Icahn School Of Medicine At Mount Sinai

AIDS MALIGNANCY CONSORTIUM (AMC)

NETWORK FOR CARDIOTHORACIC SURGICAL INVESTIGATIONS IN CARDIOVASCULAR MEDICINE(U01

WTC RESPONDER HEALTH CONSORTIUM CLINICAL CENTER

MPD RESEARCH CONSORTIUM

NONINVASIVE MARKERS AND TRANSPLANT OUTCOME IN HUMANS

ECHO CONSORTIUM ON PERINATAL PROGRAMMING OF NEURODEVELOPMENT

CONDUITS: MOUNT SINAI HEALTH SYSTEM TRANSLATIONAL SCIENCE HUB - CONTACT PD/PI: WRIGHT, ROSALIND J IN THE PAST DECADE, MOUNT SINAI HAS INVESTED SIGNIFICANTLY IN THE INTEGRATIVE TRANSLATIONAL INITIATIVES NEEDED TO ADVANCE PRECISION MEDICINE. THIS INCLUDED INVESTMENTS IN GENOMICS, HIGH-PERFORMANCE COMPUTING, CLINICAL INFORMATICS, SMART TECHNOLOGIES, AND COMPUTATIONAL BIOLOGY. IN CONCERT WITH INSTITUTIONAL STRATEGIC GOALS AND INCREASING COMMUNITY CONCERNS AROUND ENVIRONMENTAL TOXINS AND SOCIAL JUSTICE, CONDUITS, THE MOUNT SINAI INSTITUTE FOR TRANSLATIONAL SCIENCE, HAS EVOLVED ITS APPROACH TO PRECISION MEDICINE TO INCLUDE A PRECISION PUBLIC HEALTH FRAMEWORK INTEGRATING GENOMICS WITH KEY PUBLIC HEALTH DOMAINS SUCH AS ENVIRONMENTAL HEALTH, SOCIAL DETERMINANTS, AND BIG DATA TEAM SCIENCE TO MORE EFFECTIVELY ADDRESS HEALTH EQUITY CHALLENGES. CONDUITS WILL HARNESS UNIQUE STRENGTHS IN RESEARCH INFORMATICS, DIGITAL HEALTH, GENOMICS, EXPOSOMICS (THE STUDY OF ALL HEALTH RELEVANT ENVIRONMENT), AND DATA SCIENCE TO TRANSFORM ENGAGEMENT AND THE SCIENCE OF TRANSLATION TO ACCELERATE DISCOVERIES INTO BETTER HEALTH OUTCOMES ACROSS THE LIFESPAN MATCHED TO THE NEEDS OF THE DIVERSE POPULATIONS WE SERVE. WE WILL AUGMENT CONDUITS’ ROLE IN TRANSFORMING THE LOCAL, REGIONAL, AND NATIONAL TRANSLATIONAL RESEARCH ENTERPRISE BY DEVELOPING AND SHARING INNOVATIVE EDUCATIONAL PROGRAMS, INCENTIVIZING TRANSDISCIPLINARY TEAM SCIENCE IN EMERGING DATA SCIENCE FIELDS (E.G., EXPOSOMICS) AND ENTREPRENEURSHIP, AS WELL AS TRAINING A DIVERSIFIED WORKFORCE ON EMERGING CLINICAL AND BIOINFORMATICS LEARNING HEALTH SYSTEM APPROACHES THAT LEVERAGE BIG DATA. OUR AIMS CUT ACROSS THE DOMAINS SERVING AS ORGANIZING PRINCIPLES FOR OUR CTSA HUB INCLUDING: 1) WORKFORCE DEVELOPMENT. EVOLVE LEARNING OPPORTUNITIES PROMOTING TRANSDISCIPLINARY CLINICAL DATA SCIENCE AND ENTREPRENEURIAL ACTIVITIES; 2) DIVERSITY. ADVANCE JUSTICE, EQUITY, DIVERSITY, INCLUSION, AND AN ANTIRACIST MINDSET AS CORE TENETS OF SOCIALLY RESPONSIBLE RESEARCH AND TRAINING; 3) COLLABORATION AND ENGAGEMENT. ENGAGE DIVERSE STAKEHOLDERS IN ALL PHASES OF TRANSLATIONAL RESEARCH THROUGH ACCELERATOR MODELS CONSTITUTED TO ADDRESS PRIORITY COMMUNITY CONCERNS AND APPLY AN ENVIRONMENTAL JUSTICE, LIFE COURSE, AND DATA SCIENCE FRAMEWORK TO DRIVE COMMUNITY-CENTERED SOLUTIONS: 4) INFORMATICS. LEVERAGE DATA SCIENCE TO BETTER COORDINATE HEALTH CARE DELIVERY WITH TRANSLATIONAL RESEARCH BY INTEGRATING SECURE ELECTRONIC HEALTH RECORDS (EHRS), PATIENT REPORTED OUTCOMES, CLINICAL TRIALS MANAGEMENT SYSTEMS, AND INSTITUTIONAL BIOBANKS AND DATA REPOSITORIES, ENABLING CLINICAL DATA SCIENCE RESEARCH; 5) METHODS AND PROCESSES. INNOVATE AND STREAMLINE RESEARCH ADMINISTRATIVE OVERSIGHT AND PROCESSES TO MINIMIZE ROADBLOCKS, ENSURE QUALITY AND INTEGRITY; MONITOR OUTCOMES AND GARNER FEEDBACK FROM STAKEHOLDERS TO FACILITATE AND ENHANCE PARTICIPATION IN CLINICAL TRANSLATIONAL RESEARCH SUPPORTED BY CONDUITS, REGIONAL CTSA HUBS, AND THE CTSA NATIONAL NETWORK; AND 6) INTEGRATION. INCORPORATE TRANSLATIONAL RESEARCH ACROSS THE LIFESPAN, FOCUSING ON PERINATAL AND PEDIATRIC RESEARCH, GERIATRIC POPULATIONS, AND POPULATIONS IMPACTED BY HEALTH DISPARITIES; ACCELERATING INCLUSION OF ENVIRONMENT IN LIFE COURSE PRECISION MEDICINE VIA OUR INNOVATIVE EXPOSOMICS OPTIONAL FUNCTION. . PROJECT SUMMARY/ABSTRACT PAGE 309 CONTACT PD/PI: WRIGHT, ROSALIND J CONDUITS WILL HARNESS UNIQUE STRENGTHS IN TRANSLATIONAL RESEARCH INFORMATICS, DIGITAL HEALTH, AND DATA SCIENCE TO TRANSFORM RESEARCH, ENGAGEMENT, AND THE SCIENCE OF TRANSLATION TO ACCELERATE DISCOVERIES INTO BETTER HEALTH OUTCOMES MATCHED TO DIVERSE POPULATION NEEDS ACROSS THE LIFESPAN. WE WILL AUGMENT CONDUITS’ ROLE IN TRANSFORMING THE LOCAL, REGIONAL, AND NATIONAL TRANSLATIONAL RESEARCH ENTERPRISE TO IMPROVE HEALTH THROUGH DEVELOPMENT AND SHARING OF INNOVATIVE EDUCATIONAL PROGRAMS, PARTICIPATING IN MULTI-SITE TRIALS INCLUDING CENTRALIZED REGULATORY OVERSIGHT, SUBCONTRACTING AND DATA-SHARING, INCENTIVIZING TRANSDISCIPLINARY TEAM

DENGUE HUMAN IMMUNOLOGY PROJECT CONSORTIUM (DHIPC)

IMMUNOBIOLOGY OF PEANUT ALLERGY AND ITS TREATMENT: A PROTOTYPE

CELLULAR AND MOLECULAR STUDIES OF BONE MARROW TRANSPLANT

THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT

MSHS TRANSLATIONAL SCIENCE HUB

CHEAR CENTER FOR DATA SCIENCE

ALZHEIMER'S DISEASE RESEARCH CENTER

NIOSH REGION II EDUCATION AND RESEARCH CENTER

MULTISCALE ANALYSIS OF INFLUENZA HOST-PATHOGEN INTERACTIONS: FLUOMICS

INTEGRATIVE BIOLOGY APPROACH TO COMPLEXITY OF ALZHEIMER'S DISEASE

FSH - AN AGING HORMONE?

CELLULAR/ MOLECULAR DEFECTS IN HUMAN B CELL DEVELOPMENT

FLUOMICS: THE NEXT GENERATION

MOUNT SINAI CHEAR NETWORK LABORATORY HUB

DATA COORDINATION AND INTEGRATION CENTER FOR LINCS-BD2K

ALZHEIMER'S DISEASE RESEARCH CENTER

COMBINATION THERAPY IN MULTIPLE SCLEROSIS

SYSTEM BIOLOGY CENTER IN NEW YORK

EPIGENETIC MECHANISMS OF DEPRESSION

HIGH-DIMENSIONAL IMMUNE MONITORING OF NCI-SUPPORTED IMMUNOTHERAPY TRIALS

STRESS AND ATHEROSCLEROTIC PLAQUE MACROPHAGES - A SYSTEMS BIOLOGY APPROACH

THE MOUNT SINAI TRANSDISCIPLINARY CENTER ON EARLY ENVIRONMENTAL EXPOSURES

PROMOTING INDEPENDENCE THROUGH PAIN AND SYMPTOM MANAGEMENT

MOUNT SINAI INSTITUTES FOR CLINICAL AND TRANSLATIONAL SCIENCES

CENTRAL HUB FOR KIDNEY PRECISION MEDICINE - ABSTRACT THE OVERARCHING OBJECTIVE OF THIS KPMP CENTRAL HUB APPLICATION IS TO CREATE AND SUPPORT A COLLABORATIVE ENVIRONMENT COMMITTED TO PROMOTING PARTICIPANT SAFETY, SCIENTIFIC RIGOR, PATIENT ENGAGEMENT, HIGH ETHICAL STANDARDS, INCLUSIVITY, AND THE INTERDISCIPLINARY TEAM SCIENCE NECESSARY TO RESULT IN MAJOR ADVANCES IN KIDNEY PRECISION MEDICINE. THE CENTRAL HUB WILL COORDINATE THE KPMP RECRUITMENT SITES, TISSUE INTERROGATION SITES, AND OPPORTUNITY POOL RESEARCH GROUPS; ENGAGE THE BROADER PATIENT, CLINICAL, AND RESEARCH COMMUNITIES; AND PARTNER WITH THE KIDNEY TISSUE ATLAS COORDINATING CENTER TO SECURELY, EFFICIENTLY, AND TRANSPARENTLY DELIVER FINDABLE, ACCESSIBLE, INTEROPERABLE, AND REUSABLE DATA TO THESE COMMUNITIES. OUR EXPERIENCED MULTIDISCIPLINARY TEAM WAS INSTRUMENTAL IN BUILDING THE INFRASTRUCTURE AND FUNCTIONAL ECOSYSTEM NEEDED TO LAUNCH AND MAINTAIN THE FIRST PHASE OF THE KPMP. WE WILL BUILD ON THIS EXPERIENCE TO PROVIDE SCIENTIFIC, TECHNICAL, ADMINISTRATIVE, OPERATIONAL, AND LOGISTICAL SUPPORT TO PURSUE THE FOLLOWING SPECIFIC AIMS: (1) COORDINATE ETHICAL, SAFE, AND RIGOROUS IMPLEMENTATION OF KPMP PROTOCOLS AND PROCEDURES; (2) SUPPORT THE COLLECTION AND DISTRIBUTION OF HIGH-QUALITY DATA AND SAMPLES WITH RIGOROUS QUALITY ASSURANCE AND QUALITY CONTROL; (3) BUILD, SUPPORT, AND MAINTAIN AN INCLUSIVE, COLLABORATIVE CULTURE WITHIN KPMP THAT CONTINUOUSLY HONORS AND VALUES THE CONTRIBUTIONS OF STUDY PARTICIPANTS; AND (4) FOSTER EXTERNAL COLLABORATIONS AND CATALYZE NEW PARTNERSHIPS THROUGH AN OPPORTUNITY POOL OF FUNDS DEDICATED TO MAINTAINING KPMP DYNAMISM.

IDENTIFYING NEWBORNS AT RISK OF ADVERSE NEURODEVELOPMENTAL OUTCOMES AND OBESITY FROM AIR POLLUTION.

ECHO CONSORTIUM ON PERINATAL PROGRAMMING OF NEURODEVELOPMENT

PORPHYRIA RARE DISEASE CLINICAL RESEARCH CONSORTIUM (RDCRC)

PAGES: PHYSICAL ACTIVITY GENOMICS, EPIGENOMICS/TRANSCRIPTOMICS SITE

WTC RHC DATA AND COORDINATION CENTER

CERVICAL, ANAL, AND ORAL HPV PERSISTENCE AND RISK FACTORS AMONG ADOLESCENT GIRLS

MOLECULAR NEUROBIOLOGY OF DRUG ADDICTION

TOWARD A UNIVERSAL INFLUENZA VIRUS VACCINE

NIH FIRST COHORT CLUSTER HIRING INITIATIVE AT ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI - SUMMARY THE BARRIERS TO RESEARCH AND CAREER SUCCESS FOR UNDERREPRESENTED GROUPS IN ACADEMIC MEDICINE HAVE BEEN WIDELY DOCUMENTED—AN INHOSPITABLE CLIMATE, DISCRIMINATORY POLICIES, LOWER FINANCIAL COMPENSATION, LACK OF LEADERSHIP OPPORTUNITIES, A SENSE OF MARGINALIZATION, AND RACISM, AMONG OTHERS. STRATEGIES TO ELIMINATE THESE BARRIERS HAVE BEEN LARGELY UNSUCCESSFUL AS EVIDENCED BY THE PERSISTENT “REPRESENTATION GAP.” RESEARCH SUGGESTS THAT WHILE STRATEGIES FOCUSED ON INDIVIDUALS ARE USEFUL, AN INTEGRATED APPROACH WILL BE NECESSARY TO EFFECT SYSTEMIC CHANGE. EFFORTS TOWARD INCLUSIVE EXCELLENCE ARE UNDERWAY AT THE ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI (ISMMS) WITH SUCH TRANSFORMATIVE INITIATIVES AS THE MOUNT SINAI HEALTH SYSTEM (MSHS) TASK FORCE TO ADDRESS RACISM; A NOVEL RECRUITMENT PROGRAM TO ATTRACT JUNIOR AND SENIOR BLACK/AA AND LATINX FACULTY (THE BIOMEDICAL LAUREATES PROGRAM); CREATION OF THE OFFICE FOR GENDER EQUITY; ESTABLISHMENT OF THE INSTITUTE FOR HEALTH EQUITY RESEARCH; AND LAUNCH OF THE CENTER FOR SCIENTIFIC DIVERSITY. THE PURPOSE OF THE PROPOSED FIRST COHORT PROGRAM IS TO ACCELERATE INCLUSIVE EXCELLENCE AT OUR INSTITUTION AND, BY EXTENSION, CONTRIBUTE TO ACCELERATING INCLUSIVE EXCELLENCE MORE BROADLY IN THE NATIONAL BIOMEDICAL RESEARCH ENTERPRISE. BUILDING ON CURRENT INITIATIVES, OUR GOALS ARE TO (1) FOSTER SUSTAINABLE CULTURE/CLIMATE CHANGE; (2) PROMOTE INCLUSIVE EXCELLENCE BY HIRING A DIVERSE COHORT OF NEW EARLY-CAREER FACULTY; AND (3) SUPPORT FACULTY DEVELOPMENT, MENTORING, SPONSORSHIP, AND PROMOTION. OUR PRIMARY OUTCOME IS FOR FIRST COHORT FACULTY HIRES TO SECURE AN NIH R-AWARD BY THE CONCLUSION OF THE GRANT PERIOD. WE WILL PURSUE THREE RELATED AIMS. FIRST, WE WILL MODIFY THE MSHS TASK FORCE TO ADDRESS RACISM ROADMAP FOR CHANGE WITH KEY STRATEGIES AS THE BASIS FOR AN ISMMS ROADMAP FOR INCLUSIVE EXCELLENCE TO INCLUDE (1) DEVELOPMENT OF A PROCESS TO COLLECT ACCURATE, COMPREHENSIVE DEMOGRAPHIC FACULTY DATA AND TO MAKE THIS DATA ACCESSIBLE; (2) ENGAGEMENT OF THE FACULTY IN REGULAR CLIMATE SURVEYS AND THE SHARING OF RESULTS WITH FACULTY AND INSTITUTIONAL LEADERS; (3) DEPARTMENTAL/INSTITUTE LEVEL REVIEW OF ADVANCEMENT & PROMOTION PRACTICES, POLICIES, AND PROCESSES; AMONG OTHER KEY STRATEGIES. SECOND, WE WILL RECRUIT A DIVERSE COHORT COMPRISED OF 4 CLUSTERS OF 3 FACULTY PER CLUSTER TO BE EMBEDDED WITHIN OUR INTERDISCIPLINARY INSTITUTES. WE WILL DEVELOP A NEW RECRUITMENT PROTOCOL TO ENSURE FAIRNESS AND EQUITY IN THE HIRING PROCESS, REQUIRE BIAS REDUCTION TRAINING FOR SEARCH COMMITTEE MEMBERS, AND ESTABLISH STANDARDIZED INTERVIEW PROCESSES. NEXT, WE WILL PROVIDE AN INTEGRATED PROGRAM OF FACULTY DEVELOPMENT TO INCLUDE BOTH CAREER ADVANCEMENT AND PROFESSIONAL DEVELOPMENT ACTIVITIES (E.G., INDIVIDUAL DEVELOPMENT PLANS, MENTOR/SPONSOR COMMITTEES, GRANTS-IN-PROGRESS WORKSHOPS, INDIVIDUAL COACHING AROUND SUCH ISSUES AS WORK-LIFE INTEGRATION, PEER MENTORING, ETC.) CLUSTER SPONSORS WILL LEAD THE WAY IN IDENTIFYING OPPORTUNITIES FOR FORMAL AND INFORMAL NETWORKING ACROSS THE ISMMS AND IN THE LARGER SCIENTIFIC COMMUNITY. WITH THE SUPPORT OF AN INSTITUTIONAL INVESTMENT, ALL FIRST COHORT FACULTY WILL BE RETAINED AT THE CONCLUSION OF THE AWARD PERIOD. WE WILL CONDUCT A RIGOROUS EVALUATION OF THE PROGRAM AND COLLABORATE CLOSELY WITH NIH CEC AS REQUIRED.

INCORPORATING GENOMICS INTO THE CLINICAL CARE OF DIVERSE NYC CHILDREN

MOUNT SINAI INSTITUTES FOR CLINICAL AND TRANSLATIONAL SCIENCES

MOUNT SINAI MEDICAL SCIENTIST TRAINING PROGRAM

DEPLOYING HIGH VALUE LONGITUDINAL POPULATION-BASED DATA IN DEMENTIA RESEARCH (DEVELOP AD RESEARCH)

ESTROGEN AND THE AGING BRAIN

INFLAMMATORY BOWEL DISEASE GENETICS CONSORTIUM DATA COORDINATING CENTER

THE MANHATTAN HIV BRAIN BANK

CORONARY REVASCULARIZATION IN DIABETIC PATIENTS

TRANSCRIPTIONAL MECHANISMS OF DRUG ADDICTION

GERIATRIC EMERGENCY DEPARTMENT INNOVATIONS IN CARE THROUGH WORKFORCE, INFORMATICS AND STRUCTURAL ENHANCEMENTS (GEDI WISE)

STRESS, LEAD, IRON DEFICIENCY AND NEURODEVELOPMENT

INNATE/ADAPTIVE IMMUNE INTERACTIONS IN GUT INFLAMMATION

VIRAL IMMUNITY AND VACCINATION (VIVA) HUMAN IMMUNOLOGY PROJECT CONSORTIUM (HIPC) - SUMMARY THE VIRAL IMMUNITY AND VACCINATION (VIVA) HUMAN IMMUNOLOGY PROJECT CONSORTIUM (HIPC) WILL CARRY OUT A COMPREHENSIVE SYSTEMS IMMUNOLOGY PROGRAM TO ASSESS THE DYNAMIC HUMAN IMMUNE RESPONSE TO SARS-COV- 2, SEASONAL INFLUENZA VIRUSES AND TETRAVALENT AND TRIVALENT DENGUE VACCINES AND SUBSEQUENT INFECTIONS BY THOSE PATHOGENS. IT WILL GENERATE COMPREHENSIVE INNATE, CELLULAR AND ADAPTIVE IMMUNE SIGNATURES THAT CORRELATE WITH VACCINE OUTCOMES. THE VIVA HIPC WILL LEVERAGE RECENT ADVANCES IN HUMAN IMMUNE PROFILING METHODS TO CHARACTERIZE THE DIVERSE STATES OF THE HUMAN IMMUNE SYSTEM BEFORE AND AFTER VACCINATION AGAINST THESE VIRAL PATHOGENS OF GREAT PUBLIC HEALTH CONCERN USING NOVEL IMMUNE PHENOTYPING AND GENOMICS STRATEGIES THAT GENERATE DATA AND TOOLS TO BE USED FOR DOWNSTREAM DATA ANALYSIS AND FUNCTIONAL INVESTIGATIONS. THE PROPOSED STUDIES WILL USE LONGITUDINAL BIOSPECIMENS FROM ESTABLISHED HUMAN COHORTS OF RESPIRATORY INFECTIONS AND VACCINATIONS IN THE US AND ARGENTINA AS WELL AS FROM VACCINE TRIALS IN THE US (PROVIDED BY THE CLINICAL CORE, CORE B). IN ADDITION, VALIDATION EXPERIMENTS USING HUMAN TONSILS SOURCED FROM HEALTHY INDIVIDUALS AND EXPOSED EX VIVO TO THE DIFFERENT VACCINE TYPES WILL BE CONDUCTED. THREE COMPLEMENTARY, WELL-INTEGRATED PROJECTS WILL PRODUCE IN-DEPTH HUMAN IMMUNE PROFILES AND SIGNATURES OF SARS-COV-2 VACCINATIONS AND INFECTIONS (PROJECT 1), SEASONAL INFLUENZA VACCINATIONS AND INFECTIONS (PROJECT 2) AS WELL AS DENGUE VACCINE AND HUMAN CHALLENGE STUDIES (PROJECT 3). UNIQUE IN OUR APPROACH IS THE USE OF LONGITUDINAL COHORTS FOR IN VIVO PROFILING, SUPPORTED BY EX VIVO HUMAN TONSILLAR HISTOCULTURE (HC) MODELS FOR INFECTION AND VACCINATION. OUR HOLISTIC APPROACH WILL PROVIDE CUTTING- RESPONSES TO VACCINATIONS AND INFECTIONS BY THE IMMUNE PHENOTYPING CORE (CORE C), GENOMICS/TRANSCRIPTOMICS, INCLUDING SCRNASEQ, CITESEQ AND SPATIAL TISSUE TRANSCRIPTOMICS BY THE GENOMICS CORE (CORE D), AND EXPERIMENTAL VACCINATIONS IN PRIMARY HUMAN TONSILLAR HISTOCULTURES (HC) IN PROJECTS 1, 2 AND 3. DATA MINING, BIOINFORMATICS TO IDENTIFY THE NETWORK COMPONENTS AND INFER THEIR INTERACTIONS AND CORRELATIONS IMPORTANT FOR VACCINE OUTCOMES WILL BE DONE BY THE DATA MANAGEMENT AND ANALYSIS CORE (CORE E). THE VIVA HIPC WILL MAKE THE DATA, ANALYSES AND IMMUNE PROFILES GENERATED AVAILABLE TO THE SCIENTIFIC COMMUNITY BY COUPLING OUR LOCAL DATA INFRASTRUCTURE TO IMMPORT (DIRECTLY OR THROUGH THE HIPC COORDINATING CENTER). THIS INTEGRATION WILL ENSURE FULL AND TIMELY RELEASE OF CLINICAL, SAMPLE, AND EXPERIMENTAL METADATA IN SYNCHRONY WITH GENOMIC DATA RELEASES TO STANDARD DATA REPOSITORIES INCLUDING SRA, GEO, AND GENBANK (CORE E). THE VIVA TEAM (DRS. KRAMMER, GARCIA-SASTRE, DURBIN, GAMARNIK, VAN BAKEL AND SEBRA) LED BY DR. FERNANDEZ-SESMA AND DR. SIMON INCLUDES PHYSICIANS, PHYSICIAN SCIENTISTS AND SCIENTISTS WITH COMPLEMENTARY EXPERTISE IN VIRAL IMMUNOLOGY, VIRAL PATHOGENESIS, VACCINOLOGY, GENOMICS, DATA ANALYSIS AND A PROVEN TRACK RECORD OF COLLABORATION AND EXCELLENCE.

TARGETING TRAINED IMMUNITY IN TRANSPLANTATION - SUMMARY – OVERVIEW TRANSPLANTATION HAS REVOLUTIONIZED THE LIVES OF PATIENTS SUFFERING FROM ORGAN FAILURE. THE DESIGN OF MODERN IMMUNOSUPPRESSION HAS EMPLOYED A TIME-HONORED FOCUS ON CONTROLLING T CELL-MEDIATED RESPONSES. HOWEVER, CURRENT IMMUNOSUPPRESSIVE THERAPIES HAVE SUBOPTIMAL SUCCESS RATES AND INDUCE SIGNIFICANT SIDE EFFECTS, INCLUDING INCREASED SUSCEPTIBILITY TO INFECTIONS, METABOLIC TOXICITY, AND CANCER RISK. GIVEN THE GROWING BODY OF EVIDENCE SHOWING THAT INNATE IMMUNITY IS ALSO CRITICAL TO ALLORESPONSE INITIATION AND ALLOGRAFT SURVIVAL, IT IS NOT SURPRISING THAT CURRENT IMMUNOSUPPRESSIVE REGIMENS DO NOT ACHIEVE SATISFACTORY LONG-TERM GRAFT AND PATIENT SURVIVAL. RECENT WORK BY THIS P01’S INVESTIGATORS HAS SHOWN THAT TRAINED IMMUNITY PLAYS A VITAL ROLE IN ALLOGRAFT SURVIVAL. TRAINED IMMUNITY IS A LONG-TERM INCREASE IN THE FUNCTIONAL RESPONSIVENESS OF INNATE IMMUNE CELLS, WHICH IS MAINTAINED BY EPIGENETIC MODIFICATIONS AND CAN BE CONSIDERED DE FACTO INNATE IMMUNE MEMORY. ON A SYSTEMS LEVEL, WE DEMONSTRATED THAT TRAINED IMMUNITY IS REGULATED AND MAINTAINED BY EPIGENETIC MODIFICATIONS IN BONE MARROW HEMATOPOIETIC PROGENITORS, WHICH CONSEQUENTLY RELEASE TRAINED INNATE IMMUNE CELLS WITH AUGMENTED INFLAMMATORY AND ANTIMICROBIAL FUNCTION. OUR PRECLINICAL AND CLINICAL PRELIMINARY DATA REVEALED A DISCRETE CAUSATIVE CONNECTION BETWEEN ALLOGRAFT TRANSPLANTATION, THE INDUCTION OF TRAINED IMMUNITY, SYSTEMIC INFLAMMATORY RESPONSE, AND ACTIVATED OR AMPLIFIED T CELL-MEDIATED ALLOIMMUNITY. FURTHERMORE, WE IDENTIFIED TRAINED IMMUNITY AS A COMPELLING THERAPEUTIC TARGET IN MOUSE AND NON-HUMAN PRIMATE HEART ALLOGRAFT MODELS. BASED ON THESE RESULTS, OUR CENTRAL HYPOTHESIS IS THAT TRAINED IMMUNITY IS A CRITICAL MECHANISM THAT AMPLIFIES AND SUSTAINS BOTH INNATE AND ADAPTIVE REJECTION RESPONSES AND IS THEREFORE A COMPELLING CLINICAL THERAPEUTIC TARGET FOR ACHIEVING LONG-TERM ALLOGRAFT SURVIVAL WITHOUT REQUIRING CHRONIC IMMUNOSUPPRESSION. IN THIS P01, WE WILL ADDRESS OUR CENTRAL HYPOTHESIS BY DRAWING ON THE EXPERTISE OF AUTHORITIES IN THE FIELDS OF IMMUNOLOGY AND BIOENGINEERING. THIS MULTIDISCIPLINARY TEAM OF SCIENTISTS AND CLINICIANS WILL WORK TOGETHER TO I) UNDERSTAND TRAINED IMMUNITY’S CLINICAL RELEVANCE IN KIDNEY TRANSPLANTATION, II) ELUCIDATE THE MECHANISMS BY WHICH TRAINED IMMUNITY IS INDUCED AND LEADS TO ORGAN REJECTION, AND III) DEVELOP BIOENGINEERING SOLUTIONS FOR DIAGNOSING AND THERAPEUTICALLY REGULATING TRAINED IMMUNITY IN TRANSPLANTATION. WE ANTICIPATE THAT, TOGETHER, THESE HIGHLY INTERACTIVE PROJECTS WILL GENERATE INNOVATIVE NEW THERAPEUTIC STRATEGIES TO MORE EFFECTIVELY PREVENT REJECTION AND POTENTIALLY ACHIEVE IMMUNE TOLERANCE. IF SUCCESSFUL, THESE STUDIES COULD IMPACT THE ENTIRE FIELD OF TRANSPLANTATION AND PROVIDE INSIGHTS THAT COULD ALSO BE HIGHLY RELEVANT FOR BONE MARROW TRANSPLANTATION AND AUTOIMMUNE DISEASE.

PHENOTYPES REIMAGINED TO DEFINE CLINICAL TREATMENT AND OUTCOME RESEARCH (PREDICTOR) - PROJECT SUMMARY PSYCHIATRY FACES A SIGNIFICANT CHALLENGE IN THE ABSENCE OF OBJECTIVE MEASURES TO ASSESS BEHAVIOR. CLINICIANS FORM CLINICAL OPINIONS BASED LARGELY ON THEIR IMPRESSIONS FROM INTERVIEWING AND WHAT THEY READ IN THE ELECTRONIC HEALTH RECORD. AS A RESULT, WE ARE CURRENTLY UNABLE TO PROVIDE RELIABLE PROGNOSES ON AN INDIVIDUAL BASIS. ONE UNTAPPED SOURCE OF BEHAVIORAL INFORMATION FOR CLINICAL DECISION-MAKING IS THE CLINICAL INTERVIEW ITSELF, WHICH FORMS THE FOUNDATION OF THE ELECTRONIC HEALTH RECORD (EHR). EVERY CLINICAL VISIT PROVIDES A WEALTH OF BEHAVIORAL INFORMATION COMPRISING SPOKEN LANGUAGE, EYE CONTACT, AND FACIAL EXPRESSIONS FROM BOTH THE PATIENT AND THE CLINICIAN. ANOTHER SOURCE OF BEHAVIORAL DATA, WHICH IS ECOLOGICALLY VALID, COMES FROM SMARTPHONES, WHICH PROVIDE PHYSICAL ACTIVITY METRICS (E.G., STEP COUNT, DISTANCE TRAVELED), GEOLOCATION, SOCIAL INTERACTIONS (E.G., SMS MESSAGES AND PHONE CALLS MADE AND RECEIVED), SLEEP PATTERNS AND AUDIO DATA FROM DIARIES. BY ANALYZING THESE RICH BEHAVIORAL DATASETS FROM ROUTINE CLINICAL VISITS AND SMARTPHONES, WE CAN DEVELOP CLINICAL SIGNATURES FOR PARTICULARLY CLINICALLY RELEVANT OUTCOMES IN YOUNG HELP-SEEKING PEOPLE, NAMELY TREATMENT DISENGAGEMENT, ER VISITS AND HOSPITALIZATIONS. THESE INDIVIDUALIZED CLINICAL SIGNATURES ARE IMPORTANT FOR THE REAL-LIFE SITUATION THAT CONFRONTS BOTH CLINICIAN AND PATIENT AT THE FIRST VISIT TO A MENTAL HEALTH CLINIC. THIS PROPOSAL INCLUDES ALL NEW PATIENTS (N = 2100), AGES 15 TO 30, WHO SEEK TREATMENT FOR THE FIRST TIME AT ONE OF SIX OUTPATIENT MENTAL HEALTH CLINICS IN THE MOUNT SINAI HEALTH SYSTEM. AIM 1 IS TO CREATE A BASELINE CLINICAL SIGNATURE FOR OUTCOMES USING DEEP NEURAL NETWORK MODELING OF LEGACY EHR DATA AND BASELINE BEHAVIOR, WHICH INCLUDES AUDIOVISUAL RECORDINGS OF INTAKE INTERVIEWS, RATINGS OF WORKING ALLIANCE, AND BRIEF SURVEYS AND TESTS OF COGNITION. AIM 2 IS TO USE CONTEXTUAL BANDIT TO CREATE A LONGITUDINAL CLINICAL SIGNATURE FOR OUTCOMES BASED ON SUBSEQUENT BEHAVIORAL DATA FROM CLINICAL INTERVIEWS (AND THEIR ACCOMPANYING NOTES), AND SMARTPHONE PASSIVE DATA AND AUDIO DIARY DATA. CONTEXTUAL BANDIT IS A MODEL THAT KEEPS UPDATING PROBABILITIES AND ODDS OVER TIME AS IT IS GIVEN NEW DATA. AIM 3 IS TO CREATE CLINICAL SIGNATURES BASED ON EHR DATA ALONE, SUCH THAT THE ADDED VALUE OF BEHAVIORAL DATA FOR AIMS 1 AND 2 CAN BE QUANTIFIED. STUDY ASSESSMENTS ARE STANDARD, LOW-COST, AND EASY TO ADMINISTER, WITH GOOD VARIANCE, VALIDITY, RELIABILITY, AND GENERALIZABILITY. ACROSS ALL AIMS, FUSION WILL BE USED FOR BEHAVIORAL FEATURE EXTRACTION AND NATURAL LANGUAGE PROCESSING (NLP) FOR ANALYSIS OF BOTH WRITTEN LANGUAGE (CLINICAL TEXT) AND SPOKEN LANGUAGE (CLINICAL VISITS AND AUDIO DIARIES). DATA SCIENCE METHODS HAVE BEEN OPTIMIZED FOR PARTNERSHIP WITH THE DCC. COMMUNITY ENGAGEMENT AND ETHICAL ISSUES RE PRIVACY, INFORMED CONSENT AND FAIRNESS HAVE BEEN PRIORITIZED.

DRUG COMBINATION SIGNATURES FOR PREDICTION AND MITIGATION OF TOXICITY

UNDERSTANDING THE MOLECULAR MECHANISMS THAT CONTRIBUTE TO NEUROPSYCHIATRIC SYMPTOMS IN ALZHEIMER DISEASE

LOS ANGELES STROKE PREVENTION/INTERVENTION RESEARCH PROGRAM IN HEALTH DISPARITIES

PASINETTI: OVERALL; DIETARY BOTANICALS IN THE PRESERVATION OF COGNITIVE AND PSYCHOLOGICAL RESILIENCE (PASINETTI)

HIGHER ORDER CHROMATIN AND GENETIC RISK FOR ALZHEIMER'S DISEASE

SINGLE CELL BRAIN TRANSCRIPTOME CHANGES DURING CHRONIC HIV INFECTION AND OPIATE USE IN CONVENTIONAL MICE - PROJECT SUMMARY THIS APPLICATION IS SUBMITTED IN RESPONSE TO RFA-D-21-019: SINGLE CELL OPIOID RESPONSES IN THE CONTEXT OF HIV (SCORCH) PROGRAM EXPANSION: CNS DATA GENERATION FOR CHRONIC OPIOID, METHAMPHETAMINE, AND/OR COCAINE EXPOSURES. HUMAN IMMUNODEFICIENCY VIRUS (HIV) CAN INFECT NONNEURONAL CELLS IN THE BRAIN, PARTICULARLY MICROGLIA, WITH THESE CELLS ACTING AS A RESERVOIR OF LATENT INFECTION. HIV INFECTION HAS DELETIONS EFFECTS ON THE FUNCTION OF NONNEURONAL AND NEURONAL CELLS, INCLUDING THOSE CELLS LOCATED IN BRAIN SITES RELEVANT TO COGNITION, EMOTION AND MOTIVATION. THE SAME BRAIN SITES IMPACTED BY HIV ARE KNOWN TO REGULATE THE ACTIONS OF OPIOIDS AND OTHER CLASSES OF ADDICTIVE DRUGS, AND OPIOID USE DISORDER (OUD) IS MORE PREVALENT IN HIV-INFECTED INDIVIDUALS THAN THE GENERAL POPULATION. MOREOVER, HIV INFECTION AND OUD RECIPROCALLY INTERACT, WITH EACH CONDITION POTENTIALLY EXACERBATING THE SEVERITY OF THE OTHER. MICE INFECTED WITH ECOHIV, A MODIFIED HIV STRAIN THAT TARGETS CD4+ T CELLS, MACROPHAGES AND MICROGLIA, RECAPITULATES THE MAJOR PATHOBIOLOGICAL FEATURES OF CHRONIC HIV INFECTION IN INDIVIDUALS ON ANTIRETROVIRAL THERAPY (ART). HERE, WE WILL LEVERAGE STATE-OF-THE-ART SINGLE CELL SEQUENCING (SCSEQ), MOLECULAR, CELLULAR AND BEHAVIORAL APPROACHES TO DEFINE CELL TYPE-SPECIFIC INTERACTIONS BETWEEN HIV AND OPIOIDS IN THE BRAINS OF ECOHIV-INFECTED MICE. IN SPECIFIC AIM I, WE OPTIMIZE THE INTRAVENOUS (IV) HEROIN SELF-ADMINISTRATION PROCEDURE, ALREADY WELL-ESTABLISHED IN OUR LABORATORIES, FOR USE IN ECOHIV- INFECTED MICE. WE WILL THEN EXAMINE THE EFFECTS OF ECOHIV INFECTION ON THE EXPRESSION OF OPIOID ADDICTION-RELEVANT BEHAVIORS. CONVERSELY, WE WILL EXAMINE THE EFFECTS OF HEROIN CONSUMPTION ON THE EXPRESSION OF COGNITIVE ABNORMALITIES IN ECOHIV-INFECTED MICE RELEVANT TO HIV-ASSOCIATED NEUROCOGNITIVE IMPAIRMENT (HIV-NCI) IN HUMANS. FINALLY, WILL EXAMINE THE EFFECTS OF ART ON THE EXPRESSION OF ADDICTION- AND HIV-NCI-RELEVANT BEHAVIORAL ABNORMALITIES IN ECOHIV-INFECTED MICE. IN SPECIFIC AIM II, WE WILL PERFORM SCSEQ ON BRAIN REGIONS RELEVANT TO OPIOID ADDICTION AND HIV-NCI, COLLECTED FROM ECOHIV MICE WITH OUR WITHOUT A HISTORY OF INTRAVENOUS OPIOID SELF- ADMINISTRATION BEHAVIOR. WE WILL INVESTIGATE THE EFFECTS OF ART ON SCSEQ PATTERNS IN THESE MICE. THE SCSEQ DATA WILL BE MINED TO IDENTIFY CELLS IN THE BRAIN INFECTED BY ECOHIV, AND DETERMINE WHICH CELLS SHOW THE MOST ROBUST TRANSCRIPTIONAL RESPONSES TO ECOHIV IN OPIOID-NAÏVE AND OPIOID-EXPERIENCED MICE. IN SITU HYBRIDIZATION AND IMMUNOHISTOCHEMISTRY WILL BE USED TO VALIDATE KEY FINDINGS AND PRIORITIZE CANDIDATE GENES FOR FURTHER INVESTIGATION. IN SPECIFIC AIM III, WE WILL USE IN VIVO CRISPR-CAS9 TO TARGET PRIORITIZED GENES IDENTIFIED IN AIM II IN A CELL TYPE- AND BRAIN REGION-SPECIFIC MANNER. THE IMPACT OF CRISPR CLEAVAGE OF PRIORITIZED GENES ON THE EXPRESSION OF ADDICTION- AND HIV-NCI-RELEVANT BEHAVIORAL ABNORMALITIES IN ECOHIV-INFECTED MICE WILL BE EXAMINED. THIS INNOVATIVE PROGRAM OF RESEARCH MAY YIELD FUNDAMENTAL NEW INSIGHTS INTO DISEASE-RELEVANT INTERACTIONS BETWEEN HIV INFECTION AND OPIOID DRUGS.

A HUMANIZED MONOCLONAL FSH BLOCKING ANTIBODY FOR ALZHEIMER'S DISEASE - PROJECT SUMMARY ALZHEIMER’S DISEASE (AD) STANDS OUT AS NOTABLE IN NOT HAVING A CURE AMONG MANY DISEASES THAT AFFECT ELDERLY MEN AND WOMEN––IN ESSENCE, CREATING AN URGENT NEED FOR A NEW THERAPY. IT IS ALSO UNCLEAR WHY MENOPAUSAL WOMEN HAVE A PREPONDERANCE OF AD, AND, WHILE DECLINING ESTROGEN BAS BEEN IMPLICATED, THERE IS CLEAR CLINICAL CORRELATION WITH RISING LEVELS OF FOLLICLE STIMULATING HORMONE (FSH). WE HAVE IDENTIFIED FSH AS A TARGET FOR SEVERAL AGING DISORDERS––OSTEOPOROSIS, OBESITY, HYPERCHOLESTEREMIA––AND NOW, AD. INHIBITING THE ACTION OF FSH USING BLOCKING ANTIBODIES REDUCES BODY FAT, INCREASES BONE MASS, LOWERS SERUM CHOLESTEROL, AND FROM OUR NEWEST AND MOST EXCITING RESULTS, PREVENTS AD IN TWO MOUSE MODELS. WE HAVE DESIGNED A NOVEL HUMANIZED MONOCLONAL ANTIBODY, HU6, THAT BINDS TO A SMALL EPITOPE WITHIN THE RECEPTOR–BINDING DOMAIN OF FSHSS, THUS BLOCKING ITS ACTION ON THE FSH RECEPTOR (FSHR). OUR ASPIRATIONAL GOAL IS TO USE THIS LEAD THERAPEUTIC FOR THE THERAPY AND PREVENTION OF ALL FOUR DISORDERS––OR, AT THE VERY LEAST, AD. SELECTED FROM A POOL OF 30 NEWLY SYNTHESIZED HUMANIZED ANTIBODIES, HU6 DISPLAYS HIGH–AFFINITY BINDING TO FSH (KD ~7 NM) AND THUS PREVENTS ITS ACTION ON HIPPOCAMPAL FSHRS TO IMPROVE COGNITION IN AD MICE. THESE OBSERVATIONS, TOGETHER WITH ITS OPTIMAL PHARMACOKINETIC PROFILE, LAY THE GROUNDWORK FOR HU6 TO ENTER EARLY STAGE DEVELOPMENT. IN SPECIFIC AIM 1, WE PROPOSE TO SCALE UP PRODUCTION OF RESEARCH–GRADE HU6; CREATE AN OPTIMAL FORMULATION; TEST ITS PHYSICOCHEMICAL PROPERTIES; STUDY THE STRUCTURE OF THE FSH:HU6 COMPLEX; AND MANUFACTURE A MASTER CELL BANK FOR CGMP–GRADE HU6. IN SPECIFIC AIM 2, WE WILL PERFORM PHARMACOKINETIC STUDIES IN TG32 MICE ‘HUMANIZED’ FOR ANTIBODY CLEARANCE, AND IN AFRICAN GREEN VERVET MONKEYS; DETERMINE MINIMUM EFFECTIVE DOSE(S) IN PREVENTING AND/OR TREATING AD IN 3XTG MICE; EXAMINE EFFICACY AND SAFETY IN YOUNG AND AGED 3XTG MICE; AND DOCUMENT SAFETY IN VERVET MONKEYS. THE WORK WILL BE CONDUCTED USING GOOD LABORATORY PRACTICE (GLP) STANDARDS ESTABLISHED AT MOUNT SINAI, EMORY, WAKE FOREST AND SAN ANTONIO. WE HAVE ALSO CREATED CROSS–FUNCTIONAL RESEARCH TEAMS THAT WILL BE SUPPORTED BY A DISTINGUISHED PANEL OF ADVISORS, COMPRISING SCIENCE AND MEDICINE EXPERTS, BUSINESS LEADERS, AND ENTREPRENEURS IN BIOTECHNOLOGY. DEFINITIVE INFORMATION ON DOSAGE, ROUTE AND FREQUENCY, TOGETHER WITH EARLY PROOF OF SAFETY SHOULD PROPEL US INTO LATE STAGE DEVELOPMENT AND FIRST–IN–HUMAN STUDIES.

SYSTEMS BIOLOGY OF EARLY ATOPY (SUNBEAM) ANALYSIS AND BIOINFORMATICS CENTER - PROJECT SUMMARY FOOD ALLERGY (FA) AND ATOPIC DERMATITIS (AD) ARE COMMON CHRONIC CONDITIONS OF ATOPY AFFECTING 10% AND 20% OF CHILDREN, RESPECTIVELY. INDIVIDUALS WITH FA ARE AT DAILY RISK FOR POTENTIALLY LIFE-THREATENING HIVES, ANGIOEDEMA, RESPIRATORY DIFFICULTY, CARDIOVASCULAR COMPROMISE, GASTROINTESTINAL DISTRESS, AND/OR ANAPHYLAXIS FOLLOWING INGESTION OF A FOOD ANTIGEN TO WHICH THEY ARE SENSITIZED. INDIVIDUALS WITH AD MUST LIVE WITH CHRONICALLY PRURITIC, INFLAMED SKIN THAT CAN COVER A SIGNIFICANT PROPORTION OF THEIR BODIES AND BECOME INFECTED. THE DEVELOPMENT OF FA IS FREQUENTLY PRECEDED BY AD, SUGGESTING SHARED RISK FACTORS AND OVERLAPPING PATHOBIOLOGY. FA AND AD ARE COMPLEX DISEASES, AND PARSING THE BIOLOGICAL HETEROGENEITY HIDDEN UNDER THEIR CLINICAL UMBRELLAS IS PARAMOUNT TO IMPROVING THEIR PREVENTION, DIAGNOSIS, AND CLINICAL MANAGEMENT. A SYSTEMS BIOLOGY APPROACH WHERE THE BIOLOGY OF FA AND AD ARE INVESTIGATED COMPREHENSIVELY AT SEVERAL LEVELS MAY HELP IDENTIFY NEW KNOWLEDGE ABOUT THE DEVELOPMENT OF ALLERGY. SYSTEMS BIOLOGY OF EARLY ATOPY (SUNBEAM) IS A GENERAL POPULATION PRE-BIRTH COHORT STUDY INITIATED BY THE NIAID TO STUDY THE ROLE AND INTER-RELATIONSHIPS OF GENETIC, CLINICAL, BIOLOGICAL, AND ENVIRONMENTAL EARLY-LIFE FACTORS IN THE DEVELOPMENT OF ALLERGIC DISEASES, WITH AN EMPHASIS ON FA AND AD. PREGNANT WOMEN, CHILDREN BORN TO THEM, AND THE CHILDREN'S BIOLOGICAL FATHERS ARE BEING ENROLLED AND PHENOTYPED WITH LONGITUDINAL BIOSAMPLE COLLECTIONS. A CENTRAL GOAL OF SUNBEAM IS TO APPLY SYSTEMS BIOLOGY TO IDENTIFY MECHANISMS AND BIOMARKERS UNDERLYING THE DEVELOPMENT OF FA, AD, AND THEIR ENDOTYPES. THE OVERARCHING GOAL OF THIS SUNBEAM ANALYSIS & BIOINFORMATICS CENTER (ABC) APPLICATION IS TO CREATE A CENTER FOR ASSAYING SUNBEAM BIOSAMPLES USING OMICS, AND TO APPLY INTEGRATIVE SYSTEMS BIOLOGY TO IDENTIFY NOVEL DETERMINANTS OF FA AND AD. OUR APPLICATION CENTERS ON THESE FIVE SPECIFIC AIMS: (1) ASSAY BIOSAMPLES FROM SUNBEAM PARTICIPANTS TO GENERATE LONGITUDINAL, MULTI-SCALE OMIC DATA THAT WILL INFORM ON THE DEVELOPMENT OF FA AND AD; (2) ANALYZE THE SYSTEMS-WIDE OMIC DATA GENERATED TO IDENTIFY NOVEL BIOMARKERS, ENDOTYPES, AND MECHANISMS UNDERLYING THE DEVELOPMENT OF FA AND AD; (3) INTEGRATE DATA ACROSS MOLECULAR DIMENSIONS TO IDENTIFY KEY DRIVERS AND PREDICTORS OF FA AND AD DEVELOPMENT; (4) SHARE ALL GENERATED DATA, CREATE A CENTRALIZED PLATFORM FOR SUNBEAM DATA AND BIOINFORMATIC INNOVATIONS, AND BUILD CAPACITY FOR THE INTEGRATION OF FUTURE SUNBEAM OMICS DATA; AND (5) DEVELOP INFRASTRUCTURE FOR INTERACTIONS WITH THE SUNBEAM STEERING GROUP, THE NIAID STATISTICAL AND CLINICAL COORDINATING CENTER, AND NIAID. WITH THIS AWARD, WE WILL CREATE A CENTER FOR UNPRECEDENTED SYSTEMS ALLERGY RESEARCH. IN ADDITION TO AN INVESTIGATOR TEAM WITH WORLD- CLASS EXPERTISE IN MULTI-OMICS, SYSTEMS BIOLOGY, COMPUTATIONAL BIOLOGY, DATA SCIENCE, AND BIOINFORMATICS, OUR TEAM ALSO INCLUDES PHYSICIAN-SCIENTISTS AND IMMUNOLOGISTS WHO DIRECTLY DESIGNED AND CONTINUE TO ACTIVELY DRIVE THE ONGOING ENROLLMENT AND IMPLEMENTATION OF SUNBEAM. OUR TEAM'S EXPERIENCE, EXPERTISE, AND PROVEN TRACK RECORD WILL ENSURE THE SUCCESS OF SUNBEAM-ABC.

GENOMIC RISK IN CLINIC CARE TO PROMOTE HEALTH EQUITY IN NEW YORK CITY PATIENTS

MOLECULAR AND BIOLOGICAL CHARACTERIZATION OF SPANISH FLU

CANNABIDIOL IN THE TREATMENT OF OPIOID USE DISORDER - PROJECT SUMMARY  THE  OPIOID-­EPIDEMIC,  ROOTED  IN  A  CHRONIC-­RELAPSING  DISEASE,  HAS  HAD  DEVASTATING  CONSEQUENCES  LEADING  TO  PROFOUND  NATIONAL  BURDEN.  RESEARCH  INTO  THE  ENHANCEMENT  OF  TREATMENT  OPTIONS  FOR  INDIVIDUALS  WITH  OPIOID  USE  DISORDER (OUD) IS CLEARLY A PRIORITY. RESPONDING TO URGENT CALLS FOR NON-­OPIOID TREATMENT, WE HAVE BEEN EVALUATING  THE  THERAPEUTIC  POTENTIAL  OF  CANNABIDIOL  (CBD),  A  NON-­INTOXICATING  CANNABINOID.  OUR  PRECLINICAL  ANIMAL  STUDIES  HAVE SHOWN THAT CBD DECREASES CUE-­INDUCED HEROIN SEEKING BEHAVIOR DURING DRUG ABSTINENCE, ASSOCIATED WITH  INCUBATION OF CRAVING. WE HAVE ALSO SHOWN THAT CBD WAS SAFE EVEN IN COMBINATION WITH A POTENT OPIOID AGONIST  TO  ADDRESS  A  POTENTIAL  RELAPSE  CONDITION  AND  THAT  CBD  DECREASED  CRAVING  AND  ANXIETY  ASSOCIATED  WITH  HEROIN  CUES  IN  ABSTINENT  INDIVIDUALS  WITH  HEROIN  USE  DISORDER,  AN  EFFECT  THAT  PERSISTED  EVEN  A  WEEK  AFTER  THE  LAST  CBD  DOSE.  BUILDING  ON  THIS  FOUNDATION  AND  RECOGNIZING  THAT  CANNABINOIDS  SUCH  AS  CBD  HAVE,  TO  DATE,  POOR  BIOAVAILABILITY, WE PROPOSE TO INVESTIGATE AN ORAL CBD POWERED BY A NOVEL PATENTED TECHNOLOGY (LEVERAGING THE  KINETICS OF LONG CHAIN FATTY ACID ABSORPTION) IN A GELCAP DELIVERY SYSTEM THAT IMPROVES BIOAVAILABILITY, REDUCES THE  INCIDENCE  OF  GASTROINTESTINAL  SIDE  EFFECTS,  REDUCES  FIRST  PASS  METABOLISM  AND  ENHANCES  ONSET  TIME.  IN  A  RANDOMIZED, DOUBLE-­BLINDED, PLACEBO-­CONTROLLED STUDY OF MED-­CBD, WE AIM TO DETERMINE THE PHARMACOKINETIC  AND PHARMACODYNAMIC EFFECTS IN OUD PARTICIPANTS AND OBTAIN INSIGHTS ABOUT THE CONCENTRATION RANGE OF MED-­ CBD THAT ACUTELY REDUCE CRAVING IN OUD INDIVIDUALS (UG3 PHASE). LEVERAGING OUR LARGE OUD POPULATION (~6,500)  AT  THE  ADDICTION  INSTITUTE  OF  MOUNT  SINAI  AND  USING ECOLOGICAL  MOMENTARY  ASSESSMENT  TECHNOLOGY  TO  MONITOR  CRAVING IN REAL-­TIME, WE WILL STUDY VARIOUS DOSES MED-­CBD EFFECTS ON OPIOID ABSTINENT INDIVIDUALS NOT MAINTAINED  ON MEDICATION ASSISTED THERAPY AS WELL AS ON THOSE MANAGED ON OPIOID AGONISTS. SUBSEQUENTLY, A LARGE CLINICAL  TRIAL  BASED  ON  THE  UG3  RESULTS  WILL  INVESTIGATE  THE  LONG-­TERM  (6  MONTHS)  AND  THE  POTENTIAL  PROTRACTED  EFFECTS  (6  WEEKS)  OF  MED-­CBD  ADMINISTRATION  ON  GENERAL  AND  CUE-­INDUCED  CRAVING,  RELAPSE,  OPIOID  MEDICATION  DOSE  AS  WELL AS PSYCHOSOCIAL FUNCTIONING IN OUD OPIATE-­ABSTINENT PARTICIPANTS MANAGED ON OPIOID AGONISTS (UH3 PHASE).  THESE  STUDIES  WILL  PROVIDE  CONCRETE  INFORMATION  NECESSARY  TO  DEVELOP  A  NON-­OPIOID,  NON-­INTOXICATING  FDA-­ APPROVED MEDICATION TO REDUCE CRAVING, RELAPSE AND RESTORE GLOBAL FUNCTIONING IN OUD INDIVIDUALS.

CLINICAL & BIOLOGICAL SIGNATURES OF POST-TRAUMATIC NEURODEGENERATION: TOWARD IN VIVO DIAGNOSIS OF THE LATE EFFECTS OF TBI.

PROGRAMMING LONG-LASTING IMMUNITY TO CORONAVIRUSES (PLUTO) - THE SARS-COV-2 PANDEMIC REPRESENTS AN EXCEPTIONAL PUBLIC HEALTH CRISIS HIGHLIGHTING THE NEED FOR BETTER UNDERSTANDING OF THE MECHANISMS CONTROLLING BROADLY PROTECTIVE IMMUNE RESPONSES AND GENERATING VACCINE CANDIDATES ABLE TO ELICIT SUCH RESPONSES. THE PROGRAM PROJECT ENTITLED “PROGRAMMING LONG-LASTING IMMUNITY TO CORONAVIRUSES (PLUTO)” PROPOSES A COMPREHENSIVE RESEARCH PLAN TOWARDS DESIGNING PAN- SARBECOVIRUS AND PAN-BETACORONAVIRUS VACCINES WITH BROAD PROTECTION BY APPLYING IN-DEPTH B CELL CHARACTERIZATION IN THE CONTEXT OF CORONAVIRUS IMMUNE HISTORIES IMPRINTED BY SUCCESSIVE VACCINATIONS AND/OR INFECTIONS. TWO COMPLEMENTARY RESEARCH PROJECTS WILL ESTABLISH CORRELATES OF ROBUST, DURABLE AND PROTECTIVE CORONAVIRUS HUMORAL IMMUNITY (PROJECT 1) AS WELL AS DESIGN AND TEST EFFICACY OF VIRAL VARIANT-PROOF PAN-SARBECOVIRUS AND PAN-BETACORONAVIRUS VACCINES (PROJECT 2). THE CORES WILL SYNERGIZE WITH THE TWO RESEARCH PROJECTS TO SUPPORT THE SUCCESSFUL COMPLETION OF THE RESEARCH AIMS. THE ADMINISTRATIVE CORE WILL MANAGE THE CONSORTIUM, COORDINATE CROSS-PROJECT ACTIVITIES, AND CREATE THE STRUCTURE AND ENVIRONMENT NEEDED TO ACCOMPLISH PLUTO'S GOALS. THE ANTIBODY CORE WILL DEVELOP LARGE PANELS OF RECOMBINANT MONOCLONAL ANTIBODIES (MABS) AGAINST CORONAVIRUS SPIKE PROTEINS TO DEFINE SPECIFICITY AND BREATH OF IMMUNE RESPONSES ELICITED BY CORONAVIRUS INFECTIONS AND/OR VACCINATIONS IN HUMANS AND ANIMAL MODELS. THE ANIMAL MODEL CORE WILL PROVIDE A CENTRAL RESOURCE WITH APPROVALS, FACILITIES, AND EXPERTISE TO ASSESS EFFICACY OF BROADLY CROSS-REACTIVE CORONAVIRUS ANTIBODIES AND VACCINES IN ROBUST PRE-CLINICAL MODELS AGAINST A SPECTRUM OF CORONAVIRUSES, INCLUDING SELECT AGENTS. A MULTIDISCIPLINARY TEAM OF SCIENTISTS FROM FIVE INSTITUTIONS WHO HAVE AN OUTSTANDING TRACK RECORD OF WORKING COLLABORATIVELY WILL CONDUCT THE PROPOSED STUDIES. THE RESEARCH PROJECTS WILL COLLABORATE WITH EACH OTHER AND WITH THE ANTIBODY AND ANIMAL MODEL CORES, COORDINATED BY THE ADMINISTRATIVE CORE. THE INTEGRATED AND SYNERGISTIC ACTIVITIES ACROSS PROJECTS AND CORES WILL DRIVE THE SUCCESSFUL COMPLETION OF THE PROGRAM PROJECT'S AMBITIOUS RESEARCH AGENDA, ENABLING ACHIEVEMENT OF THE LONG-TERM PLUTO GOAL OF DEVELOPING VARIANT-PROOF PAN- SARBECOVIRUS AND PAN-BETACORONAVIRUS VACCINES. THESE FINDINGS WILL CONTRIBUTE TO CURBING THE CURRENT SARS- COV-2 PANDEMIC AND MITIGATE THE RISK OF FUTURE PANDEMICS WITH CORONAVIRUSES.

IMPROVING ANNENBERG 23 IN SUPPORT OF TRANSLATIONAL RESEARCH

P53 - REGULATORS AND EFFECTORS

UNDERSTANDING THE PROTECTIVE AND NEUROINFLAMMATORY ROLE OF HUMAN BRAIN IMMUNE CELLS IN ALZHEIMER DISEASE

IMMUNOLOGIC BASIS OF COW'S MILK-INDUCED HYPERSENSITIVITIES

VULNERABILITY OF SARS- COV-2 INFECTION IN LUNG CANCER BASED ON SEROLOGICAL ANTIBODY ANALYSES

MECHANISMS OF BROADLY NEUTRALIZING HUMORAL IMMUNITY AGAINST INFLUENZA VIRUSES

A NEW DISEASE PLATFORM LEVERAGING COMPLEX DROSOPHILA AND MAMMALIAN MODELS

NEUROTROPHIC FACTORS AND DRUGS OF ABUSE

UNCOVERING THE GENETIC MECHANISMS OF THE CHROMOSOME 17Q21.31 TAU HAPLOTYPE ON NEURODEGENERATION RISK IN FTD AND PSP - PROJECT SUMMARY (OVERALL) UNDERSTANDING THE PATHOPHYSIOLOGY OF DEMENTIA IS OFTEN CONFOUNDED BY THE UNCERTAIN CAUSAL ROLES OF OBSERVED PATHOLOGICAL PHENOTYPES, EVEN WHEN HIGHLY CORRELATED WITH DISEASE. GENETIC FINDINGS OVERCOME THESE LIMITATIONS BY PROVIDING A CAUSAL ANCHOR FROM WHICH TO BEGIN MECHANISTIC STUDIES. IN THIS REGARD, THE GENETIC ASSOCIATION BETWEEN CHROMOSOME 17Q21.31 AND INCREASED RISK FOR TAUOPATHIES, INCLUDING FRONTOTEMPORAL DEMENTIA (FTD) AND PROGRESSIVE SUPRANUCLEAR PALSY (PSP), IS WELL-ESTABLISHED AND STRIKING. DESPITE THIS WELL-REPLICATED ASSOCIATION, LITTLE IS KNOWN REGARDING MECHANISMS DRIVING THE DIFFERENCES IN RISK BETWEEN THE TWO MAJOR HAPLOTYPES, H1 AND H2. THIS IS IN LARGE PART BECAUSE THIS COMPLEX LOCUS ENCOMPASSES A GENOMIC INVERSION OF 970 KB, LEADING TO AN APPROXIMATELY 1.5MB REGION WHERE STRONG LD HAS CONFOUNDED THE IDENTIFICATION OF CAUSAL VARIANTS AND UNDERSTANDING OF THE GENE REGULATORY MECHANISMS CONTRIBUTING TO DISEASE. HERE, WE CAPITALIZE ON RECENT ADVANCES IN GENOMICS TO COMPREHENSIVELY CHARACTERIZE THE GENETIC MECHANISMS BY WHICH THIS REGION, AND THE MULTIPLE LOCI WITHIN IT, IMPART DISEASE RISK, THUS IDENTIFYING NEW TARGETS FOR FUTURE THERAPEUTIC DEVELOPMENT. OUR CENTRAL HYPOTHESIS IS THAT HAPLOTYPE AND CELL TYPE SPECIFIC DIFFERENCES IN GENE EXPRESSION AND REGULATION, RESULTING FROM THE H1/H2 GENOMIC INVERSION LEAD TO DIFFERENCES IN RISK FOR SPORADIC TAUOPATHIES AND DIFFERENCES IN THE EFFECTS OF MAPT MUTATIONS ASSOCIATED WITH INHERITED FORMS OF FTD. TO TEST THIS HYPOTHESIS, WE PROPOSE A MULTI-SITE, INTERDISCIPLINARY CENTER COMPOSED OF TWO HIGHLY SYNERGISTIC PROJECTS (P1, P2) AND 4 CORES (PROTEOMICS, HUMAN TISSUE VALIDATION, DATA, ADMIN) INTEGRATING A HIGHLY COMPLEMENTARY GROUP OF INVESTIGATORS WITH A STRONG HISTORY OF COLLABORATION AND DATA SHARING TO CONNECT MULTIPLE LEVELS OF FUNCTION: A) GENOTYPE TO B) CHROMATIN STRUCTURE TO C) RNA EXPRESSION AND D) SPLICING, TO PROTEIN AND E) CELL BIOLOGICAL CONSEQUENCES TO ELUCIDATE DISEASE MECHANISMS. P1 WILL APPLY CUTTING EDGE MULTI-OMICS APPROACHES IN HUMAN INDUCED PLURIPOTENT STEM CELL (IPSC)-DERIVED NEURAL CELLS AND HUMAN BRAIN TISSUE TO DETERMINE THE MOLECULAR AND CELLULAR MECHANISMS ASSOCIATED WITH THE H1 AND H2 HAPLOTYPES IN INDIVIDUALS OF EUROPEAN AND AFRICAN DESCENT. PREDICTED REGULATORY ELEMENT VARIATION BETWEEN HAPLOTYPES WILL BE VALIDATED USING A POOLED CRISPR SCREEN IN ASSEMBLOIDS. P2 USES PARALLEL APPROACHES TO DISSECT THE GENETIC MECHANISMS, CELL TYPES AND MOLECULAR PATHWAYS INVOLVED IN DOMINANT FORMS OF FTD-TAU, AND THEIR MODULATION BY THE H1 AND H2 HAPLOTYPES. PROJECT 2 WILL USE SIMILAR APPROACHES TO TEST WHETHER H1/H2-ASSOCIATED DIFFERENCES IN GENE EXPRESSION AND REGULATION MODULATE THE IMPACT OF FTD-ASSOCIATED MAPT MUTATIONS ON DISEASE-ASSOCIATED PHENOTYPES AND VALIDATE THE IMPACT OF KEY HAPLOTYPE SPECIFIC ENHANCER/REPRESSOR REGIONS USING POOLED CRISPR I/A SCREENS. DATA AND RESULTS GENERATED FROM THESE PROJECTS WILL BE INTEGRATED WITH EXISTING PUBLICLY AVAILABLE DATA AND DISTRIBUTED BROADLY TO THE RESEARCH COMMUNITY. UNDERSTANDING THE MECHANISMS THAT LEAD FROM ABNORMAL GENE EXPRESSION AND PROTEIN MODIFICATION, TO TAU AGGREGATION AND NEURODEGENERATION WILL ENABLE US TO IDENTIFY NOVEL TARGETS FOR DRUG DISCOVERY.

NEUROLOGIC FUNCTION IN CHILDREN EXPOSED TO AMBIENT MANGANESE

TRAINING PROGRAM IN CANCER BIOLOGY

CONSORTIUM FOR TRANSLATIONAL RESEARCH IN MARFAN SYNDROME

PERIPHERAL IL-6 FROM LEUKOCYTES CONTROLS SUSCEPTIBILITY TO SOCIAL DEFEAT STRESS

NEURONAL AUTOPHAGY: A CELL-AUTONOMOUS PROTECTION MECHANISM

IBD GENETICS CONSORTIUM DATA COORDINATING CENTER

TRAINING PROGRAM: MECHANISMS OF VIRUS-HOST INTERACTIONS

IMMUNE BASIS & CLINICAL IMPLICATIONS OF THRESHOLD-BASED PHENOTYPES OF PEANUT ALLERGY

THE ADAPTIVE-INNATE IMMUNE INTERACTOME ACROSS MULTIPLE TISSUES IN ALZHEIMER'S DISEASE - PROJECT SUMMARY RECENT PROGRESS HAS BEEN MADE ON UNDERSTANDING THE ROLE OF THE INNATE IMMUNE SYSTEM IN THE PATHOGENESIS OF ALZHEIMER’S DISEASE (AD); HOWEVER, THE ROLE OF ADAPTIVE IMMUNITY IN THE PERIPHERY AND THE CENTRAL NERVOUS SYSTEM IN AD REMAINS LARGELY UNEXPLORED. THEREFORE, A CRITICAL NEXT STEP IS TO UNDERSTAND THE INTERACTION BETWEEN INNATE AND ADAPTIVE IMMUNITY, AND ITS IMPACT ON BRAIN AGING AND NEURODEGENERATION. PREVIOUS WORK HAS SHOWN THAT CLONALLY EXPANDED CD8+ T CELLS ARE PRESENT IN THE PERIPHERAL BLOOD AND THE CEREBROSPINAL FLUID OF PATIENTS WITH AD. IN OUR ONGOING WORK, UTILIZING SINGLE CELL PROFILING OF HUMAN BRAIN IMMUNE CELLS, WE EXPANDED THIS OBSERVATION AND IDENTIFIED CELL TYPE CHANGES OF THE ADAPTIVE AND INNATE IMMUNE SYSTEM IN THE BRAIN PARENCHYMA OF AD DERIVED SAMPLES. IN ADDITION, PUBLISHED AND ONGOING WORK FROM OUR GROUP PROVIDES EVIDENCE IN HUMANS AND MICE THAT ASTROCYTE AND ADAPTIVE IMMUNE CELL-SOURCED INTERLEUKIN-3 (IL-3) PROGRAMS MICROGLIA TO AMELIORATE THE PATHOLOGY OF AD. FURTHER ANALYSIS OF THE INTERACTION BETWEEN INNATE AND ADAPTIVE IMMUNITY IN HUMANS AND MICE IS NEEDED TO MECHANISTICALLY UNDERSTAND ITS ROLE IN AD AT DIFFERENT STAGES OF THE DISEASE. STUDYING THE INTERACTION BETWEEN INNATE AND ADAPTIVE IMMUNITY IN AD IN HUMANS IS CHALLENGING DUE TO LIMITED AVAILABILITY OF FRESH TISSUE SPECIMENS. OVER THE LAST 5 YEARS, OUR TEAM HAS ESTABLISHED A PIPELINE TO ISOLATE IMMUNE CELLS FROM FRESH BRAIN TISSUE TO GENERATE MULTISCALE SINGLE CELL DATA. BUILDING ON OUR EXPERTISE AND EXISTING RESOURCES, HERE WE PROPOSE TO PERFORM MULTI-TISSUE SINGLE CELL MULTIOMICS AND SPATIAL TRANSCRIPTOMICS OF IMMUNE CELLS FROM AD CASES AND HEALTHY CONTROLS. TO GAIN ADDITIONAL MECHANISTIC INSIGHTS INTO THE INTERACTIONS BETWEEN ADAPTIVE AND INNATE IMMUNITY, WE WILL PERFORM PARALLEL STUDIES IN AD MOUSE MODELS. IN AIM 1, WE WILL EXAMINE THE DIVERSITY, ABUNDANCE AND SPATIAL LOCATION OF ADAPTIVE AND INNATE IMMUNE CELLS ACROSS THE BRAIN-BARRIER-BLOOD AXIS (BRAIN, MENINGES, CHOROID PLEXUS, AND PERIPHERAL BLOOD) TO IDENTIFY DIFFERENCES IN THE COMPOSITION, PHENOTYPE, AND ANTIGEN SPECIFICITY OF ADAPTIVE IMMUNITY (T AND B CELLS) IN AD THAT ARE SHARED OR DISTINCT ACROSS TISSUES. IN AIM 2, WE WILL EXPLORE THE INTERACTOME OF ADAPTIVE AND INNATE IMMUNE SYSTEMS IN THE BRAIN-BARRIER-BLOOD AXIS TO IDENTIFY DIFFERENTIAL CELL-TO-CELL INTERACTION NETWORKS IN AD, POINTING TO GAIN OR LOSS OF LIGAND-RECEPTOR RELATIONSHIPS AMONG IMMUNE CELL SUBPOPULATIONS. IN AIM 3, WE WILL MECHANISTICALLY DELINEATE INTERCELLULAR CROSSTALK BETWEEN ADAPTIVE IMMUNE CELLS AND CENTRAL INNATE IMMUNE CELLS IN MURINE MODELS OF AD. COLLECTIVELY, THESE STUDIES WILL ENABLE US, AT UNPRECEDENTED RESOLUTION, TO EXPLORE THE ADAPTIVE AND INNATE IMMUNE RESPONSE IN AD CASES AND PROVIDE A PUTATIVE MECHANISTIC EXPLANATION FOR OUR OBSERVATIONS BY UTILIZING MOUSE MODELS. IMPORTANTLY, OUR WORK WILL PROVIDE THE SCIENTIFIC COMMUNITY WITH AN URGENTLY NEEDED RESOURCE FOR ADAPTIVE AND INNATE IMMUNITY IN THE CENTRAL NERVOUS SYSTEM THAT CAN BE UTILIZED IN FUTURE STUDIES.

GENYC: GENOMIC IMPLEMENTATION RESEARCH IN THE DIVERSE SETTINGS AND POPULATIONS OF NEW YORK CITY

THE MANHATTAN HIV BRAIN BANK

GNRH RECEPTOR SIGNALING SPECIFICITY

FUNCTION OF A PUTATIVE DETERMINANT IN HEMATOPOIESIS

MODELING EARLY IMMUNITY TO HUMAN INFLUENZA INFECTION

YALE UNIVERSITY IBD GENETICS RESEARCH CENTER

BUNDLED PAYMENT FOR MOBILE ACUTE CARE TEAM SERVICES

TRANSLATIONAL STUDIES IN HEART FAILURE GENE THERAPY

WHITE MATTER ABNORMALITIES IN SCHIZOPHRENIA

NEW START

PET/MRI IMAGING OF MITRAL VALVE PROLAPSE - PROJECT SUMMARY MITRAL VALVE PROLAPSE (MVP), IDENTIFIED IN 1-3% OF THE GENERAL POPULATION, IS THE MOST COMMON CARDIAC VALVULAR ABNORMALITY, WITH COMPLICATIONS THAT INCLUDE HEART FAILURE, VENTRICULAR ARRHYTHMIAS AND SUDDEN CARDIAC DEATH (SCD). IT HAS BEEN ESTIMATED THAT THE INCIDENCE OF MVP-RELATED SCD IS 0.14% TO 1.5% PER YEAR, DEPENDING ON THE CLINICAL CHARACTERISTICS OF THE POPULATION STUDIED. WHILE THERE HAVE BEEN MULTIPLE FEATURES IDENTIFIED AS MARKERS OF INCREASED RISK, LEFT VENTRICULAR REPLACEMENT FIBROSIS APPEARS TO BE A CONSISTENT FINDING IN ARRHYTHMIC MVP. LATE GADOLINIUM ENHANCEMENT (LGE) BY CARDIAC MAGNETIC RESONANCE IMAGING (MRI) IS CONSIDERED THE MOST SENSITIVE AND SPECIFIC MODALITY FOR ASSESSING THE PRESENCE AND DISTRIBUTION OF REPLACEMENT FIBROSIS AND IT HAS BEEN STRONGLY ASSOCIATED WITH INCREASED INCIDENCE OF ARRHYTHMIC EVENTS IN PATIENTS WITH MVP. PRELIMINARY INVESTIGATIONS FROM OUR GROUP SUGGEST THAT THESE FIBROTIC CHANGES MAY BE PRECEDED BY A CHRONIC INFLAMMATORY PHASE AND THAT INFLAMMATION AND SCARRING MAY BE PART OF A CONTINUUM OF VENTRICULAR TRANSFORMATION AND DIRECTLY ASSOCIATED WITH ARRHYTHMIA DEVELOPMENT AND COMPLEXITY. WE NOW PROPOSE AN IN-DEPTH CHARACTERIZATION OF THE RELATIONSHIP BETWEEN INTENSITY AND PATTERN OF 18F-FLUORODEOXYGLUCOSE (FDG) UPTAKE ON HYBRID POSITRON EMISSION TOMOGRAPHY (PET)/MRI, ARRHYTHMIA BURDEN, SEVERITY OF MVP AND MITRAL REGURGITATION (MR). DETAILED DATA INCLUDING PATIENTS’ BASELINE CHARACTERISTICS, ECHOCARDIOGRAPHIC FEATURES, HISTOLOGICAL AND BIOMARKER DATA, ARRHYTHMIC BURDEN AND CHARACTERIZATION WILL BE OBTAINED IN PATIENTS WITH MVP, MILD, MODERATE AND SEVERE MR, IN ORDER TO ESTABLISH THE CORRELATION BETWEEN THE DISEASE PROCESS IN ITS VARIOUS STAGES AND THE PET/MRI PHENOTYPE. SPECIFICALLY, IN AIM 1 WE WILL ESTABLISH THE INFLAMMATORY ORIGIN OF THE 18F-FDG SIGNATURE IN A COHORT OF PATIENTS WITH MVP, SEVERE MR AND CLASS I/II INDICATIONS FOR MITRAL VALVE SURGERY. HISTOLOGY AND SERUM FOR BIOMARKER ANALYSIS WILL BE COLLECTED AT THE TIME OF SURGERY. PATIENTS WILL ADDITIONALLY UNDERGO A SECOND IMAGING SESSION WITH A NOVEL PET TRACER, 68GA-DOTATATE, MORE SPECIFIC FOR INFLAMMATION. IN AIM 2, PATIENTS WITH MVP, MILD OR MODERATE MR, AND A HISTORY OF VENTRICULAR ECTOPY, WHO DO NOT HAVE AN INDICATION FOR SURGERY, WILL BE ENROLLED INTO A LONGITUDINAL OBSERVATIONAL CLINICAL STUDY. WE WILL PERFORM 18F-FDG PET/MRI IMAGING, ECHOCARDIOGRAPHY, 7-DAY EVENT MONITORING (PVC BURDEN AND COMPLEXITY) AS WELL AS COLLECT CIRCULATING BIOMARKERS AT BASELINE AND AT FOLLOW- UP AFTER 24 MONTHS. LASTLY, IN AIM 3, WE WILL ASSESS THE IMPACT OF MV SURGERY ON MYOCARDIAL INFLAMMATION AND FUNCTION, BY REPEATING THE SAME ASSESSMENT AS IN AIM 2 BUT 12 MONTHS POST-SURGERY TO EXPLORE ASSOCIATIONS BETWEEN MV SURGERY AND CHANGES IN MYOCARDIAL INFLAMMATION. WITH THIS COMPREHENSIVE APPROACH, OUR ULTIMATE GOAL IS THE CREATION OF A NOVEL PLATFORM FOR THE ASSESSMENT OF MVP, PARTICULARLY AS IT RELATES TO RISK STRATIFICATION OF VENTRICULAR ARRHYTHMIAS AND SCD. WE POSIT THAT THE RESULTS OF OUR STUDIES MAY LEAD TO MORE ACCURATE IMAGING- GUIDED PATIENT MANAGEMENT AND HAVE THE POTENTIAL TO SIGNIFICANTLY INFLUENCE CURRENT GUIDELINE RECOMMENDATIONS FOR RISK STRATIFICATION ASSESSMENT, MEDICAL THERAPY, AND TIMING FOR SURGICAL INTERVENTION.

FRONTIERS IN CONGENITAL DISORDERS OF GLYCOSYLATION

PHENOTYPES REIMAGINED TO DEFINE CLINICAL TREATMENT AND OUTCOME RESEARCH (PREDICTOR) - PROJECT SUMMARY PSYCHIATRY FACES A SIGNIFICANT CHALLENGE IN THE ABSENCE OF OBJECTIVE MEASURES TO ASSESS BEHAVIOR. CLINICIANS FORM CLINICAL OPINIONS BASED LARGELY ON THEIR IMPRESSIONS FROM INTERVIEWING AND WHAT THEY READ IN THE ELECTRONIC HEALTH RECORD. AS A RESULT, WE ARE CURRENTLY UNABLE TO PROVIDE RELIABLE PROGNOSES ON AN INDIVIDUAL BASIS. ONE UNTAPPED SOURCE OF BEHAVIORAL INFORMATION FOR CLINICAL DECISION-MAKING IS THE CLINICAL INTERVIEW ITSELF, WHICH FORMS THE FOUNDATION OF THE ELECTRONIC HEALTH RECORD (EHR). EVERY CLINICAL VISIT PROVIDES A WEALTH OF BEHAVIORAL INFORMATION COMPRISING SPOKEN LANGUAGE, EYE CONTACT, AND FACIAL EXPRESSIONS FROM BOTH THE PATIENT AND THE CLINICIAN. ANOTHER SOURCE OF BEHAVIORAL DATA, WHICH IS ECOLOGICALLY VALID, COMES FROM SMARTPHONES, WHICH PROVIDE PHYSICAL ACTIVITY METRICS (E.G., STEP COUNT, DISTANCE TRAVELED), GEOLOCATION, SOCIAL INTERACTIONS (E.G., SMS MESSAGES AND PHONE CALLS MADE AND RECEIVED), SLEEP PATTERNS AND AUDIO DATA FROM DIARIES. BY ANALYZING THESE RICH BEHAVIORAL DATASETS FROM ROUTINE CLINICAL VISITS AND SMARTPHONES, WE CAN DEVELOP CLINICAL SIGNATURES FOR PARTICULARLY CLINICALLY RELEVANT OUTCOMES IN YOUNG HELP-SEEKING PEOPLE, NAMELY TREATMENT DISENGAGEMENT, ER VISITS AND HOSPITALIZATIONS. THESE INDIVIDUALIZED CLINICAL SIGNATURES ARE IMPORTANT FOR THE REAL-LIFE SITUATION THAT CONFRONTS BOTH CLINICIAN AND PATIENT AT THE FIRST VISIT TO A MENTAL HEALTH CLINIC. THIS PROPOSAL INCLUDES ALL NEW PATIENTS (N = 2100), AGES 15 TO 30, WHO SEEK TREATMENT FOR THE FIRST TIME AT ONE OF SIX OUTPATIENT MENTAL HEALTH CLINICS IN THE MOUNT SINAI HEALTH SYSTEM. AIM 1 IS TO CREATE A BASELINE CLINICAL SIGNATURE FOR OUTCOMES USING DEEP NEURAL NETWORK MODELING OF LEGACY EHR DATA AND BASELINE BEHAVIOR, WHICH INCLUDES AUDIOVISUAL RECORDINGS OF INTAKE INTERVIEWS, RATINGS OF WORKING ALLIANCE, AND BRIEF SURVEYS AND TESTS OF COGNITION. AIM 2 IS TO USE CONTEXTUAL BANDIT TO CREATE A LONGITUDINAL CLINICAL SIGNATURE FOR OUTCOMES BASED ON SUBSEQUENT BEHAVIORAL DATA FROM CLINICAL INTERVIEWS (AND THEIR ACCOMPANYING NOTES), AND SMARTPHONE PASSIVE DATA AND AUDIO DIARY DATA. CONTEXTUAL BANDIT IS A MODEL THAT KEEPS UPDATING PROBABILITIES AND ODDS OVER TIME AS IT IS GIVEN NEW DATA. AIM 3 IS TO CREATE CLINICAL SIGNATURES BASED ON EHR DATA ALONE, SUCH THAT THE ADDED VALUE OF BEHAVIORAL DATA FOR AIMS 1 AND 2 CAN BE QUANTIFIED. STUDY ASSESSMENTS ARE STANDARD, LOW-COST, AND EASY TO ADMINISTER, WITH GOOD VARIANCE, VALIDITY, RELIABILITY, AND ATTENTION TO BIAS. ACROSS ALL AIMS, FUSION WILL BE USED FOR BEHAVIORAL FEATURE EXTRACTION AND NATURAL LANGUAGE PROCESSING (NLP) FOR ANALYSIS OF BOTH WRITTEN LANGUAGE (CLINICAL TEXT) AND SPOKEN LANGUAGE (CLINICAL VISITS AND AUDIO DIARIES). DATA SCIENCE METHODS HAVE BEEN OPTIMIZED FOR PARTNERSHIP WITH THE DCC. HEALTH EQUITY, COMMUNITY ENGAGEMENT AND ETHICAL ISSUES RE PRIVACY, INFORMED CONSENT AND FAIRNESS HAVE BEEN PRIORITIZED.

MOUNT SINAI HHEAR NETWORK UNTARGETED LAB HUB

NEURAL SUBSTRATES OF APPETITIVE BEHAVIOR IN MOOD AND MOTIVATION

LEVERAGING NATIONWIDE RESEARCH INFRASTRUCTURE TO ENRICH BRAIN HEALTH AFTER TBI: THE ENRICH BRAIN HEALTH STUDY

METHODOLOGY ISSUES IN A TAILORED LIGHT TREATMENT FOR PERSONS WITH DEMENTIA

TRANSCRIPTION FACTORS IN EARLY KIDNEY DEVELOPMENT

(LIVEWELL) LIVING WITH VIOLENCE-RELATED BRAIN INJURY: OPTIMIZING COGNITIVE AND PSYCHOLOGICAL WELLNESS THROUGH THE LIVEWELL BRAIN HEALTH STUDY

PHARMACOLOGICAL ACTIONS OF STRESS AND ANTIDEPRESSANTS

ELECTROPHYSIOLOGICAL BIOMARKERS TO OPTIMIZE DBS FOR DEPRESSION

CENTER FOR ACHIEVING AND SUSTAINING IMPROVED HEALTH IN HARLEM

CIS-REGULATORY EPIGENOME MAPPINGS IN SCHIZOPHRENIA

CANNABIDIOL IN THE TREATMENT OF OPIOID USE DISORDER

MOUNT SINAI COLLABORATION FOR ADVANCING PEDIATRIC QUALITY MEASURES

"REAL ANSWERS" (REGISTRY EXPANSION ANALYSES TO LEARN) - SICKLE CELL DISEASE (SCD) IS AN INHERITED DISORDER OF HUMAN ADULT HEMOGLOBIN, WHICH PRIMARILY AFFLICTS AMERICANS OF AFRICAN DESCENT. THE MUTANT HEMOGLOBIN, HB S, POLYMERIZES UPON DEOXYGENATION, LEADING TO IMPAIRED RED BLOOD CELL RHEOLOGY, MICROVASCULAR OCCLUSION, CHRONIC INFLAMMATORY STATE, AND CHRONIC HEMOLYTIC ANEMIA, CULMINATING IN CHRONIC ORGAN DAMAGE AND A SHORTENED LIFE EXPECTANCY. SCD IS AN ORPHAN DISEASE, WITH AN ESTIMATED ~110,000 PATIENTS IN THE U.S. WHO SUFFER FROM DISPARITIES AND DISCRIMINATION AND INCREASED HEALTH CARE UTILIZATION. UNTIL RECENTLY, THE MANAGEMENT OF THE DISEASE HAS BEEN LARGELY CONFINED TO SYMPTOM CONTROL, WITH PAIN MANAGEMENT AND TRANSFUSIONS. IN 1998, THE U.S. FDA APPROVED HYDROXYUREA (HU) AS THE FIRST DISEASE MODIFYING THERAPY FOR SCD. SUBSEQUENT STUDIES IN CHILDREN AND ADULTS WITH SCD HAS CONFIRMED THE BENEFICIAL EFFECTS OF HU, WITH PREVENTION OF ORGAN DAMAGE AND DECREASE IN MORTALITY. IN THE PAST FIVE YEARS, THREE ADDITIONAL DISEASE MODIFYING DRUGS (L-GLUTAMINE, VOXELOTOR, AND CRIZANLIZUMAB) TARGETING DIFFERENT MECHANISMS IN DISEASE PATHOPHYSIOLOGY HAVE BEEN APPROVED BY THE FDA, BROADENING THE AVAILABLE THERAPEUTIC ARMAMENTARIUM FOR SCD. ALTHOUGH THIS IS A WELCOMED DEVELOPMENT, KNOWLEDGE GAPS EXIST ON THE CHOICE OF THE MOST EFFECTIVE DISEASE MODIFYING THERAPY OR COMBINATIONS, BASED ON A SPECTRUM OF SUB- PHENOTYPES OF THE DISEASE. THIS GAP IS UNLIKELY TO BE FILLED BY KNOWLEDGE GAINED FROM RANDOMIZED CLINICAL TRIALS INVOLVING THE USE OF FDA APPROVED THERAPIES. THIS APPLICATION SEEKS TO MEET THIS UNMET NEED BY TAKING ADVANTAGE OF THE INFRASTRUCTURE (PROSPECTIVE REGISTRY OF 2400 SCD PATIENTS) PROVIDED BY THE NHLBI FUNDED SICKLE CELL DISEASE IMPLEMENTATION CONSORTIUM (2016-2022) CONSISTING OF EIGHT CENTERS THROUGHOUT U.S. WE PROPOSE TO APPROACH THIS PROBLEM BY ENROLLING 1200 PATIENTS (150 PATIENTS FROM EACH CENTER) BY APPLYING THE FOLLOWING SPECIFIC AIMS: 1) COMPARE THE EFFECT OF NOVEL DISEASE MODIFYING THERAPIES (L-GLUTAMINE, VOXELOTOR, AND CRIZANLIZUMAB) ON CLINICAL OUTCOMES IN INDIVIDUALS WITH SCD. WE WILL FOLLOW THESE INDIVIDUALS PROSPECTIVELY FOR 5 YEARS, EMULATING DATA COLLECTION PROTOCOLS AND ELIGIBILITY FROM KEY, INTERVENTIONAL PHASE III SCD TRIALS, AND MONITOR ORGAN INJURY NT-PROBNP FOR HEART AND LUNG INJURY, URINE ALBUMIN/CREATININE RATIO FOR KIDNEY FUNCTION, HEMOLYSIS SCORE FOR BLOOD, AS WELL AS SYMPTOM BURDEN (ASCQ-ME) 2) IDENTIFY GENETIC AND GENOMIC PREDICTORS OF RESPONSE TO DISEASE MODIFYING THERAPIES, BY A) WHOLE EXOME SEQUENCING AND B) RNA SEQ (MONONUCLEAR CELLS, RETICS, PLATELETS); AND 3) INTEGRATE STUDY DATA INTO THE CURESCI METADATA CATALOG TO ENHANCE FUTURE CROSS STUDY ANALYSES.

GLOMERULAR CELL-CELL CROSSTALK AND INJURY

RESEARCH TRAINING PROGRAM IN ENVIRONMENTAL PEDIATRICS

SOMATIC MOSAICISM IN SCHIZOPHRENIA AND CONTROL BRAINS

4/4-PSYCHIATRIC GWAS CONSORTIUM:GENOMIC FOLLOW-UP NEXT-GEN SEQUENCING & GENOTYPI

THE BRAINCELLQTL CONSORTIUM: QTL MAPPING IN THE HUMAN BRAIN AT THE SINGLE CELL LEVEL - ALZHEIMER'S DISEASE AND RELATED DEMENTIAS (AD/ADRD) PROGRESSIVELY IMPAIR ESSENTIAL COGNITIVE AND MENTAL FUNCTIONS, RESULTING IN SIGNIFICANT EMOTIONAL, PHYSICAL, AND FINANCIAL BURDENS. GENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED THOUSANDS OF LOCI CONTRIBUTING TO THE RISK OF MORE THAN A HUNDRED SERIOUS MENTAL AND NEUROLOGICAL DISORDERS (SMND), INCLUDING AD/ADRD AND OTHERS SUCH AS SCHIZOPHRENIA, PARKINSON’S DISEASE AND MULTIPLE SCLEROSIS. INTEGRATING RISK LOCI WITH QUANTITATIVE TRAIT LOCI (QTLS) FOR MOLECULAR TRAITS, SUCH AS GENE EXPRESSION AND EPIGENOME REGULATION, IN HUMAN BRAIN TISSUE, HAS BEEN WIDELY ADOPTED AS AN ANALYTICAL STRATEGY TO NOMINATE CAUSAL MECHANISMS FOR AD/ADRD AND SMNDS. SO FAR, LARGE-SCALE INTEGRATIVE ANALYSES USING THIS APPROACH HAVE UTILIZED HOMOGENATE BRAIN TISSUE, WHICH IS COMPOSED OF MULTIPLE CELL TYPES, AND THEREFORE CELL-TYPE-SPECIFIC QTLS ARE NOT FULLY CAPTURED. THIS IS AN IMPORTANT LIMITATION GIVEN THAT RISK VARIANTS FOR AD/ADRD AND SMNDS ACT THROUGH CELL-TYPE-SPECIFIC BIOLOGICAL MECHANISMS. INITIAL EFFORTS HAVE INCLUDED CELL-TYPE-SPECIFIC QTL ANALYSIS IN THE HUMAN BRAIN BY UTILIZING SINGLE-CELL DATA, BUT THE SAMPLE SIZE OF SUCH STUDIES IS HINDERED BY THE INCREASED EXPERIMENTAL COSTS. TO OVERCOME THESE LIMITATIONS, WE PROPOSE TO ESTABLISH THE BRAIN SINGLE-CELL XQTL (BRAINCELLQTL) CONSORTIUM THAT BRINGS TOGETHER EXISTING RESOURCES OF MORE THAN 10,000 SINGLE-CELL LIBRARIES FROM MORE THAN 3,000 UNIQUE BRAIN DONORS, AS WELL AS EXPERTISE IN SINGLE-CELL BIOLOGY, NEUROSCIENCE, STATISTICAL GENETICS AND MACHINE LEARNING, TO FACILITATE THE HARMONIZATION OF BRAIN SINGLE-CELL DATA, QTL GENERATION AND DATA SHARING WITH THE SCIENTIFIC COMMUNITY. ACTIVITIES WILL BE ORGANIZED AROUND THE SYNAPSE DATA PLATFORM BY SAGE BIONETWORKS, AN NIH-DESIGNATED GENERALIST REPOSITORY THAT SUPPORTS DOZENS OF RESEARCH CONSORTIA, FOCUSED ON NEURODEGENERATION, NEUROPSYCHIATRIC DISEASE, CANCER, RARE DISEASE, AND OTHER RESEARCH AREAS. THE SYNAPSE DATA PLATFORM WILL BE UTILIZED TO RECEIVE DATA, VALIDATE IT AGAINST METADATA AND DATA STANDARDS, AND HARMONIZE THEM FOR DOWNSTREAM ANALYSIS. TO INCREASE THE REPRODUCIBILITY AND TRANSPARENCY OF BRAINCELLQTL CONSORTIUM RESEARCH, WE WILL USE CAVATICA BY SEVEN BRIDGES FOR DATA PROCESSING AND ANALYSIS. CAVATICA IS A SECURE, SCALABLE, AND EXTENDABLE DATA COMMONS PLATFORM THAT EMPOWERS COLLABORATION AND SCIENTIFIC ANALYSIS. UPON SUCCESSFUL COMPLETION OF THE PROPOSED RESEARCH, WE EXPECT TO CONSTRUCT A CELL TYPE-SPECIFIC QTL ATLAS FOR THE HUMAN BRAIN, WHICH WE WILL USE TO DERIVE GENETICALLY DRIVEN GENE DYSREGULATION IN AD/ADRD AND SMNDS, THUS, ENABLING US TO: (1) INCREASE OUR MECHANISTIC UNDERSTANDING OF DYSFUNCTION IN AD/ADRD AND SMNDS; (2) BETTER PRIORITIZE SIGNIFICANT GENES AND MOLECULAR PATHWAYS FOR FUTURE MECHANISTIC STUDIES; (3) PROVIDE A VALUABLE RESOURCE THAT CAN BE APPLIED IN ONGOING AND FUTURE GENOME-WIDE ASSOCIATION STUDIES; (4) PROVIDE PREPROCESSED AND HARMONIZED SINGLE-NUCLEUS BRAIN OMICS DATA THAT CAN BE UTILIZED BY THE RESEARCH COMMUNITY TO ADDRESS OTHER BIOLOGICALLY-DRIVEN QUESTIONS; AND (5) ESTABLISH A MECHANISM FOR DATA SHARING AND HARMONIZATION ACROSS CONSORTIA AND PROJECTS, WHICH CAN BE UTILIZED IN FUTURE STUDIES TO PERFORM SINGLE-CELL MEGA-ANALYSES AND META-ANALYSES.

PULMONARY DISEASES IN WTC WORKERS: SYMPTOMS, FUNCTION, AND CHEST CT CORRELATES

PS 1 ACTIVATES THE P13K/AKT CELL SURVIVAL PATHWAY

DEVELOPMENT OF A5* NACHR POSITIVE ALLOSTERIC MODULATORS FOR TOBACCO DEPENDENCE

CHARACTERIZING A NEW HUMAN DENDRITIC CELL LINEAGE AND ITS ROLE IN LCH

CRANIOSYNOSTOSIS NETWORK

GENE-ENVIRONMENT INTERACTIONS IN GLAUCOMA

MOLECULAR PROFILING OF SCHIZOPHRENIA

MOUNT SINAI MEDICAL SCIENTIST TRAINING PROGRAM - THE MISSION OF THE MEDICAL SCIENTIST TRAINING PROGRAM AT THE ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI IS TO EDUCATE A DIVERSE CADRE OF FUTURE PHYSICIAN-SCIENTISTS IN A RIGOROUS, INTEGRATED DUAL DEGREE PROGRAM THAT PREPARES THEM TO CONTRIBUTE TO THE IMPROVEMENT OF HUMAN HEALTH THROUGH CAREERS IN A VARIETY OF CLINICAL SPECIALTIES AND BIOMEDICAL RESEARCH ENVIRONMENTS. THE PROGRAM FEATURES AN INCLUSIVE AND COLLABORATIVE ENVIRONMENT THAT FOSTERS INNOVATION IN FUNDAMENTAL AND TRANSLATIONAL BIOMEDICAL RESEARCH. OUR ACCOMPLISHED STUDENT BODY IS SELECTED FROM A HIGHLY QUALIFIED AND DIVERSE APPLICANT POOL OF STUDENTS FROM ALL BACKGROUNDS WHO COME WITH SIGNIFICANT PRIOR RESEARCH EXPERIENCE. TRAINEE RETENTION HAS BEEN HIGH AND ATTRITION LOW, WITH AVERAGE TIME TO DEGREE OF 8 YEARS. INTENTIONAL CHANGES IN OUR ADMISSIONS AND RECRUITMENT PRACTICES, INCLUDING A MORE HOLISTIC REVIEW AND INCREASED ACCEPTANCE TARGET NUMBERS FOR WOMEN AND STUDENTS IN OTHER UNDER-REPRESENTED GROUPS, HAVE ALREADY RESULTED IN THEIR INCREASED REPRESENTATION AMONG MATRICULANTS OF THE PAST FIVE YEARS AND IN THE LARGER MSTP. THE PROPOSED PROGRAM INCLUDES A SIGNIFICANTLY INCREASED LEVEL OF INSTITUTIONAL SUPPORT, REFLECTED IN INCREASED FACULTY EFFORT AND STAFFING TO DIRECT THE MSTP AND INCREASED FINANCIAL SUPPORT (WITH A SEPARATE PROGRAM BUDGET) FOR STUDENT TRAINING AND OTHER ACTIVITIES THAT PROMOTE ESPRIT DE CORPS AND THE DEVELOPMENT OF A PHYSICIAN-SCIENTIST IDENTITY; A WELL-INTEGRATED CURRICULUM THAT FOCUSES ON THE EXPERIMENTAL BASIS OF SCIENTIFIC KNOWLEDGE AND ON ITS TRANSLATIONAL APPLICATIONS; INCREASED USE OF TEAM BUILDING ACTIVITIES; INNOVATIVE GRADUATE SCHOOL CURRICULUM THAT INCORPORATES A STRONG EMPHASIS ON DEVELOPMENT OF QUANTITATIVE AND COMPUTATIONAL SKILLS, ENTREPRENEURSHIP, EMERGING TECHNOLOGIES SUCH AS ARTIFICIAL INTELLIGENCE, AND TRAINING IN RIGOROUS AND REPRODUCIBLE RESEARCH DESIGN THROUGHOUT THE PROGRAM; INCREASED ATTENTION TO THE TRANSITION FROM PRECLINICAL TO PHD TRAINING AND CONTINUED IMPROVEMENTS IN A LONGSTANDING COURSE THAT PROMOTES A SMOOTH TRANSITION TO CLINICAL TRAINING; STRENGTHENED PARTNERSHIPS WITH PIPELINE PROGRAMS TO ENHANCE THE DIVERSITY OF THE MSTP STUDENT POPULATION AND TO PROVIDE ALTERNATIVE PATHWAYS INTO THE PROGRAM FROM THE MEDICAL SCHOOL; MSTP STUDENT ELIGIBILITY FOR EARLY ASSURANCE RESEARCH TRACK RESIDENCY PROGRAMS AT MOUNT SINAI; AND IMPROVED MENTOR TRAINING AND MECHANISMS FOR MONITORING STUDENT PROGRESS AND SATISFACTION. OUR SHORT- AND INTERMEDIATE-TERM GOALS ARE TO PROVIDE AN INCLUSIVE AND DIVERSE TRAINING ENVIRONMENT THAT WILL ALLOW OUR STUDENTS TO CONTINUE TO ACHIEVE AT A HIGH LEVEL AND TO EQUAL IF NOT SURPASS THE ACHIEVEMENTS OF STUDENTS OF THE PAST 5 YEARS, AS MEASURED BY PUBLICATIONS, RECEIPT OF INDEPENDENT FELLOWSHIP SUPPORT, AND MATCHING IN TOP RESIDENCY PROGRAMS. WHILE A LARGE PERCENTAGE OF OUR ALUMNI (82%) PURSUE BASIC, TRANSLATIONAL, AND/OR CLINICAL RESEARCH IN ACADEMIC, PHARMACEUTICAL, BIOTECHNOLOGY, AND FEDERAL AGENCIES, OUR LONG-TERM GOAL IS FOR MORE OF OUR GRADUATES TO BECOME INDEPENDENT INVESTIGATORS AND LEADERS WHO ADDRESS IMPORTANT RESEARCH QUESTIONS RELATED TO HUMAN HEALTH AND DISEASE AND TRANSLATE THEIR DISCOVERIES INTO STRATEGIES FOR THE PREVENTION AND THERAPY OF DISEASE IN ALL COMMUNITIES AND IN AN EXPANDED ARRAY OF CAREER SECTORS.

PTEN AND CANCER

INFLUENCE OF DIETARY BOTANICAL SUPPLEMENTS ON BIOLOGICAL AND BEHAVIORAL RESILIENCE

PREDICTING MEDICAL CONSEQUENCES OF NOVEL FENTANYL ANALOG OVERDOSE USING THE TOXICOLOGY INVESTIGATORS CONSORTIUM (TOXIC)

HIGHER ORDER CHROMATIN AND GENETIC RISK FOR SCHIZOPHRENIA

THE ORAL ENVIRONMENT IN FOOD ALLERGY DEVELOPMENT (ONEIDA) - PROJECT SUMMARY FOOD ALLERGY, AN INCURABLE CONDITION AFFECTING ~10% OF THE US POPULATION, IS A DEPARTURE FROM IMMUNE HOMEOSTASIS WHERE ABERRANT ANTIBODY RESPONSE, MICROBIAL DYSBIOSIS, AND LOCAL AND SYSTEMIC SYMPTOMS ARE WELL-REPORTED. WITH EXPOSURE TO CULPRIT FOODS, INDIVIDUALS WITH FOOD ALLERGY EXPERIENCE SYMPTOMS INCLUDING ORAL SWELLING, HIVES, VOMITING, AND ANAPHYLAXIS. THE ORAL MUCOSA IS THE FIRST INTERFACE BETWEEN INGESTED FOOD ANTIGENS AND THE IMMUNE SYSTEM. OUR STUDIES HAVE REVEALED DIFFERENCES IN FOOD-SPECIFIC ANTIBODY LEVELS IN SALIVA BETWEEN FOOD ALLERGIC CHILDREN AND THOSE WHO ARE ONLY FOOD SENSITIZED. WE HAVE SHOWN THAT ALLERGEN- SPECIFIC ANTIBODY PROFILES IN SALIVA CAN PREDICT FOOD ALLERGY THRESHOLD, SEVERITY, AND ORGAN-SPECIFIC SYMPTOMS. WE HAVE ALSO FOUND THAT THE SALIVA MICROBIOME AND METABOLOME DIFFER IN CHILDREN WITH AND WITHOUT FOOD ALLERGY. BUILDING ON THIS WORK, WE AIM TO STUDY THE ORIGINS OF FOOD ALLERGY AND PROPOSE TO CHARACTERIZE THE EARLY-LIFE TRAJECTORY OF THE ORAL ENVIRONMENT AS FOOD ALLERGY ARISES. TO DATE, THERE HAS BEEN NO STUDY OF THE ORAL ENVIRONMENT AS CHILDREN ACQUIRE FOOD ALLERGY. OUR CENTRAL HYPOTHESIS IS THAT THE DEVELOPMENT OF FOOD ALLERGY IS ASSOCIATED WITH DISTINCT TRAJECTORIES DURING THE FIRST THREE YEARS OF LIFE IN ORAL MUCOSAL IMMUNOLOGY, ORAL MICROBIAL COMMUNITIES AND METABOLITES, AND THEIR CROSS-TALK WITH SYSTEMIC FACTORS. WE WILL LEVERAGE LONGITUDINAL SAMPLES AND EXISTING DATA FROM THE NIH/NIAID SYSTEMS BIOLOGY OF EARLY ATOPY (SUNBEAM) STUDY, A MULTI-CENTER BIRTH COHORT OF 2,500 CHILDREN FROM ACROSS THE US WHO HAVE UNDERGONE EXTENSIVE LONGITUDINAL PHENOTYPING, INCLUDING DOCTOR-SUPERVISED FOOD CHALLENGES FOR FOOD ALLERGY ASSESSMENT. WE HAVE BEEN LEADING AND WORKING ON SUNBEAM SINCE IT BEGAN. TO ADDRESS OUR FIRST HYPOTHESIS THAT THE INCEPTION OF FOOD ALLERGY IS ASSOCIATED WITH A DISTINCT ORAL MUCOSAL IMMUNOLOGIC TRAJECTORY, WE WILL CHARACTERIZE THE DEVELOPMENT OF ALLERGEN-SPECIFIC ANTIBODIES AND CYTOKINE MILIEU IN SALIVA DURING THE FIRST 3 YEARS OF LIFE AND IDENTIFY SALIVA ANTIBODY AND CYTOKINE PREDICTORS OF FOOD ALLERGY INCEPTION (AIM 1). TO ADDRESS OUR SECOND HYPOTHESIS THAT CHILDREN WHO ATTAIN FOOD ALLERGY HOST DIFFERENT ORAL MICROBIAL COMMUNITIES AND METABOLITES, WE WILL PROFILE THE SALIVA MICROBIOME AND METABOLOME DURING THE FIRST 3 YEARS OF LIFE AND CHART MICROBIAL AND METABOLITE DYNAMICS ASSOCIATED WITH FOOD ALLERGY ACQUISITION (AIM 2). OUR THIRD HYPOTHESIS IS THAT DIRECTIONAL CROSS-TALK BETWEEN THE ORAL AND SYSTEMIC ENVIRONMENTS IS ASSOCIATED WITH FOOD ALLERGY DEVELOPMENT. WE WILL BUILD TEMPORAL NETWORKS AND EMPLOY CAUSAL METHODS TO INTEGRATE THE MULTI-DIMENSIONAL ORAL DATA GENERATED BY THIS STUDY WITH MULTI-OMIC SYSTEMIC DATA THAT WE HAVE IN HAND FOR THE SAME PARTICIPANTS TO IDENTIFY DIRECTIONAL RELATIONSHIPS BETWEEN THE ORAL AND SYSTEMIC ENVIRONMENTS OVER TIME AND THEIR CAUSAL IMPACT ON FOOD ALLERGY ONSET (AIM 3). THIS STUDY WILL GENERATE UNPRECEDENTED FINDINGS ON THE IMMUNOLOGIC, MICROBIAL, AND METABOLOMIC TRAJECTORIES OF THE EARLY-LIFE ORAL ENVIRONMENT AND THEIR RELATIONSHIP WITH FOOD ALLERGY DEVELOPMENT. FINDINGS COULD INFORM FOOD ALLERGY PREVENTION AND BIOMARKERS USING NON-INVASIVE SALIVA SAMPLES.

EARLY WARNING SYSTEMS FOR CHILDHOOD AND ADULT DISORDERS

CHEMICAL GENOMICS PARADIGM FOR EPIGENETIC REGULATION

DYNAMICS UNDERLYING TISSUE INTEGRITY

PROTECTION AGAINST COGNITIVE DECLINE IN MS: LONGITUDINAL INVESTIGATION OF RESERVE

STRUCTURAL ANALYSIS OF ALCOHOL-DEPENDENT ACTIVATION OF GIRKS

OMMATIDIAL PATTERNING DURING EYE DEVELOPMENT

DISSECTING OLIGOGENIC BIOMARKERS IN ASHKENAZI JEWS WITH PARKINSON DISEASE

PROTECTIVE ROLES OF GRAPE-DERIVED POLYPHENOLS IN ALZHEIMER'S DISEASE

IMPROVING COGNITION VIA EXERCISE IN SCHIZOPHRENIA

ELEVATED FSH - A DRIVER FOR SEX DIFFERENCES IN ALZHEIMER'S DISEASE - PROJECT SUMMARY ALZHEIMER’S DISEASE (AD) STANDS OUT AS NOTABLE IN TWO RESPECTS––IN NOT HAVING A CURE AND IN AFFECTING WOMEN MORE THAN MEN. WHILE DECLINING ESTROGEN HAS BEEN THOUGHT TO UNDERPIN POST–MENOPAUSAL AD, THERE IS A CLEAR CLINICAL CORRELATION OF AD WITH RISING LEVELS OF FOLLICLE–STIMULATING HORMONE (FSH). MOST NOTABLY, THERE IS A ‘SPIKE’ IN COGNITIVE DECLINE IN WOMEN IN THE EARLY YEARS OF THE MENOPAUSAL TRANSITION, WHEN SERUM ESTROGEN IS NORMAL AND FSH LEVELS BEGIN TO RISE. COLLABORATIVE STUDIES BETWEEN THE MOUNT SINAI AND EMORY GROUPS HAVE IDENTIFIED FSH AS A POTENTIAL DRIVER FOR AD—AND SUGGEST THAT RISING FSH LEVELS MAY CONTRIBUTE TO THE DISPROPORTIONATE INCREASE OF AD IN AGING WOMEN. NOTABLY, WE FIND THAT FSH RECEPTORS (FSHRS) ARE EXPRESSED IN BOTH MOUSE AND HUMAN BRAIN, AND THAT THE INJECTION OF RECOMBINANT FSH OR OVARIECTOMY (THAT ELEVATES SERUM FSH) AGGRAVATES AD PATHOLOGY AND COGNITIVE DECLINE IN 3XTG MICE. INHIBITING THE ACTION OF FSH IN 3XTG OR APP/PS1 MICE BY AN FSH–BLOCKING ANTIBODY OR DOWNREGULATING FSHR EXPRESSION IN THE HIPPOCAMPUS PREVENTS ONSET OF THE AD PHENOTYPE. THE EMORY GROUP ALSO PROVIDES STRONG PRELIMINARY EVIDENCE THAT FSH UPREGULATES C/EBPSS, WHICH ACTIVATES ASPARAGINE ENDOPEPTIDASE (AEP), A D–SECRETASE THAT CLEAVES AMYLOID PRECURSOR PROTEIN (APP) AND TAU––RESULTING IN NEURITIC PLAQUES AND NEUROFIBRILLARY TANGLES, RESPECTIVELY. THE GOAL OF THE TRANSDISCIPLINARY COLLABORATION BETWEEN THE DISCIPLINES OF ENDOCRINOLOGY AND NEUROSCIENCE IS TO FULLY UNDERSTAND THE MECHANISM OF FSH ACTION ON AD–VULNERABLE BRAIN REGIONS. THUS, IN SPECIFIC AIM 1, WE WILL MAP THE DISTRIBUTION AND CELLULAR LOCALIZATION OF THE FSHR AND ITS SIGNALING PARTNERS CEBPB AND LGMN IN HUMAN AND MOUSE BRAIN USING SINGLE–TRANSCRIPT TECHNOLOGIES. IN SPECIFIC AIM 2, WE WILL EXAMINE THE FUNCTION OF THE BRAIN FSHR IN DRIVING AD PATHOLOGY AND COGNITIVE DECLINE. FOR THIS, WE WILL DOWNREGULATE OR OVEREXPRESS THE FSHR IN SPECIFIC BRAIN AREAS OF 3XTG MICE BY STEREOTAXICALLY INJECTING AAV EXPRESSING SIFSHR OR FSHR. WE WILL ALSO STUDY THE EFFECT OF HIGH FSH IN 3XTG MICE RENDERED HAPLOINSUFFICIENT IN CEBPB, AND DELINEATE THE TRANSCRIPTOMIC ARCHITECTURE OF FSH–TREATED HUMAN NEURONAL CELLS BY RNA–SEQ. IN SPECIFIC AIM 3, WE WILL DETERMINE WHETHER DELETING THE FSHR OR INHIBITING FSH ACTION BY OUR MURINE FSH BLOCKING ANTIBODY, HF2, INJECTED OVER THE LIFESPAN OF 3XTG MICE CAN PREVENT THE ONSET OF COGNITIVE DECLINE. TO CONTEMPORANEOUSLY REPLICATE OUR DATA, THE EMORY GROUP WILL STUDY THE EFFECT OF TREATING ESTABLISHED COGNITIVE IMPAIRMENT WITH HF2 IN 18–MONTH–OLD APP KNOCK–IN (KI) MICE. IN ALL, OUR PROOF–OF–CONCEPT STUDIES––CONDUCTED USING OUR GOOD LABORATORY PRACTICES (GLP) PLATFORM––SHOULD NOT ONLY ESTABLISH A ROLE FOR HIGH FSH IN DRIVING AD, BUT ALSO PROVIDE A FRAMEWORK FOR THE FUTURE TESTING OF OUR HUMANIZED FSH–BLOCKING ANTIBODY, HU6, IN AGING WOMEN.

INTEGRATIVE NETWORK MODELING OF COGNITIVE RESILIENCE TO ALZHEIMER'S DISEASE

NEUROPROTECTIVE SIGNALING AND TRANSCRIPTIONAL PATHWAYS IN MICROGLIA ASSOCIATED WITH ALZHEIMER'S DISEASE - FUNCTIONAL GENOMICS STUDIES HAVE IDENTIFIED AN ENRICHMENT FOR ALZHEIMER’S DISEASE (AD) RISK VARIANTS IN ACTIVE ENHANCERS OF HUMAN MYELOID CELLS. THESE DATA, ALONG WITH MYELOID-SPECIFIC EXPRESSION OF SEVERAL AD RISK GENES, STRONGLY IMPLICATE THESE CELLS IN THE ETIOLOGY OF AD. PARTIAL LOSS-OF-FUNCTION MUTATIONS IN TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS 2 (TREM2), LINKED TO INCREASED RISK FOR AD, POINT TO A PROTECTIVE ROLE FOR TREM2 AGAINST NEURODEGENERATION. MICROGLIA ARE KNOWN TO PLAY NUMEROUS BENEFICIAL FUNCTIONS IN THE BRAIN, INCLUDING CLEARANCE OF DYING CELLS AS WELL AS CELLULAR DEBRIS AND ORCHESTRATE COMPLEX RESPONSES TO TISSUE STRESS OR DAMAGE. HOWEVER, CHRONIC ACTIVATION OF MICROGLIA CAN LEAD TO TOXIC NEUROINFLAMMATION AND IMPAIRMENT OF HOMEOSTATIC FUNCTIONS. A BETTER UNDERSTANDING OF THE MECHANISMS UNDERLYING THE NEUROPROTECTIVE FUNCTIONS OF MICROGLIA IS CRITICAL TO IDENTIFYING THERAPEUTIC TARGETS TO PREVENT OR DELAY AD ONSET. USING FINE MAPPING APPROACHES, WE HAVE IDENTIFIED LIKELY CAUSAL GENES WITHIN MANY AD GWAS LOCI. IN ONE LOCUS, THE GENE ENCODING EMBRYONIC ECTODERM DEVELOPMENT (EED) IS A STRONG CANDIDATE CAUSAL GENE AND A PUTATIVE TARGET OF A MYELOID CELL ENHANCER CONTAINING AN AD-ASSOCIATED FUNCTIONAL VARIANT. EED IS AN ESSENTIAL, NON-CATALYTIC COMPONENT OF THE POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), WHICH FUNCTIONS TO MAINTAIN THE REPRESSIVE HISTONE MARK H3K27ME3. MODULATION OF H3K27ME3 IS CRITICAL FOR EPIGENETIC REMODELING FOLLOWING INFLAMMATORY STIMULI AND HAS BEEN IMPLICATED IN MICROGLIAL CLEARANCE OF APOPTOTIC CELLS. CYTOPLASMIC PRC2 (CPRC2), ALSO EXHIBITS DIRECT SIGNALING ACTIVITY, CONTROLLING RECEPTOR-DRIVEN ACTIVATION OF ERK AS WELL AS ACTIN POLYMERIZATION IN IMMUNE CELLS, CELLULAR PROCESSES IMPLICATED BY OUR AD GENETICS STUDIES. FURTHERMORE, OUR PRELIMINARY DATA SHOW THAT MICROGLIAL EED-/- ON THE 5XFAD BACKGROUND PHENOCOPIES TREM2-/-. BASED ON THESE GENETIC AND BIOCHEMICAL OBSERVATIONS WE HYPOTHESIZE THAT EED AND PRC2 OPERATE AS A MASTER REGULATOR OF THE TREM2 SIGNALING PATHWAY AND THAT FACTORS THAT CONTROL PRC2 EXPRESSION LEVELS AND ACTIVITY DEFINE THE TREM2 DRIVEN NEUROPROTECTIVE MICROGLIAL STATE. TO TEST THIS HYPOTHESIS, WE PROPOSE 4 AIMS TO EXAMINE THE IMPACT OF EED/PRC2 ON BOTH HUMAN AND MOUSE MICROGLIAL FUNCTION AND TREM2 SIGNALING IN VITRO AND IN VIVO. WE WILL DETERMINE THE ROLE OF EED/PRC2 LOSS OF FUNCTION ON MICROGLIAL FUNCTION AND TREM2 SIGNALING USING BOTH MOUSE AND HUMAN MICROGLIA IN VITRO (AIM 1) AND IN VIVO IN 5XFAD MICE (AIM 2). IN AIM 3 WE WILL EXAMINE THE IMPACT OF CYTOPLASMIC PRC2 ON MICROGLIAL FUNCTION AND TREM2 SIGNALING IN VITRO AND IN VIVO. IN AIM 4 WE WILL USE HUMAN GENETIC DATA TO TEST FOR ENRICHMENT OF AD RISK ALLELES WITHIN THE TREM2 SIGNALING PATHWAY GENES AND IN THE EED REGULATORY NETWORK AND DETERMINE THE IMPACT OF SELECT ALLELES ON MICROGLIAL FUNCTION AND TREM2 SIGNALING. FINALLY, WE WILL TEST FOR EPISTASIS BY EXAMINING THE IMPACT OF EED+/- ON TREM2 HAPLOINSUFFICIENCY IN 5XFAD MICE IN VIVO AND IN HIPSC-DERIVED MICROGLIA IN VITRO.

INSTITUTIONAL CAREER DEVELOPMENT CORE - SUMMARY KL2 THERE IS AN EMERGING WORKFORCE CRISIS IN THE NUMBER OF SCIENTISTS ENTERING TRANSLATIONAL RESEARCH CAREERS. THIS SHORTAGE IS OCCURRING AGAINST THE BACKDROP OF INCREASING COMPLEXITY IN MODERN SCIENTIFIC RESEARCH, WHERE SINGLE DISCIPLINE RESEARCH STUDIES SIMPLY CANNOT ANSWER THE CHALLENGES THAT FACE MODERN MEDICINE TODAY. THE EVER- GROWING COMPLEXITY OF 21ST CENTURY TRANSLATIONAL SCIENCE REQUIRES TRANSDISCIPLINARY (TD) TEAM-BASED RESEARCH THAT INTEGRATES AND EXTENDS BEYOND DISCIPLINE-SPECIFIC CONCEPTS, APPROACHES, AND METHODS TO ACCELERATE THE INNOVATIONS THAT WILL SOLVE COMPLEX REAL-WORLD PROBLEMS. THE NCATS KL2 CAREER DEVELOPMENT PROGRAM IS A KEY INITIATIVE DESIGNED TO MAINTAIN AND EXPAND THE PIPELINE OF INNOVATIVE, COLLABORATIVE AND PRODUCTIVE CLINICAL-TRANSLATIONAL SCIENTISTS THOUGH IMPLEMENTATION OF CUSTOMIZED INDIVIDUAL DEVELOPMENT PLANS (IDPS), TD MENTORING, AND INDIVIDUALIZED CURRICULA. OUR GOAL IS TO DEVELOP A COHORT OF TD SCIENTISTS WHO HAVE THE BREADTH AND DEPTH OF SKILLS NECESSARY TO NAVIGATE THE CRITICAL FUTURE ISSUES OF HEALTH AND DISEASE IN OUR INCREASINGLY COMPLEX WORLD. IN OUR NEWLY ENVISAGED CONDUITS CAREER DEVELOPMENT PROGRAM, WE WILL FOCUS ON TRAINING TD CLINICAL TRANSLATIONAL RESEARCH DATA SCIENTISTS. THE KL2 SCHOLARS WILL BE TRAINED IN CORE COMPETENCIES INCLUDING EPIDEMIOLOGY, STUDY DESIGN, BIOSTATISTICS/DATA SCIENCE, INFORMATICS, CLINICAL TRIALS, AND ETHICAL/REGULATORY GUIDELINES, AS WELL AS HAVE BROAD EXPOSURE TO THE METHODOLOGICAL STEPS OF THE TRANSLATIONAL PROCESS FROM DISCOVERY TO COMMUNITY ENGAGEMENT VIA INNOVATION, LIFE COURSE RESEARCH, AND WORKFORCE DEVELOPMENT. MOREOVER, WE FOCUS ON TRAINING TEAM-BASED CLINICAL AND TRANSLATIONAL RESEARCHERS BY LEVERAGING OUR RICH RESEARCH ENVIRONMENT OF LARGE-SCALE CLINICAL DATASETS, WELL-ESTABLISHED COHORTS AND BIOBANKS, SUCH AS THE BIOME BIOBANK AND THE ENVIRONMENTAL INFLUENCES ON CHILD HEALTH OUTCOMES (ECHO) COHORT AMONG OTHER BIG DATA RESOURCES. OUR STATE OF THE ART PROGRAMS IN GENOMICS AND EXPOSOMICS, AND STRONG COMMUNITY ENGAGEMENT HAVE HELPED MOUNT SINAI DEVELOP A NUMBER OF HIGHLY INNOVATIVE PROGRAMS IN DRUG DISCOVERY, ENTREPRENEURSHIP, AND TEAM-BUILDING, BRINGING TOGETHER BIOMEDICAL RESEARCH STAKEHOLDERS THAT REFLECT SCIENTIFIC EXPERTISE ACROSS THE LIFESPAN. OUR WORKSHOPS, SHORT COURSES AND ADVANCED TRAINING SEMINARS FOCUS ON STRATEGIC AREAS, SUCH AS INFORMATICS, BIG DATA, WORKFORCE DEVELOPMENT, TEAM SCIENCE, AND COMMUNITY ENGAGEMENT, AS WELL AS ACADEMIC SKILLS INCLUDING SCIENTIFIC WRITING, NEGOTIATION SKILLS, CONFLICT RESOLUTION, INDUSTRY INTERACTIONS, FEDERAL GRANT PREPARATION AND MANAGEMENT, AND THE PROMOTION PROCESS. WE ALSO OFFER A MENTOR TRAINING PROGRAM AIMED TO TEACH MENTORS THE SKILLS THAT WILL HELP IMPROVE THE MENTORING EXPERIENCE, PROMOTE MENTEES’ GROWTH AND HELP BUILD RESILIENCE AND CONFIDENCE. FURTHERMORE, TO PROVIDE OUR YOUNGER GENERATION OF SCIENTISTS NETWORKING OPPORTUNITIES, WE ARE BUILDING AN INSTITUTIONAL K-CLUB OF SUCCESSFUL JUNIOR FACULTY WITH CAREER DEVELOPMENT GRANTS, TO SERVE AS A COMMUNICATION HUB FOR VARIOUS CAREER DEVELOPMENT ACTIVITIES. FINALLY, WE PARTNER WITH THE OFFICE OF DIVERSITY AND INCLUSION TO PROMOTE A MORE DIVERSE COHORT OF KL2 SCHOLARS.

GENOMICS OF CHRONIC RENAL ALLOGRAFT REJECTION

GENERAL CLINICAL RESEARCH CENTER

FGF SIGNALING PATHWAYS AND CRANIOFACIAL DEVELOPMENT

TOWARD A UNIVERSAL INFLUENZA VIRUS VACCINE BASED ON LIVE ATTENUATED NS1-DELETED INFLUENZA VIRUSES

PEDIATRIC HEART DISEASE: GETTING FROM MUTATIONS TO THERAPEUTICS

NEUROPATHOLOGY OF CTE AND DELAYED EFFECTS OF TBI: TOWARD IN-VIVO DIAGNOSTICS

NOVEL BIOMARKER TO IDENTIFY CRITICAL WINDOWS OF SUSCEPTIBILITY TO METAL MIXTURE

DEVELOPMENT OF NOVEL THERAPEUTICS FOR OPIOID DEPENDENCE

NOVEL CELLULAR AND VIRAL TARGETS FOR ANTI-INFLUENZA VIRUS DRUGS

GROWTH FACTOR SIGNALING AND CRANIOFACIAL DEVELOPMENT

REVEALING THE ROLE OF THE CERVICO-VAGINAL MICROBIOME IN SPONTANEOUS PRETERM BIRTH

PTSD PREVENTION USING ORAL HYDROCORTISONE IN THE IMMEDIATE AFTERMATH OF TRAUMA

SINGLE CHROMATIN FIBER SEQUENCING AND LONGITUDINAL EPIGENOMIC PROFILING IN HIV+ BRAIN CELLS EXPOSED TO NARCOTIC AND STIMULANT - HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS PERSIST IN THE ERA OF COMBINATION ANTIRETROVIRAL THERAPY (CART) WHILE HIV LATENCY, AND CELL-SPECIFIC EXPRESSION OF HIV TRANSCRIPT IN HUMAN CNS REMAINS INCOMPLETELY UNDERSTOOD. THERE IS HIGH PREVALENCE OF HIV-ASSOCIATED NEUROLOGIC DISEASE AND INCREASING RECOGNITION OF CNS VIRAL ESCAPE IN PEOPLE STABLY SUPPRESSED WITH CART, OFTEN FURTHER COMPLICATED BY THE CO-REGISTERED EPIDEMIC OF SUBSTANCE USE DISORDERS (SUD) IN PEOPLE LIVING WITH HIV/AIDS (PLWHA), AS SUD ALSO HAVE PROFOUND IMPACT ON CNS FUNCTION. ONGOING WORK IN OUR LABORATORY IS PROVIDING FIRST ASSESSMENTS OF CELL-TYPE SPECIFIC HIV 'MOLECULAR SIGNATURES', INCLUDING GENOME INTEGRATION PATTERNS AND ALTERATIONS ON THE LEVEL OF THE TRANSCRIPTOME AND EPIGENOME IN REWARD- AND ADDICTION CIRCUITRY OF THE HUMAN POSTMORTEM BRAIN. HOWEVER, LIKE VIRTUALLY ALL OTHER GENOMIC APPROACHES IN THE FIELD, OUR ONGOING STUDIES FACE TWO MASSIVE LIMITATIONS: (A) EXCLUSIVELY CROSS-SECTIONAL DESIGN, LIMITED TO A SNAPSHOT OF GENOME ORGANIZATION AND FUNCTION AT A SINGLE TIME POINT – THE TIME OF DEATH OF THE BRAIN DONOR. THE VERY SAME LIMITATION OBVIOUSLY APPLIES TO CELL CULTURE AND ANIMALS. THIS IS EXTREMELY UNFORTUNATE AS SUCH TYPES OF ENDPOINT EPIGENOME AND TRANSCRIPTOME MAPPINGS IN INFECTED AND NON-INFECTED BRAIN CELLS CANNOT INFORM ABOUT CELL-SPECIFIC CHROMATIN STATUS DURING EARLIER PERIODS IN THE LIFE OF THE CELL (B) CONVENTIONAL BRAIN NEUROGENOMICS IS THUS FAR LIMITED TO SHORT READ SEQUENCING OF CHROMATIN, TYPICALLY EXTENDING 150 BASE PAIRS OR LESS PER READ. HOWEVER, IT WOULD BE MUCH MORE INFORMATIVE TO PROFILE, AT BASE PAIR RESOLUTION, EPIGENOMIC CHROMATIN LANDSCAPES ACROSS A WIDER WINDOW ENCOMPASSING FULL LENGTH RETROVIRAL INSERTION SITES, WHICH ARE TWO ORDERS OF MAGNITUDE ABOVE CURRENT READ LENGTH. IN THIS AVANT-GARDE PROJECT, WE WILL, FOR THE FIRST TIME, FOR EACH BRAIN, EMBARK ON RETROSPECTIVE/LONGITUDINAL EPIGENOMIC PROFILING, USING A XENOGRAFT MODEL WELL ESTABLISHED IN THE HIV FIELD, TOGETHER WITH GENETICALLY ENGINEERED HUMAN IPSC- DERIVED HEMATOPOIETIC PROGENITOR CELLS (HPC). WE WILL, FOR THE FIRST TIME, EMBARK ON THE LONGITUDINAL EPIGENOMIC TAGGING OF SINGLE CHROMATIN FIBERS, AND EXPLORE DYNAMIC CHANGES AND EVEN REVERSIBILITY (OR PROGRESSIVE DETERIORATION) OF THE EPIGENOMIC DYSREGULATION IN HIV INFECTED MYELOID DERIVED CELLS RESIDING IN BRAIN AND BLOOD.

THE 3D GENOME IN TRANSCRIPTIONAL REGULATION ACROSS THE POSTNATAL LIFE SPAN, WITH IMPLICATIONS FOR SCHIZOPHRENIA AND BIPOLAR DISORDER

TRAINING PROGRAM IN MOLECULAR AND CELLULAR CARDIOLOGY

LEVERAGING EXISTING AGING RESEARCH NETWORKS TO INVESTIGATE TBI AND AD/ADRD RISK (LEARN TBI & AD)

CHEMICAL ANATOMY AND SYNAPTOLOGY OF VESTIBULO-SYMPATHETIC PATHWAYS

ENVIRONMENTAL AND GENETIC DETERMINANTS OF PUBERTY

DYNORPHIN /KAPPA MESOLIMBIC SYSTEM IN HEROIN ABUSE

IMPROVING MEDICATION ADHERENCE IN ADOLESCENTS WHO HAD A LIVER TRANSPLANT: IMALT

LEARNING THE REGULATORY CODE OF ALZHEIMER'S DISEASE GENOMES

DYNAMIC REGULATORY NETWORK MODELS OF HUMAN RESPONSE TO INFLUENZA VIRUS

LIVE ATTENUATED VACCINES FOR EPIDEMIC AND PANDEMIC FLU

GENOMIC MEDICINE PILOT FOR HYPERTENSION AND KIDNEY DISEASE IN PRIMARY CARE

IN VIVO MOLECULAR MRI OF ATHEROTHROMBOTIC LESIONS

UNDERSTANDING GENE X STRESS INTERACTIONS ACROSS THE CELL TYPES OF THE BRAIN IN PTSD

WNT/FRIZZLED-PCP SIGNALING IN DEVELOPMENT AND DISEASE

MOUNT SINAI INJURY CONTROL RESEARCH CENTER (MS-ICRC)

A REGULOME AND TRANSCRIPTOME ATLAS OF FETAL AND ADULT HUMAN NEUROGENESIS - PROJECT SUMMARY DYNAMIC CHANGES IN THE SPATIOTEMPORAL PATTERNING OF TRANSCRIPTION FACTOR BINDING ON CIS-REGULATORY DNA ELEMENTS DRIVES THE DEVELOPMENTAL TRANSITION OF CELL LINEAGES DURING NEUROGENESIS. IN THE HUMAN BRAIN, NEURONS ARE GENERATED FROM EARLY EMBRYONIC DEVELOPMENT UNTIL EARLY POSTNATAL STAGES. THE MAIN NEUROGENIC REGION IN THE ADULT BRAIN IS THE DENTATE GYRUS IN THE HIPPOCAMPUS. WHILE ADULT HIPPOCAMPAL NEUROGENESIS HAS BEEN CONFIRMED IN THE MAJORITY OF MAMMALS, IT IS UNCLEAR IF THIS PHENOMENON EXISTS IN THE HUMAN BRAIN. MULTIPLE NEUROPSYCHIATRIC CONDITIONS, INCLUDING DEPRESSION, SCHIZOPHRENIA AND ALZHEIMER'S DISEASE ARE ROOTED IN HIPPOCAMPAL DEFECTS. DESPITE ROLE THEREFORE, THE OBVIOUS IMPORTANCE OF ON AND ITS IN NEUROGENESIS, OUR UNDERSTANDING OF THE CELL DIVERSITY AND TISSUE ORGANIZATION IS HIGHLY INCOMPLETE. A DENTATE GYRUS NEUROPSYCHIATRIC CONDITIONS, MORE COMPLETE CELL CENSUS OF THE DENTATE GYRUS ACROSS LIFETIME WILL INCREASE OUR UNDERSTANDING OF THE MECHANISMS UNDERLYING FETAL, EARLY POSTNATAL AND ADULT NEUROGENESIS, WHICH COULD HAVE A KEY ROLE IN THE ETIOLOGY OF DISEASE IN HUMANS. TOOLS CHROMATIN GYRUS WORLD COMPUTATIONAL RESOURCES THE OVERARCHING GOAL OF OUR PROPOSAL IS TO OPTIMIZE AND ACCELERATE THE USE OF SCALABLE TECHNOLOGIES AND TO PERFORM UNBIASED, MULTIMODAL SINGLE-NUCLEUS OMICS-BASED ASSESSMENT OF GENE EXPRESSION AND ACCESSIBILITY COMBINED WITH SPATIAL TRANSCRIPTOMICS PROFILING ON TISSUE SECTIONS OF HUMAN ACROSS STAGES. IN THIS STUDY, WE BRING TOGETHER AN INTERDISCIPLINARY TEAM OF EXPERTS ANATOMY, SPATIAL TRANSCRIPTOMICS, NEURODEVELOPMENT AND BIOLOGY TO CREATE A CELL CENSUS OF THE DENTATE GYRUS THAT WILL BE INTEGRATED WITH EXISTING FROM THE BRAIN INITIATIVE CELL CENSUS NETWORK AND WILL BE MADE FREELY AVAILABLE TO THE SCIENTIFIC DENTATE FETAL, EARLY POSTNATAL AND ADULT IN SINGLE CELL OMICS, HUMAN COMMUNITY. ANALYSES EARLY EMBRYONIC HIPPOCAMPAL AND THIS UTILIZING THIS LARGE RESOURCE OF OMICS DATA FROM THE HUMAN DENTATE GYRUS, WE WILL PERFORM THE FOLLOWING THREE THAT AIM TO: (1) IDENTIFY THE CELL DIVERSITY AND TISSUE ORGANIZATION OF HUMAN DENTATE GYRUS ACROSS FETAL, POSTNATAL AND ADULT STAGES; (2) UNCOVER SHARED AND DISTINCT GENE REGULATORY NETWORKS ASSOCIATED WITH AND ADULT HUMAN HIPPOCAMPAL NEUROGENESIS; AND (3) STUDY THE EVOLUTION CONSERVATION OF NEUROGENESIS BY PERFORMING COMPARATIVE ANALYSIS WITH MOUSE AND NON-HUMAN PRIMATE SINGLE-CELL SPATIAL TRANSCRIPTOMIC DATA THAT ARE READILY ACCESSIBLE THROUGH THE BRAIN INITIATIVE CELL CENSUS NETWORK. INNOVATIVE RESEARCH PROGRAM WILL, IF SUCCESSFUL,PROVIDE SCALABLE TECHNOLOGIES FOR MULTIMODAL AND SPATIAL OMICS PROFILING AND A DEVELOPMENTAL AND ADULT CELL ATLAS OF CELL TYPE DIVERSITY IN THE DENTATE GYRUS , WHICH WILL SERVE AS A BLUEPRINT FOR STUDIES OF HUMAN HIPPOCAMPAL NEUROGENESIS, SELECTIVE VULNERABILITY OF CELL TYPES IN DISEASE, AND THE FEATURES OF BRAIN EVOLUTION THAT DIFFERENTIATES HUMANS FROM OTHER SPECIES.

NEURODEVELOPMENTAL EFFECTS OF CANNABIS AND ITS EPIGENETIC REGULATION

THE GENETICS OF OCULAR MELANOMA

LIGHT-DRIVEN CONTROL OF NEURONS IN VITRO AND IN VIVO

POST-BACCALAUREATE RESEARCH EDUCATION PROGRAM (PREP)

MACROPHAGES IN HOMEOSTASIS AND CARDIOVASCULAR DISEASE

CENTER FOR INVESTIGATING VIRAL IMMUNITY AND ANTAGONISM

COMMUNITY VOICES (2):COMMUNITY VOICES ON INFORMED CONSENT IN EMERGENCY SITUATIONS

THE INFLUENCE OF GUT MICROBIOTA STABILITY IN INFLAMMATORY BOWEL DISEASE

MOLECULAR AND DEVELOPMENTAL ANALYSIS OF HOLOPROSENCEPHALY

MECHANISTIC REGISTRY TO STUDY WHETHER INFECTION WITH CORONA VIRUS DISEASE 2019 (COVID-19) ALTERS ATHEROSCLEROTIC PLAQUE PROGRESSION - PROJECT SUMMARY / ABSTRACT THE PRIMARY OBJECTIVE OF THE CORONA VIRUS DISEASE 2019 (COVID-19) (COVID-CT) REGISTRY IS TO DETERMINE IF INFECTION WITH THE SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS-2 (SARS-COV-2), THE VIRUS WHICH CAUSES COVID-19, RESULTS IN MARKED PROGRESSION OF CORONARY ATHEROSCLEROTIC PLAQUE IN PATIENTS WITH PREVIOUSLY DEFINED ANATOMIC CORONARY ARTERY DISEASE (CAD). COVID-19 INDUCES A PRO-INFLAMMATORY CYTOKINE RELEASE AND PRO- THROMBOTIC PROCESSES THAT WE HYPOTHESIZE WILL ACCELERATE ATHEROSCLEROTIC PLAQUE PROGRESSION. CORONARY COMPUTED TOMOGRAPHIC ANGIOGRAPHY (CCTA) IS A ROBUST NONINVASIVE METHOD UNIQUELY CAPABLE OF MEASURING ANGIOGRAPHIC STENOSIS AND QUANTIFYING AND CHARACTERIZING ATHEROSCLEROTIC PLAQUE. OUR GROUP HAS EXTENSIVE EXPERIENCE IN LARGE MULTICENTER TRIALS AND REGISTRIES USING CCTA TO IDENTIFY KEY ATHEROSCLEROTIC PLAQUE FEATURES ASSOCIATED WITH PROGRESSION AND MAJOR CAD EVENTS. MOREOVER, WE PROPOSE USE OF A NOVEL CT MARKER OF CORONARY ARTERY INFLAMMATION - THE PERIVASCULAR FAT ATTENUATION INDEX (FAI) – A MARKER HIGHLY PREDICTIVE OF ACUTE CAD EVENTS AND TO ASSESS SERIAL CHANGES IN CORONARY INFLAMMATION. COVID-19 IS RAPIDLY BECOMING A LEADING CAUSE OF DEATH WITH SUBSTANTIAL EVIDENCE THAT PRE-EXISTING CAD INCREASES RISK OF SERIOUS ILLNESS AND MORTALITY FROM COVID-19. BY ENROLLING PATIENTS WITH HIGH RISK, ATHEROSCLEROTIC PLAQUE, FINDINGS FROM THE COVID-CT REGISTRY WILL INFORM THIS LINK BETWEEN THE INFLAMMATORY RESPONSE SUSTAINED DURING COVID-19 TO ACCELERATED ATHEROSCLEROTIC PLAQUE PROGRESSION. IF OUR HYPOTHESES ARE CONFIRMED, THEN CLINICIANS AND PATIENTS WILL HAVE CLEAR INFORMATION THAT VIRAL INFECTIONS, SUCH AS SARS-COV-2, ALTER THE INFLAMMATORY MILIEU AND ACCELERATE PROGRESSION OF ATHEROSCLEROSIS. IMPORTANTLY, A CONNECTION BETWEEN COVID- 19 AND CAD WILL BROADLY IMPACT PREVENTIVE RISK ASSESSMENT FOR THE ~7 MILLION PATIENTS INFECTED WITH SARS-COV- 2 AND MILLIONS MORE YET TO BE TESTED IN THE UNITED STATES. TO DATE, EVIDENCE IS LACKING AS TO WHETHER THE COVID-19 RESULTS IN MARKED ATHEROSCLEROTIC PLAQUE PROGRESSION AMONG RACIALLY AND ETHNICALLY DIVERSE PATIENTS WITH CCTA-DEFINED CAD WHO RESIDE ACROSS A SOCIOECONOMICALLY- DIVERSE, URBAN SETTING. THE PRESENT PROPOSAL CONSTITUTES A COMPREHENSIVE APPROACH ASSESSING THE CLINICAL IMPORTANCE OF ATHEROSCLEROTIC PLAQUE PROGRESSION FOLLOWING COVID-19. CURRENTLY, THE IMPLICATIONS OF EPICARDIAL CORONARY INJURY FOLLOWING SARS-COV-2 INFECTION IS UNKNOWN. YET, THE INFLAMMATORY PATHWAY OF ATHEROSCLEROTIC PLAQUE PROGRESSION IS WELL STUDIED AND, AS SUCH, OUR HYPOTHESES ARE SUPPORTED BY THIS KNOWLEDGE BASE. THE PROPOSED COVID-19 REGISTRY IS POISED TO PROVIDE AN IMPROVED MECHANISTIC UNDERSTANDING OF THE ROLE OF VIRAL INFECTION ON ALTERATIONS IN ATHEROSCLEROTIC PLAQUE.

POPULATION-BASED AUTISM GENETICS & ENVIRONMENT STUDY

HEALTH CAREERS OPPORTUNITY PROGRAM

MODELING CELL REGULATORY NETWORKS

NEURAL BASIS OF BEHAVIORAL AROUSAL

MECHANISMS ASSOCIATED WITH FLARES AND REMISSION IN COLITIS

GMP PRODUCTION OF CANDIDATE PAN-GROUP 2 INFLUENZA A VIRUS

MODEL OF HUMAN DISC REGENERATION IN THE SPECTRUM OF DEGENERATIVE DISC DISEASE

MOLECULAR STUDIES OF COCAINE ACTION IN BRAIN

CLINICAL & BIOLOGICAL SIGNATURES OF POST-TRAUMATIC NEURODEGENERATION: LEVERAGING THE TBI MODEL SYSTEMS OF CARE TO ACCELERATE IN VIVO DIAGNOSIS OF THE LATE EFFECTS OF TBI (LETBI) - PROJECT SUMMARY/ABSTRACT THIS R01 PROPOSAL, “CLINICAL & BIOLOGICAL SIGNATURES OF POST-TRAUMATIC NEURODEGENERATION: LEVERAGING THE TBI MODEL SYSTEMS OF CARE TO ACCELERATE IN VIVO DIAGNOSIS OF THE LATE EFFECTS OF TBI (LETBI)” IS SUBMITTED IN RESPONSE TO PAR-22-024, WHICH REQUESTS INVESTIGATION INTO THE CLINICAL AND BIOLOGICAL FEATURES THAT DISTINGUISH CHRONIC STATIC EFFECTS OF TRAUMATIC BRAIN INJURY (CSTBI) FROM THOSE ASSOCIATED WITH PROGRESSIVE POST-TRAUMATIC NEURODEGENERATION (PTND). THIS WILL REQUIRE LONGITUDINAL, MULTIMODAL DATA FROM A WELL-CHARACTERIZED DIVERSE COHORT OF TBI SURVIVORS. THE LETBI STUDY IS A PROSPECTIVE LONGITUDINAL STUDY WITH MULTIMODAL CLINICAL CHARACTERIZATION AND AUTOPSY ENDPOINTS DESIGNED TO CHARACTERIZE THE NEUROPATHOLOGY OF TBI AND ITS IN VIVO CLINICAL SIGNATURES. LETBI PARTICIPANTS WERE RECRUITED FROM ONGOING LONGITUDINAL STUDIES INCLUDING THE TBI MODEL SYSTEMS WHICH ENSURES EXCELLENT TBI CHARACTERIZATION AND EXTENSIVE LONGITUDINAL DATA. HERE, WE PROPOSE TO FOLLOW THE ORIGINAL LETBI COHORT, AND EXPAND TO INCLUDE 4 ADDITIONAL TBI MODEL SYSTEMS CENTERS. BY RECRUITING INDIVIDUALS WITH A HISTORY OF WELL-CHARACTERIZED MODERATE-SEVERE TBI WHO ARE AT LEAST 5 YEARS POST-TBI, WE WILL STUDY A COHORT OF INDIVIDUALS AT RISK FOR DECLINE, WITH MULTIMODAL LETBI FOLLOW-UP VISITS CONDUCTED AT 2-3 YEAR INTERVALS. WE WILL APPLY ADVANCED PSYCHOMETRIC AND STATISTICAL METHODS TO CONSIDER LIFE COURSE EXPOSURES THAT ELEVATE RISK FOR ALZHEIMER’S DISEASE (AD) AND AD-RELATED DEMENTIAS (ADRDS), NOVEL NEUROIMAGING PROCESSING TOOLS, ULTRA-SENSITIVE SINGLE MOLECULE ARRAY (SIMOA) TECHNOLOGY, AND STATE-OF-THE-ART NEUROPATHOLOGY METHODS IN A LETBI COHORT ENHANCED BY EXPANDED RECRUITMENT FROM A TOTAL OF 6 TBI MODEL SYSTEM CENTERS. WE WILL LEVERAGE EXISTING DATA COLLECTED VIA TELEPHONE IN THE TBI MODEL SYSTEM NATIONAL DATABASE TO CHARACTERIZE CLINICAL COURSE FROM THE TIME OF INJURY TO LETBI ENROLLMENT. IN AIM 1 WE WILL USE EXISTING TBIMS AND NEWLY COLLECTED LETBI DATA TO IDENTIFY INDIVIDUALS WHO HAVE DECLINED FROM A PREVIOUSLY ACHIEVED POST-INJURY LEVEL OF FUNCTION (I.E., PTND) TO DETERMINE INJURY CHARACTERISTICS AND LIFETIME HEAD TRAUMA EXPOSURE THRESHOLDS ASSOCIATED WITH DOMAIN-SPECIFIC PTND RISK AND TRAUMATIC ENCEPHALOPATHY SYNDROME (TES) RISK, BEYOND INDEX INJURY SEVERITY. IN AIM 2 WE WILL APPLY ADVANCED CAUSAL INFERENCE METHODS TO QUANTIFY EARLY LIFE ENVIRONMENT AND ISOLATE THE CONTRIBUTION OF EXPOSURES OTHER THAN TBI TO PTND AND AD/ADRD RISK. IN AIM 3 WE WILL DEFINE THE UNDERLYING PATHOLOGY(S) OF PTND BY IDENTIFYING IN VIVO FLUID (NFL, GFAP, T-TAU, PTAU, ASS42/40) AND IMAGING (NETWORK- SPECIFIC CONNECTIVITY CHANGES PER DIFFUSION MRI (DMRI)) BIOMARKERS OF PTND. IN AIM 4 WE WILL SEEK POSTMORTEM VALIDATION OF THESE IN VIVO BIOMARKERS IN THE LETBI AUTOPSY COHORT, IDENTIFYING THEIR POSTMORTEM TISSUE CORRELATES AND BURDEN OF NEURODEGENERATIVE DISEASE INCLUDING CTE ACROSS INJURY EXPOSURE AND TES DIAGNOSTIC GROUPS. OUR STRONG TRANSDISCIPLINARY TEAM IS IDEALLY POSITIONED TO DEFINE THE RISK FACTORS, CLINICAL, AND BIOLOGICAL SIGNATURES OF PTND, THEREBY IDENTIFYING TOOLS FOR DIAGNOSIS AND DISEASE PROGRESSION WHILE CREATING RICH DATA RESOURCES TO SHARE WITH THE SCIENTIFIC COMMUNITY TO ACCELERATE AD/ADRD TREATMENT DEVELOPMENT.

MULTIETHNIC GENOMIC EPIGENOMIC AND TRANSCRIPTOMIC FINE-MAPPING AND FUNCTIONAL VALIDATION ANALYSIS OF SCHIZOPHRENIA AND BIPOLAR DISORDER RISK LOCI - PROJECT SUMMARY SERIOUS MENTAL ILLNESS (SMI) THAT INCLUDES SCHIZOPHRENIA (SCZ) AND BIPOLAR DISORDER (BD) ARE COMMON, COMPLEX AND DEBILITATING PSYCHIATRIC DISORDERS THAT TOGETHER AFFECT OVER 2% OF THE POPULATION AND CARRY CONSIDERABLE MORBIDITY, MORTALITY, AND PERSONAL AND SOCIETAL COST. OVER THE LAST DECADE, LARGE-SCALE GENOME WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED HUNDREDS OF LOCI CONTRIBUTING TO THE RISK OF SCZ AND BD. ADVANCING THESE STATISTICAL ASSOCIATIONS TO CAUSAL MECHANISMS FOR SMIS IS VERY CHALLENGING DUE TO INCOMPLETE UNDERSTANDING OF THE NON-CODING REGULATORY MECHANISMS IN THE HUMAN BRAIN TISSUE AND THE LOCAL CORRELATION OF RISK VARIANTS. THEREFORE, A SYSTEMATIC ANALYSIS THAT PERFORMS FINE-MAPPING TO JOINTLY IDENTIFY AND VALIDATE A CREDIBLE SET OF CAUSAL VARIANTS IN SMI AND MOLECULAR FEATURES THAT INCLUDES TRANSCRIPTS AND REGULATORY SEQUENCES, IN RELEVANT TISSUES AND CELL TYPES IS A CRITICAL NEXT STEP. THE OVERARCHING GOAL OF OUR PROPOSAL IS TO LEVERAGE GENOMICS AND MULTISCALE FUNCTIONAL OMICS (GENE EXPRESSION AND EPIGENOME REGULATION) DATA AND PERFORM FINE MAPPING TO DETECT AND VALIDATE CAUSAL VARIANTS, TRANSCRIPTS AND REGULATORY SEQUENCES IN SMI. IN AIM 1, WE WILL PERFORM LARGE-SCALE TRANS- ANCESTRY GWAS OF SCZ AND BD TO EXPAND THE CURRENT REPERTOIRE OF RISK (AND RESILIENCE) LOCI AND REFINE THE CREDIBLE SETS OF CAUSAL VARIANTS UNDERLYING GENOME-WIDE SIGNIFICANT ASSOCIATIONS. IN AIM 2, WE WILL INTEGRATE PUTATIVE CAUSAL VARIANTS WITH MULTISCALE FUNCTIONAL OMICS DATA FROM HUMAN BRAIN TISSUE THAT CAPTURE GENE EXPRESSION AND EPIGENOME REGULATION AT THE BULK, CELL TYPE-SPECIFIC AND SINGLE CELL LEVEL TO IDENTIFY CREDIBLE SETS OF TRANSCRIPTS AND REGULATORY SEQUENCES. IN AIM 3, WE WILL FUNCTIONALLY VALIDATE PUTATIVE CAUSAL VARIANTS AND REGULATORY SEQUENCES, BY USING NOVEL APPROACHES THAT COMBINE MASSIVELY PARALLEL REPORTER ASSAYS AND GENOME EDITING IN EXCITATORY AND INHIBITORY NEURONS DERIVED FROM HUMAN INDUCED PLURIPOTENT STEM CELLS. OUR COMPUTATIONAL AND EXPERIMENTAL AIMS BRIDGE THE GAP BETWEEN THE FINE-MAPPING OF CAUSAL VARIANTS, THE MOLECULAR GENE- REGULATORY EFFECTS OF RISK VARIANTS ON ENHANCER ACTIVITY AND GENE EXPRESSION AND THEIR BIOLOGICAL EFFECTS AT THE CELLULAR LEVEL. IF SUCCESSFUL, OUR PROJECT CAN ELUCIDATE THE GENES, PATHWAYS, AND MECHANISMS UNDERLYING SCZ AND BD, AND PROVIDE NEW INSIGHTS AND AVENUES FOR THERAPEUTIC DEVELOPMENT.

NEW YORK CITY SICKLE CELL IMPLEMENTATION SCIENCE CONSORTIUM

REGULATION OF CELL POLARITY BY WNT SIGNALING

DYRK INHIBITORS FOR HUMAN BETA CELL EXPANSION

HIGH RESOLUTION CHARACTERIZATION OF BACTERIAL EPIGENOMES AND MICROBIOME - PROJECT SUMMARY/ABSTRACT MY LONG TERM GOAL IS TO COMPREHENSIVELY UNDERSTAND THE DIVERSITY, HETEROGENEITY AND FUNCTIONS OF BACTERIAL EPIGENOMES BOTH IN TERMS OF BASIC SCIENCE AND BIOMEDICAL IMPACT. IN THE BACTERIAL WORLD, METHYLATED ADENINE AND CYTOSINE RESIDUES WAS PREVIOUSLY THOUGHT TO BE ONLY ASSOCIATED WITH RESTRICTION-MODIFICATION SYSTEMS THAT PROVIDE A DEFENSE MECHANISM AGAINST INVADING FOREIGN GENOMES. HOWEVER, INCREASING EVIDENCE SUPPORTS THAT THEY ALSO PLAY IMPORTANT ROLES IN THE REGULATION OF CELL CYCLE, GENE EXPRESSION, VIRULENCE, SPORULATION, BIOFILM FORMATION, MICROBE-HOST INTERACTION AND ANTIBIOTIC RESISTANCE. EFFICIENT AND HIGH RESOLUTION PROFILING OF BACTERIAL DNA METHYLATION EVENTS HAS NOT BEEN POSSIBLE UNTIL THE ADVENT OF SINGLE MOLECULE REAL-TIME (SMRT) SEQUENCING. THIS TECHNIQUE ENABLED US TO CHARACTERIZE THE FIRST BACTERIAL METHYLOME AT SINGLE NUCLEOTIDE RESOLUTION. A FAST GROWING NUMBER OF BACTERIA ARE BEING CHARACTERIZED, FROM WHICH EXCITING DISCOVERIES HAVE BEEN MADE. HOWEVER, THESE STUDIES HAVE ALSO REVEALED UNEXPECTED COMPLEXITY AND DIVERSITY IN BACTERIAL METHYLOMES, CALLING FOR THE DEVELOPMENT NEW TECHNOLOGIES, ANALYTICAL AND EXPERIMENTAL METHODS IN ORDER TO MORE COMPREHENSIVELY UNDERSTAND BACTERIAL EPIGENOMES. IN THIS R35 PROJECT, WE WILL BUILD ON THE PROGRESS WE HAVE MADE IN THE PAST FIVE YEARS TO FURTHER DEVELOP AN INTEGRATED RESEARCH PROGRAM WITH A BROADER SCOPE INTEGRATING TWO ONGOING FOCUSED R01 PROJECTS. THE OVERARCHING THEME IS FOCUSED ON THE MAPPING, CHARACTERIZATION AND EXPLOITATION OF BACTERIAL METHYLOMES TO BETTER UNDERSTAND INDIVIDUAL BACTERIA AND MICROBIOME COMMUNITY. WE WILL DEVELOP THIS RESEARCH PROGRAM ALONG FOUR COMPLEMENTARY THEMES. FIRST, TO MORE COMPREHENSIVELY MAP BACTERIAL METHYLOME, WE WILL CONTINUE TO INNOVATE ON TECHNOLOGY DEVELOPMENT TO MAKE SIGNIFICANT IMPROVEMENTS BOTH IN TERMS OF IN TERMS OF COMPLETENESS AND RESOLUTION. SECOND, TO BETTER ELUCIDATE EPIGENETIC REGULATION IN BACTERIA, WE WILL COMBINE COMPUTATIONAL AND EXPERIMENTAL APPROACHES TO PRIORITIZE AND FUNCTIONALLY CHARACTERIZE SPECIFIC METHYLATION EVENTS ACROSS DIFFERENT BACTERIAL ORGANISMS. THIRD, TO SYSTEMATICALLY EXPAND BACTERIAL METHYLOME RESEARCH FROM CULTURED INDIVIDUAL BACTERIA TO MICROBIOME, WE WILL CHARACTERIZE BACTERIAL EPIGENETICS IN RESPONSE TO DIFFERENT TYPES OF PERTURBATIONS. LAST, WE WILL PROVIDE THE SOFTWARE WE DEVELOP AS AN INTEGRATED PACKAGE TO EASE BROAD USAGE, AND ORGANIZE RELEVANT CONFERENCE TUTORIALS TO HELP THE BROADER COMMUNITY. COMBINED TOGETHER, WE EXPECT THIS PROJECT TO PROVIDE BROADLY APPLICABLE METHODS TO THE MICROBIOLOGY AND MICROBIOME COMMUNITY, AND DISCOVER NOVEL BIOLOGICAL INSIGHTS INTO EPIGENETIC REGULATION IN INDIVIDUAL BACTERIA AND MICROBIOME.

MONOCLONAL THYROID STIMULATING ANTIBODIES

PHOTOCHEMICAL REGULATION OF CALCIUM IN CELL PHYSIOLOGY

ROLE OF THE ATP-DEPENDENT CHROMATIN-REMODELING ENZYME BRG1 IN INNER EAR MORPHOGENESIS