DISORDER
AND IN A SLIGHTLY DIFFERENT WAY
AND IT'S SUMMARIZED IN THE SLIDE
WHETHER IT'S ALCOHOL USE
DISORDER OR OTHER PSYCHIATRIC
DISEASES.
WE ARE TRYING TO LEARN ABOUT
WHAT ARE THE MOLECULES AND
SYSTEMS THAT CONTRIBUTE TO A
HEALTHY STATE VERSUS A
PRE-DISEASE STATE AND FINALLY A
DISEASED STATE AND AN
UNDERSTANDING OF THESE PROCESSES
REALLY REQUIRES KNOWLEDGE OF A
LOT OF DIFFERENT DATA TYPES.
SO EACH OF THESE TWO DIMENSIONAL
LAYERS ARE COMPOSED OF DIFFERENT
TYPES OF DATA WHETHER IT'S
EPIDEMIOLOGIC DATA AND PROTEOME
AND SO ON AND THIS STARTS TO
BUILD A MORE COMPLETE PICTURE OF
A COMPLEX DISEASE STATE AND IT
IMPACTS MANY PROTEINS AND MANY
DIFFERENT GENES AND ALL AT THE
SAME TIME.
SO THIS IS ONE OF THE THINGS
THAT REALLY MOVED ME INTO A
SYSTEMS LEVEL STUDY APPROACH OF
ALCOHOL.
IF YOU LOOK AT ALCOHOL USE
DISORDER AND HERE I'M SHOWING
THE MODEL OF THE THREE STAGES OF
ADDICTION.
THIS IS SOMETHING THAT GUIDES A
LOT OF THE WORK IN THE HUMAN
BRAIN AND I THINK EVERYONE HAS
SHOWN THE PICTURE OR TALK AT
SOME POINT AND CAPTURES THE
DIFFERENT ASPECTS OF ALCOHOL USE
DISORDER WHETHER PREOCCUPATION,
INTOXICATION OR NEGATIVE AFFECT
AND THE BRAIN REGIONS INVOLVED.
THEY'RE VERY DIFFERENT
CONSTRUCTED AND HAVE TO BE
THOUGHT OF IN DIFFERENT WAYS.
AND THEY CONTRIBUTE TO THE
ADDICTION CYCLE AND I'VE
UTILIZED POSTMORTEM BRAIN FROM
DONORS COMPARED TO THE
NEUROTYPICAL CONTROLS FOR MANY
YEARS TO GET AN IDEA OF THE
HUMAN SIDE OF THIS EQUATION BUT
WE ALSO USE ANIMAL MODELS.
WE USE GENETIC MODELS AND ANIMAL
MODELS OF VOLUNTARY CONSUMPTION
AND WE IN MY LAB WE TRY TO FOCUS
ON THESE TRANSLATION EVENTS AND
WHAT I'VE LEARNED IN HUMAN BRAIN
I WANT TO MAKE SURE THE ANIMAL
MODELS ARE ACTUALLY VALID MODELS
TO STUDY THESE PLAYERS AND VICE
VERSA, THE ANIMAL MODELS ARE
INFORMING AND PROVIDING
TRANSLATIONAL VALUE TO THE HUMAN
AUD CONDITION.
SO THE ANIMAL MODELS AND HUMAN
BRAIN ARE THE STARS OF THE SHOW.
AND MANY YEARS I'LL CALL THE
TURN OF THE CENTURY BECAUSE IT
MAKES IT SEEM LIKE A LONG TIME
AGO BUT WAS ONLY 25 YEARS AGO.
WHEN WE STARTED DOING
TRANSCRIPTOME WORK IN HUMAN
BRAIN WE SAW SOMETHING WE DIDN'T
EXPECT AND KNEW WE'D FINE NEURON
COUPLE RECEPTOR CHANGES BUT WHAT
WE SAW WITH ARE GENES AND MANY
GENES THAT ARE KNOWN TO BE
INVOLVED IN THE IMMUNITY DEFENSE
AND OTHER IMMUNE SYSTEMS AND WE
DIDN'T REALLY FOCUS ON THIS A
LONG TIME WE DON'T KNOW IF IT
WAS FACTUAL OR REAL BECAUSE THE
BRAIN IS A CLEAN ORGAN AND
DIDN'T KNOW WHY THE SIGNALS WERE
PRESENT IN DATA.
AFTER A NUMBER OF OTHER STUDIES
AND A FEW ARE HIGHLIGHTED ON THE
PAGE MOST ARE NEXT GENERATION
SEQUENCING FROM BULK BRAIN, BUT
ALL OF THEM CONTAIN IMMUNE
RESPONSES.
I WANT TO SHOW A LARGER STUDY.
THIS IS PART OF THE NEUROIMMUNE
AND COLLABORATIVE EFFORTS THAT
WE'VE DONE.
THIS IS A FEW YEARS AGO AT THE
TIME WE INTEGRATED MULTI-OMIC
DATA FROM A LARGE COHORT OF
POSTMORTEM BRAIN.
WE UTILIZED TRANSCRIPTOME
INFORMATION AND INTEGRATED GWAS
FROM ALCOHOL DEPENDENCE FROM THE
PGC AS WELL AS U.K. BIO BANK AND
ALCOHOL CONSUMPTION DATA AS WELL
AS THE DATA FROM 461 POSTMORTEM
BRAIN PART OF THE PROJECT.
IT'S A LARGE INTEGRATIVE EFFORT
TO TO UNDERSTAND THE IMPORTANT
PLAYERS IN HUMAN BRAIN.
THE IMMUNE RESPONSE WAS THERE
AND A STRONG SIGNAL THE MORE
PRONOUNCED THE SIGNALS WERE, G
WAS ENRICHMENT AND MODULES
RELATED TO IMMUNE RESPONSE.
IT'S PRETTY CONVINCING THE
IMMUNE SIGNALS ARE REAL.
THEY'RE ALL ASSOCIATED WITH
ALCOHOL USE AND SO THESE ARE
CORRELATED WITH LIFE TIME
ALCOHOL CONSUMPTION.
WE AND OTHERS STARTED TO FOCUS
IN ON NEURO IMMUNE SIGNALLING AS
BEING INVOLVED IN EXCESSIVE
ALCOHOL CONSUMPTION AND WE AND
OTHERS DEVELOPED THIS
NEUROIMMUNE HYPOTHESIS THAT
BASICALLY STATES OVER ACTIVATION
OF THE IMMUNE SIGNALLING WITH
ALCOHOL CONSUMPTION WE KNOW TOLL
WIDE RECEPTORS AND OTHER
RECEPTORS AND PATHWAYS ARE
INVOLVED AND INITIATING P
PROINFLAMMATORY RESPONSES AND
ALTERED IN RESPONSE TO CHRONIC
ALCOHOL.
SO THE PLOT ON THE RIDE
SUMMARIZES A LOT OF THIS
INFORMATION AND IT'S SHOWING
THAT WHETHER IT'S LIFE TIME
ALCOHOL CONSUMPTION ACROSS THE X
AXIS AND LIFE TIME CONSUMPTION
IN HUMANS OR REPEATED BINGE
DRINKING IN AN ANIMAL MODEL OR
INTERMITTENT VAPOR
ADMINISTRATION LEAD TO THE
INCREASE IN NEUROIMMUNE
EXPRESSION OVER TIME RESULTING
IN INCREASED LIFE TIME
CONSUMPTION OF ALCOHOL OR
INCREASED ALCOHOL CONSUMPTION IN
ANIMAL MODELS.
IT'S BEEN THE DRIVER FOR A
NUMBER OF YEARS FOR A LOT OF THE
WORK WE'VE DONE.
SO, FOR TODAY'S TALK, I CAN'T
TALK ABOUT ALL THE GLIAL CELLS
BUT GIVEN WHAT WE'VE SEEN WE
KNOW THE IMMUNE SIGNALLING IN
BRAIN HAS MORE THAN JUST NEURONS
INVOLVED SO I'LL TALK
SPECIFICALLY ABOUT MICROGLIA
TODAY FOR THE TALK AND A LOT OF
IS KNOWN IN THE ALCOHOL FIELD
ABOUT THE ROLE OF GLIAL CELLS,
MICROGLIAL CELLS IN AUD, CHRONIC
ALCOHOL LEADS TO
PRO-INFLAMMATORY STATES FOR THE
CELLS AND ALSO CAUSES NEURONAL
DAMAGE DEGRADATION.
ALSO IMMUNE SIGNALLING RELEASES
CHEMOKINE ACTIVATE OTHER IMMUNE
SYSTEMS IN THE BRAIN THAT ALTER
ALCOHOL CONSUMPTION.
SO WE DO KNOW A LOT ABOUT
MICROGLIA AT A SPECIFIC CELL
LEVEL.
WE DON'T KNOW HOW THIS MIGHT BE
IMPACTING IMMUNE SIGNALLING AND
WE DON'T KNOW EXACTLY WHERE
MICROGLIA SIGNALLING COMES FROM.
DOES IT ORIGINATE FROM BRAIN OR
NOT.
AND A LOT OF THE WORK WE'VE DONE
FOR YEARS HAS TAKEN THIS SORT OF
DICHOTOMY APPROACH WHERE
MICROGLIA ARE GOOD OR BAD AND
RESTING VERSUS ACTIVATED AND
THAT'S GREAT.
WE'RE USUALLY MORPHOLOGICAL
CHARACTERISTICS AND IT'S A GOOD
WAY TO CLASSIFY CELLS.
IT'S EASY TO QUANTITATE AND
OBSERVE AND THAT'S FINE BUT WITH
THE SYSTEM LEVELS APPROACHES THE
GLIAL CELLS ARE EXISTING IN
MULTIPLE STATES.
THEY TRANSITION BETWEEN THESE
STATES SO RATHER THAN A SIMPLE
DICHOTOMY, THE IMPACT THAT
ALCOHOL HAS ON GLIAL CELLS AND
MICROGLIA ESPECIALLY RESULTS IN
SHIFTS IN STATES THAT ULTIMATELY
REDUCES THE DIFFERENT FUNCTION
FOR THE CELL.
ONE OTHER PIECE OF INFORMATION
AND WE DIDN'T KNOW WHAT
MICROGLIA DID IN THE CONTEXT OF
ANIMAL MODELS AND THE CIV
DEPENDENCE MODEL WHERE REPEATED
BOUTS OF ALCOHOL VAPOR REDUCE
THE ESCALATION AND VOLUNTARY IN
TAKE OF ALCOHOL.
WE WERE CURIOUS DOES
MANIPULATION OF MICROGLIA ALTER
THE IMPORTANT PHENOTYPE AND THE
PHENOTYPE'S IMPORTANT BECAUSE
THE COMMON FEATURE IS THE
DEPENDENCE COMPONENT AND I
WANTED TO RELATE THAT TO THE
HUMAN AUD DONORS.
THE SIMPLE EXPERIMENT WASN'T
SIMPLE BUT LONG AND HARD AND
USED THE COLONY STIMULATING ONE
RECEPTOR INHIBITOR TO BASICALLY
ELIMINATE MICROGLIA AND LOOK AT
THE IMPACT IT HAD ON MICROGLIA
PERFORATION AND
ELECTROPHYSIOLOGICAL RESPONSES
AND ALCOHOL RELATED PHENOTYPES.
AND SO THE IMPORTANT THING I
WANT TO THROW YOUR ATTENTION TO
HERE WILL BE THE PHENOTYPES THAT
WE SAW IN THESE ANIMALS
NON-DEPENDENT ANIMALS THAT DID
NOT GO THROUGH CHRONIC
INTERMITTENT ALCOHOL.
THEY DID THEIR USUAL DRINKING
AND THEY WOULD DRINK THE SAME
AMOUNT OF ALCOHOL AND ALMOST
COMPLETE DEPLETION OF MICROGLIA
DID NOTHING TO NON-DEPENDENT
DRINKING ANIMALS BUT IN THE
DEPENDENT COHORT ELIMINATION
RESULTED IN THIS CLASSIC
INCREASE THAT WAS BLOCKED BY
ELIMINATION OF MICROGLIA.
WE KNOW THERE'S SOMETHING
SPECIAL ABOUT THIS PARTICULAR
CELL TYPE.
SO WE'VE FOCUSSED A LOT ON
MICROGLIA IN THE LAST FEW YEARS.
FOR A MIXTURE OF ALL BRAIN CELL
TYPES.
BRAIN WAS COMPOSED OF DIFFERENT
CELLS AND STATES OF CELLS AND SO
FOR THE LAST SEVERAL YEARS WE'VE
BEEN UTILIZING SINGLE CELLS AND
NUCLEUS APPROACHES AS WELL AS
SPATIAL APPROACHES TO START TO
TEASE A PART THE IMPACT OF
CELLS.
WE SEE THE MULTIPLE SUB CLASSES
OF CELLS CAN BE OBSERVE D IT THS
IS A VERY POWERFUL APPROACH WE
CAN USE IN OUR ALCOHOL STUDIES.
ULTIMATELY WE WANT TO DISCOVER
CELL TYPES OR STATES IMPORTANT
AND HOW THE CELLS CHANGE OVER
TIME BUT REALLY WE WANT TO KNOW
WHAT ARE THE OVER ALL
CROSS-SPECIES OVERLAPS BETWEEN
THE TRANSCRIPTOMES.
SO GEORGE MENTIONED THIS EARLY
STUDY WE DID WITH HUMAN
POSTMORTEM BRAIN USING
TRANSCRIPTOME PROFILING.
IT WAS A SMALL COHORT AND PROOF
OF CONCEPT.
WE CAN LOOK AT A CLUSTER OF
CELLS THAT REPRESENT THE CELL
TYPES IN BRAIN THIS IS SHOWN IN
EXAMPLES OF INDIVIDUAL GENES
SHOWN AS THE VIOLIN PLOTS AS A
FUNCTION OF DIFFERENT CELL TYPES
IN BRAIN.
BOTH OF THESE ARE KNOWN TO BE
ALCOHOL RESPONSIVE AND SHOWING
THE DATA FROM THE AUD AND GREEN
IS FROM CONTROLS.
YOU SEE THE EXPRESSION LEVEL AND
CASE CONTROL AND A SPECIAL
PATTERN WHERE MICROGLIA EXPRESS
RATHER THAN THE OTHERS.
IN ADDITION TO THE SPECIFIC CELL
TYPE IDENTIFIERS IT WAS CLEAR
WHAT WE WERE MISSING IN OUR
SEQUENCING WAS THE MICROGLIA
SIGNAL AND WE WERE MISSING A LOT
OF INFORMATION ABOUT MICROGLIA.
MOVING TO JUSTIFYING THE COST OF
THE LARGER EXPERIMENT.
WE DID PROFILE AN ADDITIONAL
COHORT OF INDIVIDUALS.
THIS IS A LARGE COHORT.
THIS WAS 73 INDIVIDUAL DONORS.
ALL THIS WORK IS DONE ENDORSAL
ENDORSAL -- IN DORSAL LATERAL
BRAIN AND THIS IS REPRESENTED
ACROSS THE 73 SAMPLES ARE
PRESENTATIONS OF DSM5 SEVERITY.
THERE'S A RICH SET OF CLINICAL
INFORMATION AVAILABLE FOR ALL
AND I'M LISTING A FEW YEAR.
WE DO HAVE VERY STRICT INCLUSION
CRITERIA FOR OUR CASES SO
THERE'S NO COMORBIDITYIES AND TE
ALCOHOL DRINK EERS HAVE FEW
COMORBIDITIES FOR THIS COHORT.
WITH 73 INDIVIDUAL CASES, THIS
RESULTS IN SOME 650,000 TO
700,000 TRANSCRIPTOME.
THIS RESULTS IN A LOT OF DATA.
I'M NOT GOING TO TALK ABOUT THE
DATA PROCESSING BUT THE STUDY IS
DOING JUST THAT.
IDENTIFYING THE DATA AND MAKING
SURE THERE'S NO DOWN STREAM AND
THE DOWN STREAM ANALYSIS IS WHAT
I'LL TALK ABOUT AND THE
EXPRESSION GENE NETWORK THE WAY
IT EXPRESSES IN ANALYSIS AND SO
ON.
WITH WE IDENTIFIED 32 DISTINCT
CELL TYPE CLUSTERS SHOWN IN THE
SPACE.
WHICH THIS IS A SIMPLE WAY TO
DISPLAY A LOT OF DATA.
YOU CAN SEE IT IN TWO
DIMENSIONS.
THE SUB CLUSTERS OF CELLS ARE
SHOWN AND THIS IS MULTIPLE SUB
CLUSTERS.
ASTROCYTES AND IF YOU LOOK AT
THE PROPORTION OF CELL TYPES
THEY FOLLOW WHAT WE HAVE KNOWN
FOR BRAIN FOR A WHILE.
AND EXCITATORY NEURON HAVE THE
HIGHEST PROPORTION AND
DENDROCYTES AND ASTROCYTES.
ALL THE PROPORTIONS ARE THOUGHT
OF AND THE PROPORTIONS ARE NOT
ALTERED BY AUD STATE.
ONE OF THE THINGS WE'RE ALWAYS
CONCERNED ABOUT IS IF WE HAVE A
HIGHLY DECEASED BRAIN WE'LL LOSE
REPRESENTATION OF CELLS BECAUSE
THEY'LL HAVE DIED OFF AND THAT
WAS NOT EVIDENT IN THE DATA.
THAT'S ALSO SHOWN HERE IF YOU
TALK THE MAP AND SPLIT IT AUD
AND CONTROL DONORS THE CLUSTER
OF CELLS ARE REPRESENTED BY AUD
DONORS AND NEUROTYPICAL
CONTROLS.
WE HAVE A COHORT OF INDIVIDUALS
AND THE OTHER GLIAL CELLS WERE
HIGHLY DYSREGULATED.
THERE'S NOT TIME TO GO INTO ALL
THE FINDINGS.
THIS WORK SINCE WE DIDN'T GET TO
PRESENT THIS IN FEBRUARY, THE
MANUSCRIPT CAME OUT BETWEEN
FEBRUARY AND NOW AND IS
AVAILABLE ONLINE IF YOU WANT TO
LOOK AT IT.
THE GLIAL CELLS ARE THE MOST
DYSREGULATED AND SHOWN HERE FOR
ALL CELL TYPES WHERE THE UPWARD
DEFLECTED BARS SHOWING
UPREGULATION OF DIFFERENTIAL
EXPRESSION THE DOWNWARD
DEFLECTIONS ARE DOWN REGULATED
GENES FOR THE MAJOR CELL
CLASSES.
EACH OF THE BARS ARE DIVIDED
INTO SUB CLUSTERS OF CELLS AND
IT'S CLEAR ASTROCYTES HAVE BY
FAR THE GREATEST NUMBER OF
DYSREGULATED GENES FOLLOWED BY
THE ADENDROCYTES AND MICROGLIA
AND THEY WERE THE MOST
DYSREGULATED IN TERMS OF
DIFFERENTIAL EXPRESSION.
NOW IT TAKE A DEEP DIVE IN THE
MICROGLIA POPULATION AND WHERE I
WANTED TO GET WITH THE DATA SET.
LET'S FOCUS ON WHAT'S
HIGHLIGHTED IN THE SQUARE.
THE MICROGLIA POPULATION SUB
CLUSTERED INTO TWO DIFFERENT
POPULATIONS I'M CALLING THOSE
MG1 AND MG2.
NOT TO BE CONFUSED WITH THE
CLASSIFICATION SCHEMES I TALKED
ABOUT EARLIER.
THAT'S A DIFFERENT AND THIS IS A
CLUSTER NAME THAT WAS APPLIED TO
THE CLUSTER.
IF YOU LOOK AT THE AUD DONORS IN
TERMS OF THE PROPORTION OR
CONTRIBUTIONS TO MG1 AND MG2,
YOU SEE THE CONTROL SAMPLES HAD
A MUCH GREATER PROPORTION OF THE
LARGER MG1 CLUSTER COMPARED TO
AUD WHILE THE AUD SAMPLES HAD A
HIGHER PROPORTION OF THE MG2
CLASSIFICATION.
AS A CLUSTER THE MICROGLIA
CLUSTER OF CELLS SEEMS TO BE
CHANGING OR TRANSITION TRANSITIF
YOU LOOK AT THE INDIVIDUAL
CLUSTER, THIS IS WHERE WE
STARTED TO FIND THINGS THAT WERE
NOT EXPECTED IN THE DATA
NECESSARILY.
SO THIS IS A LITTLE BIT OF A
COMPLICATED PLOT BUT HERE I'M
BREAKING DOWN EACH OF THE GLIAL
CLUSTERS 1 AND 2 AND SHOWING
REPRESENTATION OF CANONICAL
MARKERS ASSOCIATED WITH
MICROGLIA OR INFLAMMATORY CELL
STATES.
AND SO THE COLOR CODES HERE THE
HOMEOSTATIC AND PRO-INFLAMMATORY
AND PAINTED ON THE RIGHT SIDE SO
YOU SEE THE CANONICAL MARKERS
AND EXPRESSION LEVEL FOR EACH OF
THE MARKERS.
AND THE STRIKING THING HERE IS
THAT WITH HOMEOSTATIC MARKERS,
THE MG1 CLUSTER IS PRIMARILY
ASSOCIATED WITH HOMEOSTASIS
WHEREAS THE MG2 HAS A
COMBINATION OF INFLAMMATORY
MARKERS, WHICH WOULD BE
EXPECTED.
THAT'S NOT NEW, BUT WHAT WE
DIDN'T EXPECT IS TO HAVE
REPRESENTATION OF
DISEASE-ASSOCIATED MACROPHAGES
THE DAM SIGNATURE AND
BORDER-ASSOCIATED MACROPHAGE
THAT I'LL CALL DAB HERE AND THIS
IS IMPORTANT.
WE DON'T KNOW WHERE THESE
SIGNALS ORIGINATE.
THIS CAN COME BACK TO AS THE
PREVIOUS TALK AND THE SIGNALS IN
THE PERIPHERY WITH MACROPHAGE
INVOLVEMENT ARE THESE SIGNALS
THAT ARE MAYBE ORIGINATING IN
THE PERIPHERY AND GETTING TO THE
BRAIN.
WE DON'T KNOW.
THAT'S SOMETHING WE'RE WORKING
ON.
IT'S VERY CLEAR FROM WHAT WE'RE
SEEING HERE AND THIS WAS PRETTY
MUCH UNEXPECTED THAT THE MIC
MICROGLIA MARKERS TELL US ABOUT
THE GENE EXPRESSION SIGNATURES
WITHIN THE CLUSTERS.
AND IF YOU LOOK AT ENRICHMENTS
OF GENE ONCOLOGIES WITHIN THE
CLUSTERS, THE GREEN REPRESENTING
WHAT'S PRIMARILY IMMUNOSTATIC
MICROGLIA ASSOCIATED WITH
CONTROL INDIVIDUALS.
THESE ARE ENRICHED WITH PATHWAYS
KNOWN TO BE INVOLVED WITH
HOMEOSTASIS AND SIGNALLING AND A
TRANS MEMBRANE IMMUNE SIGNALLING
ADAPTER.
ALL OF THESE ARE DONE BY
HOMEOSTATIC MARKERS.
WHEREAS THE MT2 CLUSTER IS
ASSOCIATED MORE WITH CYTOKINE
SIGNALLING AND IMMUNE RESPONSE
AS YOU SEE FROM THE ONTOLOGIES
WITH IMMUNE SYSTEM DEVELOPMENT
AND DISEASE STATES.
THERE'S A CLEAR TRANSMISSION
ASSOCIATED WITH AUD.
I'M GOING TO MOVE NOW TO GENE
COEXPRESSION AND GO TO A MORE
SYSTEMS LEVEL LOOK AT THESE
CLUSTERS AND FOR THOSE THAT
DON'T KNOW ABOUT CO-EXPRESSION
NETWORKS.
THE BASIC IDEA IS YOU TAKE A SET
OF TRANSCRIPTS.
IF YOU PULL ALL THE MICROGLIA
TRANSCRIPTS AND ORGANIZE THEM
INTO GROUPS OF GENES WITH
SIMILAR EXPRESSION PATTERNS, AB
AND C FOR EACH IN THE CASE AND
YOU CAN IDENTIFY THE GENE
MODULES.
THE IDEA IS THEY USUALLY HAVE
DIFFERENT FUNCTIONS AND START TO
IDENTIFY THE GENE MODULES
CO-EXPRESSED WITH ONE ANOTHER.
WITHIN THE MODULES THERE ARE KEY
GENES THE ONES SHOWN IN GOLD.
THESE ARE GENES HIGHLY CONNECTED
TO THE OTHERS.
SO THESE ARE THE DRIVER GENES
FOR EACH OF THESE WHERE YOU CAN
DO CORRELATIONS WITH PHENOTYPES
AND SHOWN IN THE CARTOON IS YOU
CAN CORRELATE THE CO-EXPRESSION
MODELS WITH THINGS LIKE ALCOHOL
AND GENDER AND DSM5 STATUS TO
GET AN IDEA OF SETS OF GENES
THAT FUNCTION TOGETHER AND MAY
DRIVE SOME OF THESE CELLS WE'RE
TALKING ABOUT.
CO-EXPRESSION NETWORK ANALYSIS
RESULTED IN EIGHT SEPARATE
MICROGLIA EXPRESSION MODULES
SHOWN IN 1-M8 AND SEPARATED BY
AUD STATUS AND THE RED CIRCLES
IN THE STOP PLOT REPRESENT THE
GENE VALUES AND IT'S THE FIRST
COMPONENT OF THE CLUSTERS SO IT
GIVES YOU AN EXPRESSION AND YOU
SEE THE UP REGULATION OF AUD
RESULTED IN THREE MODULES UP
REGULATED GENE EXPRESSION.
IF YOU LOOK AT THE CLINICAL
VARIABLES COLLECTED AND I'M
SHOWING SIX HERE WHERE EACH OF
THE MODULES OF GENES ARE
CORRELATED WITH SEX, LIVER,
CLASS AND TOTAL DRINKING YEARS
AND SO ON AND YOU SEE A NUMBER
ARE HIGHLY CORRELATED WITH TOTAL
DRINKING YEARS RATHER THAN
INTAKE PER DAY OF ALCOHOL.
SO THE LONGER AN INDIVIDUAL
DRINKS, THE HIGHER THE
RELATIONSHIP IN THE COHORTS.
I WANT TO FOCUS ON TWO OF THESE.
THERE'S INFORMATION IN ALL THE
MODULES BUT I ONLY HAVE TIME TO
YOU CAN TA ABOUT TWO.
I'LL TALK MORE ABOUT AND WE'LL
LOOK AT 103 GENES AND I WANT TO
FOCUS ON THOSE BECAUSE THESE WE
DIDN'T EXPECT TO SEE IN THE
PARTICULAR STUDY.
IF YOU LOOK AT THE CRITERIA FOR
MODERATE AND SEVERE AND THE
MODULE 2 GENES OERCORRELATE TO D
TO MODERATE AND MODULE 3 IS
ASSOCIATED WITH SEVERE DRINKING.
SO MODULE 3 STANDS OUT IN THIS
CASE.
IF YOU CONSIDER THE DISEASE
ASSOCIATED MACROPHAGE POPULATION
AND START TO ASK QUESTIONS WHICH
PARTICULAR CLUSTERS ARE THESE
REGULATED IN, WHAT WILL THE HUB
GENES AND CONNECTIONS AND WHAT
DOES IT TELL US ABOUT THE MOTHER
YOU'LL SIGNATURE?
WHAT I'M DRAWING HERE THE
ORIGINAL MICROGLIAL STRUG TURE
IS IN MG1 AND 2 DIVIDED INTO AUD
STATUS AND CONTROL AND AND THIS
IS 70 GENES WORTH OF DATA AND
PLOTTED ON TOP OF CLUSTERS TO
SEE WHICH CLUSTERS THEY'RE
INVOLVED WITH.
THE FUNCTIONS ASSOCIATED WITH
THE DISEASE ASSOCIATED
MACROPHAGE INCLUDED F1, L2, CD83
AND IL1 BETA AND THEY SUBJECT
STRONG UP REGULATION OF
DISEASE-ASSOCIATED BORDERS
MACROPHAGE IN AUDs.
AND AGAIN THIS WAS NOT EXPECTED
AND GOT IMMUNE MOLECULES AND THE
CAPPA B.
THE MODULE 2 DOES CONTAIN A
STRONG SIGNATURE OF GENES NOVEL
TO THE ALCOHOL FIELD AND CONTAIN
RELEVANT KNOWN MARKERS.
AND MODULE 3 I WANT TO POINT
OUT.
THIS IS A WHITE MATTER WHITE
MATTER ASSOCIATED STATE AND
SOMETHING I WANT TO POINT OUT
BECAUSE THIS HAS BEEN ASSOCIATED
WITH PARKINSON'S DISEASE AND
THESE MACROPHAGES ARE KNOWN TO
BE INVOLVED WITH DISEASE-RELATED
SIGNATURES.
AND A BIOMARKER IN HUMANS AND WE
HAVE CLUSTERS OF MICROGLIA.
THESE ARE TWO OF THE FEATURES OF
THE GENE COEXPRESSION IN HUMAN
MICROGLIA.
IF YOU LOOK AT THIS AT THE WHEEL
OF MICROGLIA AND THE HOMEOSTATIC
MICROGLIA AND DISEASE STATES,
YOU SEE AUD IS REALLY RESULTING
IN STATE TRANSITIONS FROM THE
HOMEOSTATIC MICROGLIA PHENOTYPE
TO OTHER STATES OF MICROGLIA
WHICH IS INTERESTING BECAUSE WE
NEED TO LEARN MORE ABOUT WHERE
THESE ORIGINATE.
ARE THESE ORIGINATING IN THE
BRAIN OR MAKING THEIR WAY INTO
THE BRAIN.
SO THAT'S THE HIGH-LEVEL SUMMARY
FOR THE HUMAN DATA.
WE ALWAYS WANT TO GO BACK TO
ANIMAL MODELS AND ASK QUESTIOS
IDENTIFY FROM THE HUMAN AUD
DONORS OR CHECK TO MAKE SURE
THAT OUR ANIMAL MODELS ARE
TRANSLATING TO HUMAN AND WANT TO
SHOW AN INTEGRATING STUDY WITH
ANOTHER SINGLE CELL STUDY
PUBLISHED IN THE LAB LAST YEAR.
THESE ARE ANIMALS TREATED WITH
THE ALCOHOL DRINKING PARADIGM
THAT RESULTS IN ALCOHOL
DEPENDENCE.
THESE WERE PROVIDED BY MARISSA
ROBERTO'S GROUP AT SCRIPPS.
WE PROFILES PREFRONTAL CORTEX
AND INTEGRATED THE SIGNAL CELL
DATA FROM MOUSE AND HUMAN.
HERE THIS WAS ROUGHLY 150,000
TOTAL NUCLEI.
THIS WAS PUBLISHED AND
APPROACHES WITH SINGLE CELL
TECHNOLOGY.
WE UTILIZED ANCHOR BASED
UTILIZATION AND WE USED THE
PLOTS, BLUE REPRESENTS NUCLEI
FROM MOUSE POPULATIONS, THE RED
FROM HUMAN AND THEY CLUSTER
SEPARATE AND WE CAN START TO
INTEGRATE THE DATA.
THIS IS DONE BY IDENTIFYING THE
CELLS IN EACH SPECIES THAT HAVE
THE GREATEST AMOUNT OF
SIMILARITIES.
IF YOU TAKE PAIR OF CELLS ONE
FROM MOUSE AND IDENTIFY CELLS
THAT OVERLAP IN THE EXPRESSION
PATTERNS CAN BE USED AS ANCHORS
TO BUILD THE ORTHOLOGOUS GENE
NETWORKS TO PULL TOGETHER CELLS
THAT ARE REPRESENTING EACH CELL
TYPE FROM EACH SPECIES.
SO AFTER DOING THIS YOU CAN SEE
FOR THE DATA SET THERE WAS A
GOOD OVERLAP BETWEEN MOUSE AND
HUMAN FROM THE ANCHOR-BASED
APPROACH AND CAN START TO ASK
QUESTI
QUESTIONS AND IDENTIFIED
CLUSTERS OF CELLS IN HUMANS IN
THE TRANSCRIPTOME OR RELEVANT IN
MICE AND VICE VERSA.
AND 13 SPECIES AND THEY'RE
REPRESENTED ALMOST EQUALLY.
MOST CLUSTERS THOUGH A SEEM TO
BE MOUSE ONLY.
OF COURSE YOU WOULD EXPECT THIS
BECAUSE NOT ALL MOUSE CELLS WILL
BE SIMILAR TO HUMAN CELLS SO
IT'S NOT UNEXPECTED.
IS IS -- CLUSTER 12 AND 27 AND
CLUSTER 12 IS REPRESENTED BY ALL
THE CONDITIONS IN THE STUDIES.
THE HUMAN AUD AND THEIR
CONTROLS, MOUSE CONTROL, MOUSE
VAPOR, ALL COLOR CODED AND SO
THERE'S NEAR EQUAL CONTRIBUTIONS
OF ALL THE CELLS.
THIS IS TRUE FOR MANY OF THE
CLUSTERS AND I WANT TO FOCUS ON
CLUSTER 27, WHICH YOU CAN SEE IS
MOSTLY A CONTRIBUTION FROM THE
AUD.
NOW, THIS SUGGEST THERE'S
SOMETHING ABOUT THE MICROGLIA
CELL NOT FOUND IN OUR MOUSE
MODEL.
I'M POINTING THIS OUT BECAUSE
AGAIN WE NEED TO ALWAYS MAKE
SURE THAT WHEN WE ARE THINKING
ABOUT OUR TRANSLATION EVENTS
THEY'RE RELEVANT.
IF YOU LOOK AT THIS HUMAN ONLY
POPULATION WE SEE IT'S HIGHLY
OVERLAPPED WITH THE MG2 CLUSTER
I TALKED A LOT ABOUT EARLIER.
THIS HAD CYTOKINE SIGNALLING.
THIS IS AN EXAMPLE OF A
SITUATION WHERE WE WANT TO
REALLY LOOK CAREFULLY IF YOU'RE
GOING TO STUDY SOME OF THE
PATHWAYS WITHIN THE CELL TYPE
AND MAKE SURE THAT YOU HAVE
TRANSLATIONAL VALUES.
SO JUST WANTED TO POINT THIS OUT
BECAUSE THE INTEGRATION OF
EXPERIMENTS ARE IMPORTANT
BECAUSE IT DOES REALLY TELL US
SOMETHING ABOUT WHAT TO STUDY
AND WHAT NOT TO STUDY.
MICROGLIA STRUCTURES WERE FOUND
TO BE RICH WITH MARKERS AND THE
MACROPHAGE MARKERS WERE NOT
ANTICIPATED SO THAT'S A NEW
FINDING.
MICROGLIA LOSE THEIR HOMEOSTATIC
CONTROL IN THE AUD CASES AND
OBTAIN A MORE INFLAMMATORY STATE
YOU MIGHT EXPECT FROM AUD.
THERE'S ENRICHED TARGETS LIKE
TLR SIGNALLING AND IT FITS WITH
HYPOTHESIS OF ALCOHOL
CONSUMPTION.
THE DISEASE-LIKE SIGNATURES AND
RECRUITMENT AS WE SAID THIS IS
ONE OF THE ONGOING QUESTIONS WE
HAD.
WHERE ARE THE SIGNALS COMING AND
WE'RE DEVELOPING STRATEGIES TO
IDENTIFY INFILTRATION OF
LYMPHOCYTES OR MACROPHAGE FROM
THE PERIPHERY THAT MAY EXPLAIN
THE DIFFERENCES OR IDENTIFY THE
CELLS THAT MIGHT TRANSITION FROM
WITHIN THE BRAIN ITSELF.
WE JUST DON'T KNOW.
I POINTED OUT WHETHER YOU CAN
STUDY ANIMAL MODELS RELEVANT TO
AUD.
WITH THAT I'LL STOP AND TAKE
QUESTIONS.
>> THAT WAS GREAT AND I ALWAYS
TAKE THE PREROGATIVE OF ASKING
THE FIRST QUESTION.
YOU GAIN THE INFLAMMATORY STATE
AND I HAVE THE IMPRESSION THAT
THERE'S A SENSITIZATION IN
INFLAMMATORY STATES THAT ARE
ASSOCIATED WITH THE BRAIN AND I
WONDER ARE THERE ANY CLUES YET
FROM THE MORE SOPHISTICATED
ANALYSES OF HOW ONCE IT GETS
STARTED THERE'S INFLAMMATION AND
MICROGLIA ACTIVATE AND CYTOKINES
AND THEY FEEDBACK AND FURTHER
ACTIVATE IS THERE A HINT HOW
IT'S TAKING PLACE IN THE SYSTEMS
ONCE THEY GET STARTED?
>> YEAH, SO SOME OF THE WORK
THERE WAS NOT TIME TO TALK ABOUT
AND THIS IS ALSO IN WORK WE'RE
INTERESTED IN PERIODIC
ACTIVATION OF PROTEINS BECAUSE
WITH THE INTERMITTENT ACTIVATION
WE SEE OVER TIME AN INCREASE IN
ALCOHOL CONSUMPTION THAT IS
PROBABLY RELATED TO A
SENSITIZATION EVENT LIKE YOU'RE
TALKING.
ONE HIT, ONE ACTIVATION ENOUGH.
IT TAKES UP TO SO REPEAT BOUTS
OF ACTIVATION AND AFTER THAT
THERE'S A SICKNESS RESPONSE AND
MOLECULAR TOLERANCE.
SO THE ANIMALS ARE RELATIVELY
NORMAL AT THE END OF THE CHRONIC
ADMINISTRATION PARADIGM PLUS WE
ALLOW A FEW WEEKS OFF FOR THE
ANIMALS MAINTAIN THEIR STATE
WITH THE ALCOHOL CONSUMPTION AND
THAT'S SOMETHING WE'RE WORKING
TO FINALIZE THE PATHWAYS AND
WILL BRING THE BLOOD BRAIN
BARRIER INTO THE PICTURE BECAUSE
IT'S A FEATURE COMMON BETWEEN
THE TRANSCRIPTOMIC SIGNATURES
AND THE ANIMAL MODELS.
WHAT WE DON'T KNOW IS DOES THIS
HAPPEN EARLY?
IS THE BLOOD BRAIN BARRIER
DYSFUNCTION ACCUMULATED OVER
TIME?
THOSE ARE THINGS WE'RE TRYING TO
DO TO GET AT THE QUESTION.
>> SO IS THERE ANOTHER QUESTION
FROM ANYONE?
DOES IT ANYONE ONLINE HAVE A
QUESTION?
CAN YOU HEAR ME?
>> THIS IS MICHAEL LEWIS.
HAVE YOU SEEN EVIDENCE IN THE
STUDIES WHERE IF YOU TERMINATE
THE ALCOHOL EXPOSURE THERE IS
EVIDENCE OF RECOVERY OF ANY OF
THESE FUNCTIONS IT MIGHT LEAD TO
PERHAPS THERAPEUTIC APPROACHES
TO TREATMENT OF ALCOHOLISM.
>> THAT'S WHAT WE SET OUT TO DO
WITH HUMAN DONORS.
THE PROBLEM IS WE HAVE A VARIETY
OF ABSTINENCE PERIOD IN THE
HUMANS BUT DON'T HAVE THE SAMPLE
SIZE TO GET TO WHAT HAPPENS WITH
EXTENDED WITHDRAWAL AND WE CAN
DO THAT WITH THE ANIMAL MODELS.
IT BECOMES FINANCIALLY
CHALLENGING TO DO MULTIPLE TIME
POINTS AFTER INDUCTION OF
DEPENDENTS.
THERE'S CHALLENGES THERE.
NATS A THAT'S A GREAT QUESTION
AND PURSUED TO GET AT THE
THERAPEUTIC EVIDENCE.
FOR A LONG TIME WE WERE
UTILIZING SIGNATURES FROM
DIFFERENT WITHDRAWAL PERIODS TO
TRY TO PREDICT DRUGS TO LOOK AT
SIGNATURES TO REDUCE DRINKING
BUT IT'S EXPENSIVE AND TIME
CONSUMING.
THANK YOU FOR THE QUESTION.
>> I WAS MAINLY AIMED AT THE
ANIMAL STUDIES TO LOOK FOR IN
HUMANS WITH THIS BUT IT'S
EXCELLENT WORK.
IT'S WONDERFUL.
>> WE'LL HAVE TO MOVE ON BUT
PEOPLE CAN FIND YOU THROUGH
E-MAIL AND IF YOU WANT PRE
PRINTS, PLEASE FEEL FREE.
CAN YOU STOP SHARING YOUR
SCREEN?
WE'LL HAVE CONCEPT CLEARANCE.
HERE WE GO.
>> GOOD AFTERNOON.
THIS IS NOT GOING TO BE A
SCIENTIFIC PRESENTATION BUT A
HIGHER LEVEL PRESENTATION OF A
CONCEPT.
AS GEORGE MENTIONS CARRIES ON
THEMATICALLY WITH WHAT WE'VE
BEEN DISCUSSING THIS AFTERNOON.
SO I'M HERE TODAY TO DISCUSS THE
RENEWAL OF THE INITIATIVE ON THE
ALCOHOLISM IN FISCAL 2027.
THAT IS TO SUPPORT TWO
COLLABORATIVE RESEARCH
CONSORTIUMS CURRENTLY THERE ARE
TWO CONSORTIUMS COMPRISED OF 22
PROJECTS HOUSED AT 13 DIFFERENT
RESEARCH INSTITUTIONS.
AND OUR FOCUS WILL BE BRAIN BODY
MECHANISM PERPETUATING EXCESSIVE
ALCOHOL DRINKING AND RELATED
ALCOHOL-USE DISORDER PHENOTYPES.
RESEARCH GOALS LOOK AT CAUSAL
INFLUENCES ON FOCUS ON
TRAJECTORIES AND WE HAD A SLIDE
FROM INITIAL ALCOHOL EXPOSURE TO
THE DEVELOP OF PATHOLOGICAL
DRINKING WE SOME INDIVIDUALS.
TRANSLATABLE TARGETS, MARKERS
AND WE WILL PROMOTE INNOVATION
IN TWO DIFFERENT WAYS.
BOTH IN ADAPTING TOOLS AND
TECHNOLOGIES FROM THE NIH BRAIN
INITIATIVE, NIH COMMON FUND AND
OTHER ADVANCED RESOURCES.
IN TERMS OF HYPOTHESES TO REVEAL
PERIPHERAL INFLUENCES ON BRAIN
FUNCTION RELATED TO ALCOHOL
MISUSE AND AUD.
ALL LONG THE INITIATIVE HAS AND
RIGOR AS SUPPORTED BY NIH.
IT EMPHASIZES REPLICATION ACROSS
PROJECTS AND USE OF STANDARDIZED
AND COORDINATED BEHAVIORAL AND
NEURAL FUNCTIONAL MEASURES AND
PROTOCOLS.
AND INTEGRATION IS A KEY THING.
IT'S BEEN BENEFICIAL IN
ACCELERATING DISCOVERY.
SO THE CONSORTIUM HAS HYPOTHESIS
AND ANALYSES FROM MOLECULAR TO
SYSTEMS LEVEL AND COORDINATED
USE OF RESOURCES AND
CROSS-SPECIES TRANSLATION.
WE HAVE SOME EXAMPLES OF THAT.
AND THE MECHANISM SUCH THAT EACH
CONSORTIUM INCLUDES RESOURCE
SUPPORTED UNDER THE U24
MECHANISM AND INDIVIDUAL
PROJECTS SUPPORTED BY THE UL1
MECHANISM.
THIS IS JUST A CARTOON.
IT'S NOT ILLUSTRATING SPECIFIC
PROJECTS BUT AND THIS EMPHASIZES
MECHANISMS AND NEURAL PATHWAY
MECHANISMS AND THE LARGER
CIRCLES ILLUSTRATE THE
AFFILIATED CONSORTIUM.
THEY COLLABORATE THROUGH JOINT
MEETINGS AND THE INDIVIDUAL
PROJECTS COLLABORATE WITHIN EACH
THEMATIC CONSORTIUM AS INDICATED
BY THE SPOKES IN THE
ILLUSTRATION.
THEY COLLABORATE ALONG THE
CONSORTIUMS.
IT'S COMMON FOR THEM TO OCCUR.
I'M WILLING TO ENTERTAIN
CONVERSATIONS AND I'M LOOKING
FOR AN ENDORSEMENT FROM COUNCIL.
>> THERE'S FOCUS AND ARE YOU
PLANNING TO HAVE NEW ONES OR
WANT TO CONTINUE TO WORK?
THEY'RE DIRECTLY RELEVANT TO OUR
INTEREST IN LOOKING AT
HOMEOSTATIC MECHANISMS LINKING
BRAIN TO THE BODY.
SO THERE'S CERTAINLY GOING TO BE
EMPHASIZED.
THAT'S THE PLAN.
>> WE HAVE ONE MORE CONCEPT?
>> WOULD ANYBODY ON COUNCIL LIKE
TO ENDORSE THE CONCEPT.
>> I WILL.
>> THANKS, MIKE.
>> I WILL TOO.
>> THANK YOU.
WE'VE HAD GUIDANCE ON HOW TO DO
NOTICES OF FUNDING
OPPORTUNITIES.
SO MARK EGLI HAS SUBMITTED
WHAT'S CALLED A FORECAST FOR
THESE, FIRST REVIEWED AND THEN
APPROVED AT COUNCIL BY HHS
BEFORE WE MOVE FORWARD THE
CONCEPT CLEARANCE.
THE ONES YOU'RE SEEING TODAY
HAVE BEEN CLEARED BY HEALTH AND
HUMAN SERVICES FOR THE RECORD.
>> GOOD AFTERNOON I'M IN THE
DIVISION OF NATAL SCIENCE AND
BEHAVIOR.
WITH DR. LIONS IN THE AUDIENCE
IN THE BACK.
I'M HERE TO PRESENT THE
PROPOSAL.
WE JUST HEARD TWO FANTASTIC
TALKS ON ALCOHOL EFFECTS ON THE
IMMUNE SYSTEM OF THE DIFFERENT
PARTS OF THE BRAIN AND BODY
WHICH STARTS TO BOND TO THE
CELLULAR AND SYSTEMS LEVEL AND
LET'S ZOOM OUT AND LOOK AT THE
AFFECT OF ALCOHOL ON THE BRAIN
AND I'LL GIVE A BIG OVERVIEW OF
THIS THIS IS A MULTI-SITE
CONSORTIUM WITH MECHANISMS
FUNDED THE UL 1 MECHANISM AND
ONE DATA ANALYSIS SITE IT'S IN
THE UNDERSTANDING THE FUNCTIONAL
CONSEQUENCES OF EARLY ONSET
ALCOHOL USE AND THE BINGE
DRINKING AND PROGRESSION TO
ALCOHOL USE DISORDER AND HOW THE
CONSEQUENCES MANIFEST IN
ADULTHOOD.
AND CAN THEY CREATE
REPRESENTATIVE SAMPLE.
THE PRIMARY FOCUS IS TO EXAMINE
HOW ALCOHOL EXPOSURE AFFECTS
ADULT BRAIN STRUCTURE, FUNCTION
AND COGNITIVE AND MENTAL HEALTH
OUTCOMES.
TO ACHIEVE THIS THEY HAVE
LONGITUDINAL DESIGN AND THEY
FOLLOWED THE COHORT OF 831
PERSONS 12 TO 21 YEARS AS THEY
TRANSITION TO ADULTHOOD AND WE
HAVE A DATA SPANNING 12 TO 32
YEARS WHICH IS VERY IMPRESSIVE.
IT HAS AN ASSESSMENT APPROACH
AND MEASURES AND ASSESSMENT
APPROACHES INCLUDING ANALYSIS OF
PHYSICAL ACTIVITIES AND RHYTHMS
AND COMPONENTS OF DEVELOPMENT IN
ADDITION TO ALCOHOL USE.
IT ALSO EMPLOYEES OBJECTIVE
ASSESSMENT METHODS WITH SLEEP
TRACKING.
SINCE THE START OF 2022 FUNDING
CYCLE IT HAS MADE SIGNIFICANT
PROGRESS SOME ARE HIGHLIGHTED
HERE AND 77 PEER-LE --
PEER-REVIEWED PAPERS AND IT HAS
MADE DATA ACCESSIBLE WHICH HAS
ENABLED SECONDARY ANALYSIS BY
OTHER RESEARCHERS.
THERE'S STANDARDIZED DATA
HARMONIZATION AND PROVIDED EARLY
CAREER INVESTIGATORS.
AND IT ALSO REACHED THE PUBLIC
THROUGH VARIOUS NATIONAL MEDIA
OUTLETS WHICH CONTRIBUTED TO
PUBLIC AWARENESS AND EDUCATION.
IT'S TIMELY AND THEY ARE
IMPACTED BY THREE STAGES.
THE PRE-DRINKING ONSET BY AGE 12
OR LATER.
SECOND TRANSITION TO THE YOUNG
ADULTHOOD WHICH IS A CRITICAL
PERIOD FOR BINGE DRINKING AND
THE MEASURING OUT PHASE.
IT CREATES A RARE BASELINE OF
DATA FOR UNDERSTANDING ADULT
DRINKING PATTERNS CAN LOOK AT
DRINKING RATES AND THE
BEHAVIORAL DATA ALLOWS
INVESTIGATORS TO DEVELOP AND
VALIDATE PREDICTIVE MODELS OF
ADULT DRINKING PATTERNS.
THIS IS CRUCIAL FOR IDENTIFYING
EARLY RISK FACTORS AND INFORMING
INTERVENTION STRATEGIES.
THAT CONCLUDES MY PRESENTATION
AND I LOOK FORWARD TO YOUR
QUESTIONS AND ENDORSEMENT.
>> THANK YOU.
THAT'S GREAT.
SO COUNCIL MEMBERS, ANY
QUESTIONS, COMMENTS OR
ENDORSEMENTS OF THE CONCEPT
CLEARANCE?
I'LL ENDORSE IT.
>> DITTO.
>> THANK YOU.
>> THANK YOU, ALL VERY MUCH.
ANY QUESTIONS?
DAVID?
>> I'M CHIMING IN TO ENDORSE
IT'S BEEN A VERY PRODUCTIVE
PROJECT.
>> OKAY.
SO THANK YOU.
I THINK WE'RE FINISHED WITH
COUNCIL.
WE DESIGNATED SOME TIME FOR
COUNCIL DISCUSSION I'M GOING TO
OPEN IT UP FOR ANY QUESTIONS YOU
HAVE FOR ME, FOR ANYONE OF OUR
STAFF THAT ARE HERE WE CAN TAKE
01 MINUTES FOR THIS.
-- 10 MINUTES FOR THIS.
FOR THOSE GOING TO APA, FRANCES,
I'LL SEE YOU AT THE ADDICTION
PSYCHIATRY GROUP.
ANYWAY, I'LL BE THERE.
ARE THERE QUESTIONS FROM ANYONE
ON COUNCIL?
PLEASE?
>> I GUESS I'D LIKE TO ASK IF
ANY OF THE RECENT CHANGES WITH
HHS DOES HHS SEE THE MISSION OF
NIAAA CHANGING IN A FUNDAMENTAL
WAY AND WHAT THE EMPHASIZES ARE
GOING TO BE MOVING FORWARD.
>> AS OF NOW MY DISCUSSIONS WITH
BHATTACHARYA AND I OUTLINED OUR
MISSION TO HIM AND HAD A
ONE-ON-ONE WITH THE DIRECTOR OF
NIH AND I THINK I'VE ASKED HIM
REPEATEDLY ABOUT WHAT I CAN
PRESENT AT MEETINGS LIKE COUNCIL
AND THEN RSA AND HE EXPLICITLY
STATED AS LONG AS WE'RE TALK OUR
SPECIFIC AIMS AND WHERE WE'RE
GOING WE SHOULD SPEAK TO OUR
MISSION.
I HAVEN'T SEEN ANY EVIDENCE OF
CHANGING DIRECTION OF OUR
MISSION IN THAT REGARD.
SO OUR MISSION STATEMENT REMAINS
THE STATEMENT BASICALLY TO
UNDERSTAND THE AFFECTS OF
ALCOHOL MISUSE AND SPECIFICALLY
IN THE DOMAINS OF ETIOLOGY AND
PREVENTION AND TREATMENT AND
ORGAN DAMAGE.
I ALWAYS LEAVE SOMETHING OUT,
TRISH.
WHAT IS IT?
>> DIAGNOSIS AND RECOVERY.
>> THERE YOU GO, THANK YOU.
>> IT'S A LONG LIST BUT NO, THE
ANSWER IS OUR MISSION REMAINS
THE SAME.
>> THANK YOU.
>> THANK YOU FOR THAT.
WE'VE BEEN WONDERING ABOUT
THINGS LIKE THAT.
>> WELL, WE HAVE A LOT OF THINGS
THAT REMAIN TO BE WORKED OUT.
THERE IS A LOT OF EFFORTS GOING
IN THAT REGARD BUT CAN'T REALLY
COMMENT ON ANYTHING OTHER THAN
SOME OF THE CHANGES YOU HEARD
OF.
PEER REVIEW WILL NOW BE AT CSR.
WE DON'T KNOW WHAT THE BUDGET
WILL BE LIKE BECAUSE IT'S ONLY
THE BEGINNING OF THE PROCESS SO
CONGRESS WON'T BE WEIGHING IN
AND THIS IS SOMETHING THAT
OCCURS EVERY YEAR NOT JUST
TRANSITION YEARS.
WE ARE ACCEPTING APPLICATIONS
FOR ACTIVE FUNDING
OPPORTUNITIES.
YOU ALREADY HEARD ABOUT TWO
CONCEPT CLEARANCES WE PUT
FORWARD.
SOME HAVE BEEN ALIGNED WITH
PRIORITIES AND RE-READ FOR
CHANGING PRIOR TO SUBMISSION
RAND ADJUST FOUR APPLICATIONS
ACCORDINGLY AND YOU CAN PASS THE
WORD ON TO COLLEAGUES IN THIS
REGARD.
IT'S TO WHAT HAS CHANGED AND
WHAT'S ALREADY HAPPENING.
THE PAUSE WAS LONGER THAN NORMAL
BUT GO THROUGH THESE TRANSITIONS
EVERY FOUR YEARS AND BACK UP AND
RUNNING WITH GRANTS AND AS YOU
KNOW WE HAD CLOSED SESSION TODAY
AND GRANTS ARE GOING OUT AND
HAVE A PAY PLAN END OF THIS
WEEK.
WE'RE MOVING FORWARD.
>> I WONDER IF COUNCIL FUNCTIONS
WILL REMAIN THE SAME?
>> WE'RE WAITING ON GUIDANCE FOR
THAT, MICHAEL.
WE DID LOSE A FEW COUNCIL
MEMBERS AND WAITING ON SOME
SLATES TO BE APPROVED SO THERE'S
A BACKLOG TO 2023.
WE'RE JUST WAITING FOR THAT
>> THANK YOU.
ANY OTHER QUESTIONS?
DAYNE?
>> YEAH, THANKS.
I WANT TO ASK ANOTHER QUESTION
YOU DON'T KNOW THE ANSWER TO I'M
SURE BUT I'M GOING TO TRY
ANYWAY.
ONE OF THE PLACES WE ALWAYS GO
TO FIND NEW INFORMATION OR THE
NIH WEBSITES AND OF COURSE
THEY'RE NOT CURRENTLY UPDATED.
IS THERE ANY ANY INDICATION OF
WHEN INFORMATION COULD BE ADDED
WHERE THE LABS ARE TRYING TO
COLLECT INFORMATION AS THE GO-TO
SOURCE.
WONDERING IF THERE'S ANY HINT ON
WHEN SOME OF THAT MIGHT BE
UPDATED.
>> WE'RE WAITING ON GUIDANCE
FROM THAT.
DAYNE, WE SERVE ALSO THE PUBLIC.
WE HAVE AN EMPHASIS TO CONTINUE
IN SOME FASHION.
WE'RE WAITING TO SEE WHAT
EVOLVES BUT THE OTHER INSTITUTES
ARE IN THE SAME SITUATION.
THEY HAVE CLIENTS WHO ARE ALSO
WAITING FOR UPDATES ON THE
LATEST TRANSLATABLE OBSERVATIONS
IF IT COULD BE THE EYE OR THE
EAR OR MUSCLES.
ETCETERA, BY THE WAY, THAT WAS A
REALLY GOOD TALK.
I KNOW YOU WERE BEING WATCHED
LIKE AN EGRIT SO MAY BE
APPROACHED THERE.
>> THERE WAS CROSS TALK THERE.
>> SO TOMORROW WE HAVE THE
COLLABORATIVE RESEARCH ON
ADDICTIONS AT NIH.
IT'S PUBLIC AND OPEN AND LEE
HOOD DOES TEM KNOLL WORK IN
SYSTEMS BIOLOGY AS THE SPEAKER
THERE WHICH SHOULD DOVETAIL
REALLY WELL WITH WHAT YOU HEARD
TODAY.
ANYONE WHO WANTS TO CONTINUE AND
SEE A PERSON WHO ADDRESSES IT AT
MULTIPLE LEVELS AND HAS DONE
MOST OF HIS CAREER, IT'S ANOTHER
WAY OF FINDING ANOTHER VIEW
POINT FROM 30,000 FEET OF HOW
YOU INTEGRATE INFORMATION AND
SCIENCE.
I'M VERY MUCH LOOKING FORWARD TO
THAT TALK AS WELL MYSELF.
SO IT'S ONLINE.
HOW DO THEY ACCESS AND FINE IT?
IS IT ON OUR WEBSITE?
IT SHOULD BE ON THE NIH VIDEO
LINK WEBSITE.
WE HIGHLIGHT RECOMMEND IT AND
WE'LL BE WITH OUR BRETHREN AT
NIDA TOMORROW.
AND TOBACCO.
I ALWAYS LEAVE OUT NCI.
I LEAVE OUT TOBACCO -- WHAT DO
THEY CALL THEMSELVES?
IT'S A BIG OUTFIT BUT THEY HAVE
A NAME.
I FORGET IT.
IT'S THE TOBACCO SECTION OF THE
NATIONAL INSTITUTE.
ANY OTHER THOUGHTS OR QUESTION
OR COMMENTS?
>> TWO QUESTIONS.
FOR BOTH THE SPEAKERS, HAVE YOU
TRIED TO DO THIS SYSTEM APPROACH
AT TWO DIFFERENT TIME POINTS
JUST TO -- BECAUSE I KNOW THE
IMMUNE SYSTEM IMPACT REGULATION.
IT'S A HUGE DIFFERENCE IF YOU DO
THE MORNING OR EVENING AND CAN
YOU REPEAT WHAT YOU SAID ABOUT
THE BRAIN.
>> GO AHEAD BECAUSE IT'S FRESH
IN YOUR MIND AND YOU MAY HAVE TO
REPEAT THE OTHER QUESTION FOR
DAYNE.
>> FOR THE TIME PERIOD, IT WAS
ACTUALLY YOU WERE INTERESTED IN
THE TIME COURSE IN THE MOUSE
STUDY BECAUSE ONE SNAPSHOT MAY
NOT BE ENOUGH ESPECIALLY IF
YOU'RE COMPARING IT THE LIVER
AND LUNG.
WE NEED TO INFORMATION THIS
INFLAMMATORY OR PROGRESSIVE
DISEASE.
IN THE HUMAN DATA WE JUST GET A
SNAPSHOT BUT THE DATA SHOWS AND
FOR THE SECOND QUESTION FOR
EVERYBODY APPRECIATED WHAT WAS
IN THE BRAIN AND I LIKE TO MAKE
THE ANALOGY BECAUSE OUR BODY
OPERATES THE SAME PRINCIPLE TO
CONSERVE ENERGY.
WE KNOW IN THE BRAIN THERE'S
CASES AND THERE'S NEURO
TRANSMISSION AND IT MAY WORK IN
THE SAME PRINCIPLE IN THE IMMUNE
SYSTEM AND THAT IS IMMEDIATELY
RELEASED AND THAT IS MADE IN THE
BEGINNING.
IT CAN BE NEEDED TO PRIME THE
IMMUNE SYSTEM.
THEN PROLONG ACTIVATION IS THE
PROBLEM.
I THINK THAT IS WHAT WE'RE
OBSERVING AND THE TIME COURSE
STUDY ONCE WE CONDUCT IT THAT IS
THE OBSERVATION WE FIND.
>> AND DAYNE, DID YOU WANT TO
ANSWER THE TIME COURSE PIECE?
>> I'M SURE.
SO HE WE BRIDGED THE TIME SERIES
QUESTION AND ANIMAL MODELS A
COUPLE TIMES.
THIS HAS BEEN DONE IN ANIMALS
SUBJECTED SO THE CHRONIC
INTERMITTENT ALCOHOL DEPENDENCE
INDUCTION MODEL.
SO IF WE LOOK AT THE TIME FROM
INTOXICATION THROUGH VARIOUS
LEVELS OF ABSTINENCE FROM TWO
DAYS TO A WEEK OR WHATEVER, WE
HAVE ONLY DONE THAT WITH BULK
SEQUENCING NOT SINGLE CELL.
I CAN TELL YOU IT BECOMES TRICKY
TO TEASE THINGS AAPART BECAUSE
YOU DO LOSE SOME OF THE
DYSREGULATION YOU SEE DURING
INTOXICATION HOWEVER THE
DIRECTIONAL CHANGES OF
INDIVIDUAL GENES REALLY ARE VERY
PATTERN SPECIFIC.
THEY MAY BE INITIALLY AND THEN
THEY GO VERY NEGATIVE AT THE END
OR MAY START OUT UNCHANGED AND
THEN OVER TIME THEY BECOME VERY
ACTIVATED.
AND WE'VE USED APPROACHES TO
APPROACH THAT WAY.
IF WE CAN DO THAT WITH A SINGLE
CELL WORK IT WOULD BE
INFORMATIVE I THINK WITH THE
PLATFORMS BECOMING AVAILABLE
MAYBE WE'LL BE ABLE TO DO THAT
BUT RIGHT NOW WE JUST CAN'T BUT
WE'VE PUBLISHED A COUPLE PAPERS
WITH THE TIME COURSE AND BULK
SEQUENCING IN ANIMALS.
>> OKAY.
ANYMORE COMMENTS OR QUESTIONS
REAL QUICKLY?
WE CAN TAKE MAYBE ONE MORE.
>> I HAVE AN ANOTHER QUESTION
FOR DR. MAYFIELD.
I ENJOYED YOUR PRESENTATION.
MY QUESTION IS YOU'RE SHOWING
THE ALCOHOL DRINKING DURATION
AND THAT WAS AS FAR AS I SEE
THAT WAS THE ONLY ONE THAT WAS
NOT CORRELATED WITH THE ALCOHOL
AND DRINKING DURATION.
DO YOU THINK IT'S REALLY
SENSITIVE THAT ANY KIND OF
ALCOHOL DURATION CAN BE ENOUGH
TO ACTIVATE THE SYSTEM?
AND ANOTHER FOLLOW-UP POINT IS
THE PHENOTYPE HAS A MACROPHAGE
PHENOTYPE THAT MADE ME THINK
MAYBE THERE ARE SHARED
MECHANISMS WITH THE OTHER
NEURODEGENERATIVE DISEASE.
ARE YOU PLANNING TO CHECK DATA
FROM OTHER DISEASE TO SEE THE
SIMILAR SIGNATURES?
YOU HAVE WONDERFUL SIGNATURES
FROM DIFFERENT CLUSTERS.
>> I THINK WE'RE TALKING ABOUT
THE MODULE RELATIONSHIP TABLE
SHOWING THE ASSUMPTION OF THE
PHENOTYPES AND THE
CLASSIFICATION MAKES IT HARD TO
DO BECAUSE SOME OF THE
INDIVIDUALS HAVE VARYING
ABSTINENCE PERIODS THAT REALLY
HURT THE OVER ALL CORRELATION.
IT'S A LITTLE BIT MUDDY TO DO
THAT.
THAT'S WHY I BROKE IT DOWN AFTER
THAT PARTICULAR SLIDE INTO
HERE'S A SPECIFIC STATE
STRUCTURE AND THAT MAY BE MORE
INFORMATIVE AND IN ANIMAL MODELS
IT'S A DIFFERENT STORY.
IT'S VERY CLEAR WITH THE
CORRELATIONS IN TERMS OF THE
CELL TYPE OR SIGNATURE WITH HOW
MUCH AN ANIMAL IS DRINKING.
HUMANS, THERE'S SO MUCH
VARIATION AS YOU KNOW VERY WELL.
IT'S HARD TO GET A GOOD CLEAN
SIGNAL.
AND ONE MORE FOLLOW-UP TO THAT I
HAD IN MY DECK AT THE END I
FIGURED SOMEONE WOULD ASK BUT
USING SPATIAL GENOMIC APPROACHES
YOU CAN IDENTIFY THE BORDER
ASSOCIATED MACROPHAGE POPULATION
LINING THE PERIHEMISPHERIC STATE
AND THESE ARE SOME OF THE CELLS
INFILTRATING THE PARENCHYMAL
PORTION OF THE BRAIN AND DON'T
KNOW HOW THEY'RE GETTING THREE
MAYBE THE BLOOD BRAIN BARRIER
AND WITH SOME APPROACHES WE CAN
START TO RESOLVE WHERE AT LEAST
SOME OF THE GLIAL TYPE CELLS ARE
ORIGINATING ESPECIALLY THE
MACROPHAGE AND LYMPHOCY
POPULATION.
WHETHER IT'S IN LUNG, LIVER OR
GUT, EVENTUALLY IT MAKES IT'S
WAY TO THE BRAIN.
I HAVEN'T THOUGHT ABOUT IT MUCH
IN THE CONTEXT OF LUNG SO THAT
WAS VERY INTERESTING.
>> OKAY.
YOU CAN CONTINUE TO COMMUNICATE.
I HOPE YOU DO.
I'M COMPLETELY INTRIGUED WITH
THE POSSIBILITY THE LUNG IS THE
FIRST THING THAT SIGNALS THERE'S
A PROBLEM.
WE'LL SEE HOW THAT EVOLVES.
OKAY.
AS DAVID GOLDMAN SENT ME AN
E-MAIL AND SAID, I NEGLECTED TO
TELL YOU EARLIER A WRITTEN
REPORT WAS PREPARED BY THE NIAAA
OFFICE OF SCIENCE POLICY AND
COMMUNICATIONS CALLED THE
DIRECTOR'S REPORT.
MY SLIDES AND THE WRITTEN REPORT
WILL BE AVAILABLE ON THE NIAAA
WEBSITE.
IT'S GOING TO BE PUT UP THERE.
IF YOU MISSED ANYTHING FROM MY
PART OF THE DISCUSSIONS TODAY,
IT'S THERE.
NOW I'LL TURN IT OVER TO
PHILIPPE TO TALK ABOUT
CONSIDERATION OF FUTURE MEETING
MINUTES AND COUNCIL REPORT AND
FUTURE MEETING DATES.
I THINK HE CAN DO THAT IN FIVE
MINUTES.
>> I'D LIKE TO SUBMIT FOR
APPROVAL BY COUNCIL THREE
DOCUMENTS.
THE MINUTES FOR THE SEPTEMBER 12
COUNCIL MEETING.
THE COUNCIL STANDARD OPERATING
PROCEDURE AND THE REPORT ON THE
INCLUSION OF THE CLINICAL
APPROACH.
THESE DOCUMENTS WERE PROVIDED TO
COUNCIL IN THE ELECTRONIC
COUNCIL BOOK AND BEFORE ASKING
FOR A VOTE I'D ASK FOR COMMENTS
ON ANY ORGANIZATION OF THE
DOCUMENTS?
HEARING NONE I'D LIKE TO
ENTERTAIN A MOTION TO APPROVE
THE THREE DOCUMENTS.
>> SO MOVED.
>> SECOND?
>> SECOND.
>> ALL IN FAVOR ?
THOSE OPPOSED?
ANY AB TENSION?
THE MOTION CARRIES.
THANK YOU VERY MUCH AND I WOULD
LIKE ALSO TO SHARE THE UPCOMING
DATES FOR THE NEXT COUNCIL SO
IT'S ON THE SCREEN.
FOR THE NIAAA COUNCIL THE DATE
OF 2025 WILL BE SEPTEMBER 4.
FOR 2026, FEBRUARY 5, MAY 5,
SEPTEMBER 17, 2027 WOULD BE
FEBRUARY 4, 11 AND SEPTEMBER 16.
FOR THE FUTURE MEETING DAVIS THE
CRAN JOINT ADVISORY COUNCIL OF
NIAAA, NIDA AND NCI IN 2026 MAY
6, AND 2027, MAY 12.
BACK TO YOU, DR. KOOB.
>> SO I THINKS IT'S UP TO ME TO
ADJOURN THE MEETING.
THE MEETING IS NOW ADJOURNED.
THANK YOU ALL, ESPECIALLY
COUNCIL MEMBERS FOR JOINING US
TODAY.
THERE'S ONLY SIX OF YOU BUT YOU
CARRY A LOT OF IMPORTANCE TO US
AND I REALLY APPRECIATE YOUR
INTERACTIONS AND COMMENTS TODAY
AND QUESTIONS.
WE'LL SEE YOU IN SEPTEMBER AND
WE'LL SEE YOU TOMORROW AT CRAN.