Albert Einstein College Of Medicine

CORE SUPPORT FOR CANCER CENTER

EINSTEIN AGING STUDY

WOMEN'S INTERAGENCY HIV STUDY (WIHS) IV

DNA REPAIR, MUTATIONS AND CELLULAR AGING

FUNCTIONAL CONSEQUENCES OF IMPAIRED AUTOPHAGY IN AGING

CENTRAL AFRICA IEDEA

THE NYSGRC: A LARGE SCALE CENTER FOR PSI:BIOLOGY

CLINICAL RESEARCH SITES FOR THE MACS/WIHS COMBINED COHORT STUDY (MACS/WIHS-CCS)

PROVIDENT: PREPOSITIONING OPTIMIZED STRATEGIES FOR VACCINES AND IMMUNOTHERAPEUTICS AGAINST DIVERSE EMERGING INFECTIOUS THREATS - THE OVERARCHING GOAL OF PROVIDENT (PREPOSITIONING OPTIMIZED STRATEGIES FOR VACCINES AND IMMUNOTHERAPEU- TICS AGAINST DIVERSE EMERGING INFECTIOUS THREATS) IS TO DELIVER “PLUG-AND-PLAY” VACCINE AND THERAPEUTIC AN- TIBODY BLUEPRINTS FOR EMERGING ENVELOPED RNA VIRUSES BELONGING TO THREE FAMILIES—NAIROVIRIDAE, HAN- TAVIRIDAE, AND PARAMYXOVIRIDAE. PROVIDENT IS A HIGHLY INTERWOVEN PARTNERSHIP AMONG 13 INSTITUTIONAL TEAMS FROM ACADEMIA, GOVERNMENT, AND INDUSTRY. CENTRAL TO PROVIDENT IS ITS FOCUS ON PLATFORM STRATEGIES THAT CAN RAPIDLY ADVANCE MANUFACTURABLE PRODUCTS WITH PATHWAYS TO REGULATORY APPROVAL AND PLANS FOR THEIR COMMERCIALIZATION THROUGH INDUSTRY PARTNERS WHO ARE INTEGRAL TO OUR CONSORTIUM. PROVIDENT WILL ACCOMPLISH ITS GOALS BY SYNTHESIZING THE ACTIVITIES OF FOUR RESEARCH PROJECTS, SUPPORTED BY THREE RESEARCH CORES AND A DATA MANAGEMENT CORE, AND OVERSEEN BY THE ADMINISTRATIVE CORE. USING A PROTOTYPE VIRUS STRATEGY IN PHASE I, WE WILL: (I) DISCOVER AND DISSECT HOST FACTORS AND PATHWAYS CRITICAL FOR VIRAL INFECTION AND PATHOGENESIS AND DE- LIVER TOOLS TO OTHER PROVIDENT COMPONENTS TO FACILITATE VACCINE AND IMMUNOTHERAPEUTIC DEVELOPMENT; (II) USE ADVANCED ANTIGEN ENGINEERING TO REFINE VACCINE DESIGN STRATEGIES THROUGH ITERATIVE ASSESSMENTS OF IMMUNO- GENICITY AND PROTECTIVE EFFICACY TO GENERATE OPTIMIZED VACCINE IMMUNOGENS; (III) DEVELOP RNA VACCINES AND EVALUATE TWO PLATFORMS TO OPTIMIZE IMMUNOGENICITY, PROTECTIVE EFFICACY, AND SAFETY AND (IV) GENERATE AN ADAP- TIVE ANTIBODY DEVELOPMENT PIPELINE THAT WILL COMPLEMENT AND INFORM VACCINE DESIGN STRATEGIES. IN PHASE II, WE WILL EVALUATE OUR PROTOTYPE-OPTIMIZED VACCINE PLATFORMS AGAINST OUR DIVERGENT OUTGROUP VIRUSES IN A SERIES OF TIMED EXERCISES WE TERM “SPRINTS,” WHICH SEEK TO GENERATE A VACCINE PRODUCT READY TO IMMUNIZE ANIMALS IN 10 DAYS. IN DOING SO, WE WILL PERFORM CROSS-FAMILY VALIDATIONS OF OUR VACCINE PLATFORMS FOR NAIROVIRUSES, HAN- TAVIRUSES, AND PARAMYXOVIRUSES AS A RIGOROUS CHALLENGE TO THE GENERALIZABILITY OF THE PHASE I BLUEPRINT DELIVER- ABLE, AND EITHER VALIDATE THE BLUEPRINT OR IDENTIFY WEAKNESSES FOR FURTHER REFINEMENT.

EINSTEIN-ROCKEFELLER-CUNY CENTER FOR AIDS RESEARCH

EINSTEIN-MOUNT SINAI DIABETES RESEARCH CENTER

CLINICAL AND TRANSLATIONAL SCIENCE AWARD

MEDICAL SCIENTIST TRAINING PROGRAM

PROMETHEUS: A PLATFORM FOR RAPID DEVELOPMENT OF HUMAN ANTIBODY-BASED THERAPEUTICS AND PROPHYLACTICS AGAINST EMERGING VIRAL THREATS

CLINICAL AND TRANSLATIONAL SCIENCE AWARD

CLINICAL AND TRANSLATIONAL SCIENCE AWARD (UL1)

MOTILITY AND INVASION

PROTEIN DYNAMICS IN ENZYMATIC CATALYSIS

GENETIC VARIANT-BASED DRUG DISCOVERY TARGETING CONSERVED PATHWAYS OF AGING

DYNAMIC COGNITIVE PHENOTYPES FOR PREDICTION OF MENTAL HEALTH OUTCOMES IN SERIOUS MENTAL ILLNESS - PROJECT SUMMARY THE PROPOSED WORK WILL ENHANCE CLINICAL PREDICTION FOR INDIVIDUALS WITH SERIOUS MENTAL ILLNESS (SMI), ACROSS DIAGNOSES, BY INCORPORATION OF NOVEL, SCALABLE COGNITIVE MEASURES THAT CAN BE DELIVERED IN ACUTE INPATIENT SETTINGS (FOR CLINICAL SCREENING), OUTPATIENT SETTINGS (FOR IDENTIFYING TIME PERIODS OF RELATIVE RISK), AND IN ETHNORACIALLY DIVERSE POPULATIONS. OUR OVERALL GOAL IS TO IMPROVE PREDICTION OF MENTAL HEALTH OUTCOMES AND CLINICAL DECISION-MAKING THROUGH THE VALIDATION AND INTEGRATION OF DYNAMIC COGNITIVE PHENOTYPES (NOVEL AND INNOVATIVE MEASURES THAT CAPTURE FLUCTUATIONS IN COGNITION AND BEHAVIOR OVER TIME) IN CLINICAL CARE. FOR AIM 1, WE WILL RECRUIT 1500 PARTICIPANTS ACROSS FIVE INPATIENT PSYCHIATRY UNITS (FOUR ADULT, ONE NONDEMENTIA GERIATRIC) AT MCLEAN HOSPITAL THAT PROVIDE CARE TO INDIVIDUALS WITH THE HIGHEST LEVELS OF CLINICAL SEVERITY. IN THIS GROUP, WE WILL USE A COMBINATION OF BRIEF COGNITIVE ECOLOGICAL MOMENTARY ASSESSMENT (OVER 3 DAYS), ACTIGRAPHY, AND CLINICAL RECORDS TO PROSPECTIVELY PREDICT CLINICAL HEALTH OUTCOMES, INCLUDING CHANGE IN TRANSDIAGNOSTIC SYMPTOMS, CHANGE IN SUICIDALITY, LENGTH OF STAY, AND 12-MONTH HOSPITALIZATION (FROM ELECTRONIC HEALTH RECORDS). DYNAMIC COGNITIVE PHENOTYPES DERIVED FROM TIME SERIES DATA (INCLUDING SLOPE OF COGNITIVE CHANGE, DIURNAL CYCLE, VOLATILITY, COGNITION/SYMPTOM COUPLING) WILL BE USED TO IMPROVE PREDICTION. FOR AIM 2, 250 PARTICIPANTS WILL BE FOLLOWED POST-DISCHARGE TO COLLECT LONGITUDINAL COGNITIVE ECOLOGICAL MOMENTARY ASSESSMENT (EMA) DATA AND BUILD PERSONALIZED MODELS OF CLINICAL RISK. IN AIM 3, WE WILL EVALUATE GENERALIZABILITY AND TRANSFER LEARNING OF CLINICAL PREDICTION MODELS FROM AIMS 1-2, APPLIED TO 250 ETHNORACIALLY DIVERSE PARTICIPANTS WITH ELEVATED PSYCHIATRIC SYMPTOMS RECRUITED FROM BRONX COUNTY, NEW YORK WHO ARE PATIENTS IN THE MONTEFIORE HEALTH SYSTEM. FINALLY, IN AIM 4, WE WILL ADAPT COGNITIVE ASSESSMENT TO ENSURE BROAD USABILITY AMONG CULTURALLY- DIVERSE PARTICIPANTS INCLUDING THOSE WITH LOW ENGLISH LITERACY THROUGH PARTICIPATORY DESIGN SESSIONS AND LARGE- SCALE ONLINE DATA COLLECTION. ACROSS AIMS, THE PROJECT WILL INCORPORATE STRUCTURED AND ETHICAL RETURN OF INDIVIDUAL RESULTS TO PATIENTS, CLINICIANS, AND VOLUNTEERS TO ENHANCE THE POTENTIAL FOR CLINICAL INTEGRATION AND SUPPORT ENGAGEMENT AND TRUST AMONG DIVERSE PERSPECTIVES. THIS PROJECT IS SIGNIFICANT AS IT WILL IMPROVE RISK STRATIFICATION, ALLOWING RESOURCES TO BE DIRECTED TO THOSE MOST IN NEED AND DURING RISK PERIODS WHEN TIMELY INTERVENTION CAN MOST IMPROVE CLINICAL OUTCOMES. SUCCESSFUL COMPLETION OF THE AIMS WILL CREATE LOW-COST AND SCALABLE COGNITIVE PREDICTION TOOLS THAT CAN BE WIDELY DISSEMINATED (AS PART OF EXISTING DISSEMINATION INFRASTRUCTURE) FOR SCREENING AND PERSONALIZED PREDICTION ACROSS CLINICAL SETTINGS AND IN DIVERSE POPULATIONS.

EINSTEIN-MONTEFIORE CLINICAL AND TRANSLATIONAL SCIENCE AWARD HUB - THE HAROLD AND MURIEL BLOCK INSTITUTE FOR CLINICAL AND TRANSLATIONAL RESEARCH (ICTR) AT THE ALBERT EINSTEIN COLLEGE OF MEDICINE AND MONTEFIORE MEDICAL CENTER SERVES AS THE HOME OF OUR CTSA PROGRAM. THE VISION OF THE ICTR IS TO IMPROVE THE HEALTH OF THE BRONX, AND OTHER COMMUNITIES THAT DISPROPORTIONATELY AND UNJUSTLY SUFFER FROM POOR HEATH AND PREMATURE DEATH, BY ACCELERATING THE TRANSLATION OF BIOMEDICAL DISCOVERIES INTO EFFECTIVE AND SUSTAINABLE DISEASE PREVENTION AND TREATMENT STRATEGIES. CREATED IN 2007, THE ICTR HAS TRANSFORMED CLINICAL AND TRANSLATIONAL RESEARCH (CTR) THROUGHOUT EINSTEIN AND MONTEFIORE BY CREATING A ROBUST RESEARCH ENVIRONMENT; RE- ENGINEERING CTR PROCESSES; INTEGRATING RESEARCH AND HEALTHCARE; AND DEVELOPING STRONG COMMUNITY RELATIONSHIPS. THE ICTR THEME OF “BUILDING BRIDGES IN THE BRONX AND BEYOND” UNDERSCORES THE IMPORTANCE OF BRIDGING GAPS BETWEEN OUR RESEARCHERS, HEALTH SYSTEM LEADERS, CLINICIANS, PATIENTS, COMMUNITIES, AND CTSA PARTNERS TO ADVANCE TRANSLATIONAL SCIENCE AND HEALTH EQUITY. THE SPECIFIC AIMS OF THE ICTR ARE TO: (1) CATALYZE INNOVATIONS THAT WILL ENHANCE THE EFFICIENCY AND EFFECTIVENESS OF TRANSLATIONAL RESEARCH. WE WILL SUPPORT AND FUND STUDIES WITH HIGH POTENTIAL TO OVERCOME MAJOR CTR ROADBLOCKS AND HEALTH INEQUITIES; CREATE METHODOLOGICAL AND INFORMATICS TRANSLATIONAL SCIENCE INNOVATIONS; IMPROVE CTR OPERATIONS, AND ENHANCE DISSEMINATION AND IMPLEMENTATION STRATEGIES. (2) ENGAGE COMMUNITIES, PATIENTS, AND OTHER PARTNERS EARLY AND THROUGHOUT THE TRANSLATIONAL PROCESS. OUR NEW COMMUNITY AND STAKEHOLDER ENGAGEMENT RESEARCH MODULE WILL TRANSFORM OUR LEARNING HEALTH SYSTEM INTO A “LEARNING HEALTH RESEARCH COMMUNITY”; PROMOTE ACTIVE AND CONTINUOUS BIDIRECTIONAL COMMUNICATION WITH COMMUNITIES, PATIENTS AND OTHER PARTNERS; FACILITATE RESEARCH TO IDENTIFY AND MITIGATE SOCIAL DETERMINANTS OF HEALTH, AND ENHANCE UPTAKE OF EVIDENCE-BASED PROGRAMS BY TARGET POPULATIONS. (3) DEVELOP AND IMPLEMENT STATE-OF-THE-ART CLINICAL RESEARCH AND INFORMATICS RESOURCES AND SERVICES TO IMPROVE THE RIGOR, SAFETY, EFFICIENCY, EFFECTIVENESS, AND GENERALIZABILITY OF CTR. (4) TRAIN, DEVELOP, AND MAINTAIN A SKILLED, MULTIDISCIPLINARY, AND DIVERSE TRANSLATIONAL WORKFORCE TO SUPPORT AND LEAD HIGH QUALITY RESEARCH WITH NEW TRAINING AND PATHWAY PROGRAMS TO ENSURE MEMBERS OF HISTORICALLY EXCLUDED GROUPS ENGAGE IN CTR AND BECOME RESEARCH LEADERS. (5) PARTNER WITH OTHER CTSA HUBS AND THE CTSA CONSORTIUM TO ACCELERATE CTR AND RAPIDLY RESPOND TO URGENT PUBLIC HEALTH NEEDS. OUR AIMS ARE ALIGNED WITH THE NEW CTSA PROGRAM GOALS AND WILL ENABLE THE ICTR TO MAXIMALLY CONTRIBUTE TO THE COLLECTIVE EFFORTS OF THE NATIONAL COLLABORATIVE CTSA CONSORTIUM TO DELIVER MORE TREATMENTS TO MORE PATIENTS MORE QUICKLY IN THE BRONX AND BEYOND.

DEVELOPMENTAL IMPACT OF NICU EXPOSURES (DINE)

GENETIC BASIS OF SYNDROMIC AND NON-SYNDROMIC CONGENTIAL HEART DEFECTS

LIVER PATHOBIOLOGY AND GENE THERAPY RESEARCH CORE CENTER

INTEGRATED CARE FOR CHRONIC PAIN AND OPIOID USE DISORDER: THE IMPOWR RESEARCH CENTER AT MONTEFIORE/EINSTEIN (IMPOWR-ME) - ABSTRACT CHRONIC PAIN (CP) AND OPIOID USE DISORDER (OUD) ARE LEADING CAUSES OF MORBIDITY AND MORTALITY IN THE UNITED STATES. DESPITE BEING COMMONLY COMORBID, THERE IS A STRIKING LACK OF INTEGRATED TREATMENTS ACCESSIBLE TO PEOPLE IN NEED. THIS IS PARTICULARLY TRUE FOR BLACK AND HISPANIC INDIVIDUALS LIVING AND SEEKING CARE IN UNDER-RESOURCED SETTINGS LIKE THE BRONX, NY, ONE OF THE POOREST AND MOST RACIALLY DIVERSE COUNTIES IN THE U.S. SUBMITTED IN RESPONSE TO THE HEAL INITIATIVE: INTEGRATIVE MANAGEMENT OF CHRONIC PAIN AND OUD FOR WHOLE RECOVERY (IMPOWR) RFA-DA-21-030, THE OVERALL GOAL OF THIS PROPOSAL IS TO CREATE THE IMPOWR RESEARCH CENTER AT MONTEFIORE/EINSTEIN (“IMPOWR-ME”), IN THE HIGH-IMPACT COUNTY OF THE BRONX NY. IMPOWR-ME IS A SYNERGISTIC MULTIDISCIPLINARY RESEARCH CENTER THAT LEVERAGES EXCEPTIONAL RESEARCH INFRASTRUCTURE IN CP AND OUD AND EXISTING RELATIONSHIPS WITH PEOPLE LIVING WITH CP AND OUD, ADVOCATES, POLICYMAKERS AND PAYERS, AND HEALTH SYSTEM STAKEHOLDERS. THE AIMS OF IMPOWR-ME ARE TO: 1) CREATE A ROBUST AND SUSTAINABLE RESEARCH INFRASTRUCTURE TO RIGOROUSLY TEST AND DISSEMINATE INTEGRATED AND COST-EFFECTIVE EVIDENCE-BASED PRACTICES FOR PEOPLE WITH CP AND OUD; 2) PARTNER WITH PEOPLE WITH LIVED EXPERIENCE WITH CP, OUD, OR BOTH, AND DIVERSE STAKEHOLDERS IN ALL STAGES OF THE RESEARCH; AND 3) PROVIDE OPPORTUNITIES FOR MULTIDISCIPLINARY EARLY STAGE INVESTIGATORS TO BECOME INDEPENDENT RESEARCHERS FOCUSING ON CP AND OUD. THREE INNOVATIVE HYBRID TYPE 1 EFFECTIVENESS-IMPLEMENTATION TRIALS ARE PROPOSED TO RIGOROUSLY EXAMINE MULTI-MODAL EVIDENCE-BASED PRACTICES IN DIVERSE HEALTH CARE SETTINGS AND POPULATIONS OF PEOPLE WITH COMORBID CP AND OUD. SPECIFICALLY, WE PROPOSE: 1) A THREE-ARM TRIAL OF YOGA AND PHYSICAL THERAPY ONSITE AT METHADONE OPIOID TREATMENT PROGRAMS, 2) A 2X2 FACTORIAL TRIAL TO TEST ACCEPTANCE AND COMMITMENT THERAPY AND A CARE MANAGEMENT SMARTPHONE APP FOR INDIVIDUALS IN PRIMARY-CARE BASED BUPRENORPHINE TREATMENT, AND 3) A TWO-ARM TRIAL TO TEST MICRODOSING VS. STANDARD INDUCTION OF BUPRENORPHINE FOR HOSPITALIZED PATIENTS. PARTICIPANTS IN ALL PROJECTS HAVE BOTH CP AND OUD OR OPIOID MISUSE, AND SPECIFIC AIMS FOR EACH PROJECT WILL EXAMINE CP, OUD, IMPLEMENTATION, AND COST-EFFECTIVENESS OUTCOMES; ADDITIONAL PATIENT-CENTERED OUTCOMES WILL BE DRIVEN BY PEOPLE WITH LIVED EXPERIENCE. ALL THREE PROJECTS IMPROVE ACCESS TO CARE FOR BLACK AND HISPANIC INDIVIDUALS IN UNDER-RESOURCED SETTINGS BY BRINGING INTEGRATED TREATMENT OF CP AND OUD TO THEM, AND THE INTERVENTIONS HAVE HIGH POTENTIAL FOR DISSEMINATION AND SUSTAINABILITY. AN INNOVATIVE PROGRAM FOR PILOT STUDIES ACHIEVES A DUAL AIM OF CATALYZING STAKEHOLDER-DRIVEN RESEARCH AND TRAINING EARLY STAGE AND NEW INVESTIGATORS. AN EXCEPTIONAL TEAM OF INVESTIGATORS AND CLINICAL EXPERTS FOCUSED ON CP AND OUD, A LONGSTANDING HISTORY OF COLLABORATION WITH STAKEHOLDERS AND PEOPLE WITH LIVED EXPERIENCE, AND A HIGH-IMPACT POPULATION MAKE MONTEFIORE-EINSTEIN AN IDEAL SITE FOR AN IMPOWR RESEARCH CENTER.

DIABETES RESEARCH AND TRAINING CENTER

STEM CELL-BASED THERAPIES FOR MITIGATION OF ACUTE RADIATION SYNDROMES

DRUG AT THE RIGHT PLACE & CONCENTRATION: OPTIMIZING COMBINATION VAGINAL RING PR*

MOLECULAR ANALYSIS OF TUBERCULOSIS IMMUNITY

TRANSLATIONAL PLATFORM FOR EPILEPSY THERAPY AND BIOMARKER DISCOVERY - PROJECT SUMMARY THERE IS CURRENTLY NO VALIDATED TREATMENT TO PREVENT THE DEVELOPMENT OF ACQUIRED EPILEPSIES, SUCH AS POST- TRAUMATIC EPILEPSY. THE AVAILABILITY OF BIOMARKER THAT PREDICTS, AT AN EARLY STAGE, PEOPLE AT RISK TO DEVELOP EPILEPSY AND BENEFIT FROM TREATMENT INTERVENTIONS WOULD SIGNIFICANTLY ACCELERATE AND DE-RISK THE PROCESS OF IDENTIFYING AN ANTIEPILEPTOGENIC THERAPY. IN THIS STUDY, THAT IS BASED ON COLLABORATIONS AND PRELIMINARY DATA DERIVED FROM EPIBIOS4RX, AN NINDS FUNDED CENTER WITHOUT WALLS, WE AIM TO CREATE A RIGOROUS AND EFFECTIVE PRECLINICAL MODEL TO SCREEN A NEW CANDIDATE TREATMENT TO PREVENT POSTTRAUMATIC EPILEPSY IN THE LATERAL FLUID PERCUSSION INJURY MODEL AS WELL AS IDENTIFY BIOMARKERS TO GUIDE TREATMENT IMPLEMENTATION. WE WILL FOLLOW A MULTICENTER, DOUBLE-BLINDED, VEHICLE-CONTROLLED, RANDOMIZED PRECLINICAL ANTIEPILEPTOGENESIS STUDY FOLLOWING THE HIGH STANDARDS OF RIGOR ADVOCATED BY NINDS, THE AES/ILAE TRANSLATIONAL RESEARCH TASK FORCE AND THE ARRIVE GUIDELINES. WE HAVE FORMED A COLLABORATIVE GROUP OF FOUR INTERNATIONAL PRECLINICAL TESTING CENTERS (ALBERT EINSTEIN COLLEGE OF MEDICINE, UNIVERSITY OF MELBOURNE, TWO UCLA SITES), SUPPORTED BY EXPERTS IN PHARMACOKINETIC MODELING (UNIVERSITY OF MINNESOTA), PROTEIN BIOMARKER RESEARCH (UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SERVICES) AND BIOINFORMATICS (UNIVERSITY OF SOUTHERN CALIFORNIA). WE PLAN TO TEST A COMPOUND THAT REMOVES PATHOLOGICAL IRON STORES FROM THE BRAIN AND TEST WHETHER IT CAN MODIFY EARLY BIOMARKERS OF EPILEPTOGENESIS AND INJURY. WE AIM TO IDENTIFY (A) AT LEAST ONE PANEL OF MULTIMODAL BIOMARKERS THAT CAN PREDICT EARLY ON TREATMENT RESPONSE TO THE IRON CHELATOR, INCLUDING THE DEVELOPMENT OF POST-TRAUMATIC EPILEPTOGENESIS, (B) AT LEAST ONE BIOMARKER OF EPILEPTOGENESIS, (C) AND DETERMINE WHETHER IRON CHELATOR TREATMENT CAN PREVENT POST-TRAUMATIC EPILEPSY DEVELOPMENT.

MECHANISMS AND MODULATION OF ACCELLULAR HBA TOXICITY

EINSTEIN'S NATHAN SHOCK CENTER OF EXCELLENCE IN BASIC BIOLOGY OF AGING

CENTER FOR AIDS RESEARCH (CFAR)

INTRAVAGINAL RING DELIVERY OF SAFE & EFFECTIVE MICROBICIDES TO PREVENT HIV & HSV

TRAINING PROGRAM IN CELLULAR AND MOLECULAR BIOLOGY AND GENETICS

TRANSITION STATE ANALYSIS OF ENZYMATIC REACTIONS

THE BIOLOGY OF LUNG METASTASIS IN BREAST CANCER - METASTASIS IS THE MAJOR CAUSE OF MORTALITY IN HUMAN BREAST CANCER. THE MECHANISMS BY WHICH THE PRIMARY TUMOR MICROENVIRONMENT PROMOTES THE INVASION AND INTRAVASATION OF TUMOR CELLS HAS BEEN EXTENSIVELY STUDIED. IN CONTRAST, THE MECHANISMS REGULATING EXTRAVASATION OF BLOOD-BORNE TUMOR CELLS AT DISTAL SITES, THEIR SURVIVAL AND PROLIFERATION IN THEIR NEW MICROENVIRONMENT, AND THEIR RE-DISSEMINATION TO ADDITIONAL SITES, ARE LESS STUDIED AND NOT WELL UNDERSTOOD. THEREFORE, THE INVESTIGATION OF THE MECHANISMS THAT REGULATE BREAST CANCER CELLS AT THE METASTATIC SITE ARE AN AREA OF INTENSE SCIENTIFIC INTEREST WITH IMPORTANT CLINICAL APPLICATIONS. CTCS EFFICIENTLY DISSEMINATE THROUGHOUT THE BODY BUT FORM METASTASES WITH LOW FREQUENCY. THE CTCS THAT SUCCESSFULLY EXTRAVASATE, SURVIVE AND GROW AT DISTAL SITES HAVE ACQUIRED STEM-LIKE CHARACTERISTICS THAT PROMOTE THESE PROCESSES. THE ACQUISITION OF STEM-LIKE PROPERTIES IS CLOSELY LINKED TO THE EPITHELIAL-MESENCHYMAL TRANSITION (EMT). THUS, THE TRANSCRIPTIONAL CONTROL OF STEMNESS AND EMT IS AN IMPORTANT REGULATOR OF METASTATIC EFFICIENCY. STEMNESS AND/OR EMT IS INDUCED BY METABOLIC, HYPOXIC AND REDOX STRESS, AS WELL AS BY INTERACTIONS WITH MACROPHAGES AND PLATELETS. UNDERSTANDING THE REGULATION OF TUMOR CELL STEMNESS BY STROMAL CELLS COULD LEAD TO THE IDENTIFICATION OF NOVEL THERAPEUTIC TARGETS FOR THE TREATMENT OF METASTATIC DISEASE. PREVIOUS STUDIES ON THE ROLE OF STEMNESS IN METASTASIS TO DISTAL SITES HAS BEEN SIGNIFICANTLY LIMITED BY THE ANALYTIC METHODS USED. WE HAVE DEVELOPED GROUND-BREAKING NEW TECHNIQUES THAT ALLOW US TO DIRECTLY INTERROGATE THE RELATIONSHIP BETWEEN STEMNESS AND THE EFFICIENCY OF EXTRAVASATION, SURVIVAL AND GROWTH IN VIVO. OUR NOVEL IMAGING METHODS COMBINE THE USE OF A PERMANENT LUNG IMAGING WINDOW COMPATIBLE WITH MULTIPHOTON MICROSCOPY, NOVEL COMPUTATIONAL RECONSTRUCTIONS OF LARGE FIELDS OF VIEW, AND NEWLY DEVELOPED BIOSENSORS THAT REPORT ON THE INDUCTION OF STEMNESS, HYPOXIA AND ROS. THESE TOOLS ALLOW THE VISUALIZATION AND ANALYSIS OF BREAST CANCER CELLS AS THEY EXTRAVASATE AND FORM METASTATIC COLONIES IN THE LUNG. IN CONTRAST, TRADITIONAL END-POINT ANALYSES OF FIXED TISSUES CANNOT PROVIDE INFORMATION ON THE ROLE OF STEMNESS DURING EXTRAVASATION AND METASTATIC GROWTH. THIS PROGRAM PROJECT IS ORGANIZED AROUND THREE MAJOR QUESTIONS. FIRST, WE WILL DEFINE THE SIGNALING PATHWAYS THAT REGULATE BREAST CANCER CELLS IN THE LUNG METASTATIC NICHE. SECOND, WE WILL EXPLORE THE INDUCTION OF STEM-LIKE PROPERTIES IN TUMOR CELLS BY INTERACTIONS WITH STROMAL CELLS, AS A CRITICAL REGULATOR OF EXTRAVASATION AND SUBSEQUENT METASTATIC GROWTH IN THE LUNG. THIRD, WE WILL PURSUE NOVEL PRELIMINARY DATA ON THE EFFECTS OF CHEMOTHERAPY IN THE METASTATIC SITE. TAKING ADVANTAGE OF IMPORTANT SYNERGIES BETWEEN THE PROJECTS AND INNOVATIVE METHODOLOGICAL ADVANCES BY THE CORES, THIS PPG IS WELL-POSITIONED TO MAKE GROUND-BREAKING CONTRIBUTIONS TO OUR UNDERSTANDING OF CTC EXTRAVASATION AND GROW IN THE LUNG, AS WELL AS THEIR RE-DISSEMINATE TO TERTIARY SITES. THESE STUDIES WILL PROVIDE PARADIGM-SHIFTING INSIGHTS INTO THE BIOLOGY OF METASTASIS, WITH IMPORTANT IMPLICATIONS FOR THE CLINICAL TREATMENT OF SYSTEMIC METASTATIC DISEASE IN BREAST CANCER.

PAX6 AS A KEY REGULATOR OF LENS DEVELOPMENT

CONSEQUENCES OF PROLONGED FEBRILE SEIZURES IN CHILDHOOD

CENTER FOR CAENORHABDITIS ELEGANS ANATOMY

EINSTEIN STEM CELL RESEARCH INSTITUTE

DNA REPLICATION INITIATION SITES IN MAMMALIAN CELLS

HEALTHY START INITIATIVE-ELIMINATING RACIAL/ETHNIC DISPARITIES

TRANSCRIPTIONAL CONTROL OF THE MOUSE AA-CRYSTALLIN LOCUS

TRANSITIONING EARLY CAREER NEUROSURGEONS TO SCIENTIFIC INDEPENDENCE

MOLECULAR ANALYSIS OF ALPHAVIRUS MEMBRANE FUSION PROTEIN

PAUL CALABRESIS CAREER DEVELOPMENT AWARD FOR CLINICAL ONCOLOGY

CHEMOKINES IN HEALING MYOCARDIAL INFARCTS

PROTEIN RNA REARRANGEMENTS IN THE SPLICEOSOME

RESOLUTION OF INFLAMMATION IN HEALING MYOCARDIAL INFARCTS

PASOS: PERIPHERAL ARTERY DISEASE STUDY OF SOL. AN ANCILLARY STUDY OF THE HISPANIC COMMUNITY HEALTH STUDY/STUDY OF LATINOS

MECHANISM OF ACTIN MRNA LOCALIZATION AND LOCALIZED TRANSLATION IN NEURONS

BRONX EINSTEIN TRAINING IN TEACHING AND RESEARCH (BETTR)

MECHANISMS OF METHYLMERCURY INDUCED NEURONAL TOXICITY

MECHANISMS OF STRESS-ENHANCED AVERSIVE CONDITIONING

THE BIOLOGICAL UNDERPINNINGS OF MOTORIC COGNITIVE RISK SYNDROME: A MULTI-CENTER STUDY

LIVER CELL MEMBRANE PROTEIN-EXPRESSION AND FUNCTION

ADHESION MECHANISMS MEDIATING SICKLE CELL VASOOCCLUSION IN VIVO

LSDS:A PILOT NBS AND EXAMINATION OF THE ASSOCIATED ETHICAL LEGAL & SOCIAL ISSUES

MEDICAL SCIENTIST TRAINING PROGRAM - PROJECT SUMMARY THE MISSION OF THE ALBERT EINSTEIN COLLEGE OF MEDICINE MEDICAL SCIENTIST TRAINING PROGRAM (MSTP) IS TO TRAIN PHYSICIAN-SCIENTISTS WHO WILL BECOME LEADERS IN BIOMEDICAL RESEARCH TO UNDERSTAND, DETECT, TREAT, AND PREVENT HUMAN DISEASE. TO ACCOMPLISH THIS MISSION, WE HAVE THREE GOALS, 1) TO RECRUIT A DIVERSE GROUP OF STUDENTS WITH OUTSTANDING POTENTIAL TO BECOME RESEARCH-ACTIVE PHYSICIAN-SCIENTISTS, 2) TO PROVIDE TRAINING IN AN INCLUSIVE, SAFE, AND STIMULATING LEARNING ENVIRONMENT WHERE STUDENTS CAN ACQUIRE THE FOUNDATIONAL KNOWLEDGE AND THE TECHNICAL, OPERATIONAL, AND PROFESSIONAL SKILLS NECESSARY TO PURSUE A CAREER AS A RESEARCH-ACTIVE PHYSICIAN- SCIENTIST AND A LEADER IN ACADEMIC MEDICINE AND/OR BIOMEDICAL RESEARCH, AND 3) TO SUPPORT/FACILITATE THEIR PROFESSIONAL DEVELOPMENT TO TRANSITION TO THE NEXT STAGE IN THE TRAINING CONTINUUM. THROUGH A HOLISTIC ADMISSIONS PROCESS, WE SEEK TO IDENTIFY INDIVIDUALS WITH THE INTELLIGENCE, CURIOSITY, CREATIVITY, RESILIENCE, PERSEVERENCE, AND ENTHUSIAM FOR SCIENCE THAT IS ESSENTIAL FOR A SUCCESSFUL RESEARCH CAREER. WE GUIDE THE STUDENTS THROUGH A PROGRAM TAILORED TO MEET THEIR INDIVIDUAL NEEDS AND INTERESTS. THE PROGRAM PROVIDES RIGOROUS, INTEGRATED MEDICAL AND RESEARCH TRAINING THROUGH A FLEXIBLE, CONTINOUSLY EVOLVING CURRICULUM THAT INCLUDES 1) SPECIALIZED MSTP COURSES, AND 2) INTEGRATION OF GRADUATE AND MEDICAL SCHOOL CURRICULUM IN THE FIRST 2 YEARS AND THROUGHOUT THE PROGRAM. THE TRAINING PROGRAM HAS 3 PHASES. IN THE FIRST 2 YEARS STUDENTS TAKE A COMBINATION OF MEDICAL, GRADUATE, AND MSTP-SPECIFIC COURSES TO GAIN THE DIDACTIC FOUNDATION FOR THEIR RESEACH AND CLINICAL TRAINING. RESEARCH ROTATIONS AND GUIDANCE FROM PROGRAM LEADERSHIP ASSIST THEM IN THESIS LAB SELECTION. IN THE PROGRAM’S 2ND PHASE, STUDENTS PERFORM INDEPENDENT, ORIGINAL RESEARCH UNDER THEIR MENTOR’S GUIDANCE. THEY PUBLISH THEIR DISCOVERIES IN HIGH QUALITY, PEER-REVIEWED PAPERS, AND PREPARE AND DEFEND A PHD THESIS. PARTICIPATION IN A PHD PHASE MSTP-RUN, OUTPATIENT CLINIC BUILDS CLINICAL SKILLS. IN THE FINAL PHASE, THEY COMPLETE THEIR CLINICAL TRAINING. A MULTIFACETED APPROACH TRAINS STUDENTS TO PERFORM RIGOROUS AND REPRODUCIBLE RESEARCH IN A RESPONSIBLE, ETHICAL MANNER. CURRENTLY, THE PROGRAM HAS 113 TRAINEES, 41% WOMAN, 28% FROM GROUPS UNDERREPRESENTED IN MEDICINE (TWICE PERCENTAGE IN THE APPLICANT POOL), AND 11% WITH DISABILITIES. WE WILL EXPAND TO ~120-130 TRAINEES BY INCREASING THE ENTERING CLASS SIZE TO 16. SINCE ITS INCEPTION IN 1964, AS ONE OF THE FIRST THREE NIH-FUNDED MSTPS, 484 TRAINEES HAVE GRADUATED. 413 HAVE COMPLETED POSTGRADUATE TRAINING AND PUBLISHED OVER 19,000 PAPERS, AN AVERAGE OF ~47 PAPERS/GRADUATE. 74% HAVE JOBS AT ACADEMIC MEDICAL CENTERS, RESEARCH INSTITUTES, NIH OR PHARMACEUTICAL COMPANIES. BY VARIOUS MEASURES, THE GRADUATES HAVE ACHIEVED OUTSTANDING SUCCESS AND ADVANCED BIOMEDICAL RESEARCH AND ACADEMIC MEDICINE. WE PROPOSE TO FURTHER INTEGRATE GRADUATE AND MEDICAL TRAINING, AND INCREASE OPPORTUNITIES FOR INVOLVEMENT IN CLINICAL AND TRANSLATIONAL RESEARCH TO PREPARE A FUTURE GENERATION OF PHYSICIAN-SCIENTISTS WHO WILL BE AT THE LEADING EDGE OF BIOMEDICAL RESEARCH WITH THE ULTIMATE GOAL OF IMPROVING HUMAN HEALTH AND REDUCING THE BURDEN OF DISEASE.

ROLE OF GENES IN EXCEPTIONAL LONGEVITY IN HUMANS

EFFECT OF BUPRENORPHINE ON MONOCYTES IN THE CONTEXT OF NEUROAIDS AND OPIOID ABUSE

NUCLEUS ACCUMBENS PROCESSING OF REWARD-PREDICTIVE CUES

FUNCTIONAL DETERMINANTS OF METASTATIC DORMANCY

NEW YORK REGIONAL CENTER FOR DIABETES TRANSLATION RESEARCH

PLASTICITY OF ELECTRICAL SYNAPSES

EINSTEIN BSL3 LABORATORY RENOVATION TO ADVANCE BIOMEDICAL RESEARCH ON RNA VIRUSES OF PANDEMIC POTENTIAL - ABSTRACT WE PROPOSE TO RENOVATE EXISTING LABORATORY SPACE IN THE CHANIN BUILDING AT THE ALBERT EINSTEIN COLLEGE OF MEDICINE (EINSTEIN) WHICH WILL EXPAND AND IMPROVE AVAILABLE BSL-3 AND ABSL-3 FACILITIES TO SERVE THE GROWING NEEDS OF OUR EINSTEIN INVESTIGATORS WHO CONDUCT RESEARCH ON EMERGING RNA VIRUSES WITH THE ULTIMATE GOAL OF VACCINE AND THERAPEUTICS DEVELOPMENT. OUR CURRENT SMALL VIROLOGY BSL-3 FACILITY LACKS THE SPACE TO MEET CURRENT AND PROJECTED INVESTIGATOR DEMAND AND TO HOUSE THE EQUIPMENT NEEDED TO CONDUCT CUTTING-EDGE IN VITRO AND CELL-BASED STUDIES AND WORK WITH ANIMALS. IN ADDITION TO RENOVATION THAT INCLUDES EXPANDED BSL-3 AND ABSL-3 SPACE (1497 SQ FT SPECIFICALLY FOR RNA VIRUS RESEARCH), OUR PLAN INCLUDES MODERNIZATION OF BUILDING SYSTEMS AND INVESTMENTS IN FIXED EQUIPMENT AND NOVEL NONFIXED SCIENTIFIC EQUIPMENT TO ENHANCE AND STREAMLINE LABORATORY OPERATIONS. FURTHER, THE EXISTING BSL-3 SPACE IN CHANIN HAS TEMPERATURE CONTROL SYSTEMS WHICH ARE INADEQUATE AND SORELY IN NEED OF UPDATING; THIS WILL BE ALLEVIATED BY NEW AND INDEPENDENT SYSTEM FOR TEMPERATURE, HUMIDITY AND EXHAUST (DEDICATED AND REDUNDANT). WE THEREFORE REQUEST SUPPORT FOR THE FOLLOWING AIMS, WHICH ARE INTENDED TO EXPAND AND UPGRADE OUR EXISTING FACILITY, WITH NEW TECHNOLOGIES FOR LABORATORY SUPPORT, ANIMAL HOLDING, AND ENERGY EFFICIENCY. IN THE FOLLOWING SECTIONS, WE DESCRIBE AN OVERSIGHT PROCESS THAT WILL FACILITATE ALL ASPECTS OF THE RENOVATION PROCESS. AIM 1. MODERNIZE AND EXPAND OVERALL BSL-3 SPACE IN THE CHANIN BUILDING FOR EMERGING RNA VIRUS RESEARCH. AIM 2. CREATE INFRASTRUCTURE FOR ANIMAL VIRUS STUDIES AT THE BSL-3 LEVEL. AIM 3. FURNISH THE RENOVATED LABORATORY SPACE WITH FIXED EQUIPMENT AND NOVEL NONFIXED SCIENTIFIC EQUIPMENT TO RESULT IN A FULLY EQUIPPED EMERGING RNA VIRUS BSL-3 LABORATORY SPACE. THIS PROPOSAL INCLUDES INSTITUTIONAL SUPPORT TO SIGNIFICANTLY SUPPLEMENT LAB EQUIPMENT FOR THIS PROJECT, ENSURE ONGOING MAINTENANCE OF ALL EQUIPMENT AND INFRASTRUCTURE IMPROVEMENTS, AND PROVIDE NEEDED PERSONNEL SUPPORT. FINALLY, EINSTEIN IS COMMITTING PILOT FUNDING TO ENABLE MORE INVESTIGATORS TO UTILIZE THE NEW FACILITY AND OBTAIN DATA TO SUPPORT GRANT APPLICATIONS TO FUND STUDIES ON RNA VIRUSES WITH PANDEMIC POTENTIAL.

ROLE OF HEPATIC FAT METABOLISM IN GLUCOSE EFFECTIVENESS

TRAINING IN AGING RESEARCH

CENTER FOR THE STUDY OF REPRODUCTIVE BIOLOGY AND WOMEN'S HEALTH

ROLE OF CELLULAR FACTORS IN RETROVIRAL UNCOATING AND SYNTHESIS OF VIRAL DNA

MECHANISMS MEDIATING STEM/PROGENITOR CELL MOBILIZATION FROM BONE MARROW

ADOLESCENT MEDICINE TRIALS UNIT

NEUROTROPIC HERPESVIRUS ENVELOPMENT AND MICROTUBULE-MEDIATED TRANSPORT

CLINICAL GRADE CULTURED RARE RED BLOOD CELLS AS REAGENTS AND FUTURE TRANSFUSION SUPPORT

POST-DPP FOLLOW-UP STUDY

MOLECULAR MARKERS OF RISK OF SUBSEQUENT INVASIVE BREAST CANCER IN WOMEN WTH DUCTAL CARCINOMA IN SITU

BINDING AND PRESENTATION OF LIPID ANTIGENS BY CD1

VALIDATION OF THE REMOTE COGNITIVE AGING AND ALZHEIMER?S DISEASE RESEARCH (R-CARE) TOOLBOX FOR DIVERSE POPULATIONS - ABSTRACT IN-PERSON ADMINISTRATION IS THE CURRENT “GOLD-STANDARD” FOR ASSESSMENT OF COGNITION AND FUNCTION IN STUDIES OF ALZHEIMER’S DISEASE AND OTHER DEMENTIA (ADRD). REMOTE NEUROPSYCHOLOGICAL ASSESSMENT HAS BEEN ADVOCATED TO OVERCOME VARIOUS ACCESS BARRIERS AND DECREASE COSTS OF NEUROPSYCHOLOGICAL SERVICES. MOREOVER, DUE TO THE PRESSING CHALLENGES AND SAFETY CONCERNS IMPOSED BY THE COVID-19 PANDEMIC, THERE IS AN URGENT NEED FOR ROBUST METHODS FOR ASSESSING AND MONITORING COGNITIVE AND FUNCTIONAL STATUS THROUGH REMOTE ASSESSMENTS. THE OVERALL GOAL OF THE CURRENT PROJECT IS TO VALIDATE, REFINE, AND CALIBRATE THE REMOTE COGNITIVE AGING AND ALZHEIMER’S DISEASE RESEARCH (R-CARE) TOOLBOX FOR THE ASSESSMENT AND MONITORING OF COGNITION AND FUNCTION IN A DIVERSE SAMPLE OF INITIALLY DEMENTIA-FREE OLDER ADULTS. THE TOOLBOX WILL INCLUDE MEASURES FROM THE UNIFORM DATA SET, NEUROPSYCHOLOGICAL BATTERY (UDSNB-3.0), COMPLEMENTED BY FREQUENTLY USED TESTS IN PRECLINICAL AD TRIALS. IN-PERSON TESTS THAT POSE CHALLENGES FOR REMOTE ADMINISTRATION WILL BE REPLACED WITH TABLET-BASED COMPUTERIZED TASKS. WE WILL RECRUIT 600 DEMENTIA-FREE, RACIALLY/ETHNICALLY DIVERSE (~ 1/3 NON-HISPANIC BLACK, 1/3 HISPANIC, AND 1/3 NON- HISPANIC WHITE), COMMUNITY-RESIDING PARTICIPANTS AGED =65 YEARS. A RANDOMIZED, COUNTERBALANCED DESIGN WILL BE USED TO ADMINISTER A COMPREHENSIVE CLINICAL AND COGNITIVE BATTERY ACROSS BOTH ASSESSMENT MODES (IN-PERSON VS. REMOTE) SEPARATED BY 2-6 WEEKS AT BASELINE, WITH FOLLOW UP VISITS AT 18 AND 36 MONTHS. DIGITAL BIOMARKERS (COMPUTERIZED TESTS AND SPEECH-BASED) AND ADRD BLOOD-BASED BIOMARKERS WILL BE COLLECTED. AIM 1: TO EVALUATE THE PSYCHOMETRIC PROPERTIES OF REMOTE COGNITIVE TESTS AND ASSESS THEIR VALIDITY AGAINST STANDARD IN-PERSON TESTS. AIM 2: TO EVALUATE COMPARABILITY OF LONGITUDINAL CHANGE IN GLOBAL COGNITION AND WITHIN COGNITIVE DOMAINS ACROSS MODES OF ASSESSMENT (IN-PERSON VS REMOTE) FOR THE WHOLE SAMPLE AS WELL AS SUBGROUPS DEFINED BY SEX AND RACE/ETHNICITY. AIM 3 (EXPLORATORY): TO IDENTIFY NOVEL DIGITAL BIOMARKERS THAT PROVIDE INCREMENTAL VALIDITY FOR DIFFERENTIATING CLINICAL AND PATHOLOGICAL DISEASE STAGES, AND FOR MEASURING AND PREDICTING COGNITIVE AND FUNCTIONAL DECLINE. COLLECTIVELY, THIS STUDY WILL VALIDATE REMOTELY ADMINISTERED TESTS ACROSS DIFFERENT COGNITIVE DOMAINS, PROVIDE EVIDENCE FOR CROSS-SECTIONAL AND LONGITUDINAL VALIDITY, AND PROVIDE NORMATIVE DATA FOR REMOTE TESTS IN DIVERSE POPULATIONS. OUR LONG-TERM GOAL IS TO DEVELOP AN OPEN-SOURCE, RELIABLE AND VALID TOOLBOX THAT WOULD ENABLE AD-RESEARCHERS AND CLINICIANS TO EVALUATE OLDER ADULTS FROM DIVERSE BACKGROUNDS REGARDLESS OF ABILITY TO ATTEND IN-PERSON VISITS. 1

INTERDISCIPLINARY LEADERSHIP TRAINING IN NEURODEV AND RELATED DISABILITIES

CODING OF AUDITORY SPACE IN THE AVIAN BRAIN

NOVEL REPORTER PHAGES TO DETECT COMPLEX TB DRUG RESISTANCE AND PERSISTENCE

ROLE OF HYPOTHALAMIC IKK-BETA/NF-KAPPAB IN NUTRITIONAL CONTROL OF AGING

RESILIENCE TO ALZHEIMER'S DISEASE IN HUMANS WITH EXCEPTIONAL LONGEVITY

A "TROJAN HORSE" BISPECIFIC ANTIBODY STRATEGY FOR BROAD FILOVIRUS THERAPEUTICS

SUPPORT FOR THE ROSE F. KENNEDY IDDRC

THE MEDIATOR COMPLEX IN THE COORDINATE REGULATION OF LIPOGENIC GENE EXPRESSION

CORTICO-HIPPOCAMPAL MECHANISMS OF CONTEXT MEMORY

ENDOSOMAL-LYSOSOMAL FUNCTION IN NEURONAL STORAGE DISEASE

BACTERIAL N-ACETYLTRANSFERASES: RESISTANCE TO REGULATION

GENETIC ANALYSIS OF THE P13K/AKT PATHWAY IN THYROID BENIGN AND MALIGNANT DISEASE

VACCINES FOR EXTENSIVELY DRUG RESISTANT TUBERCULOSIS

PERSISTENT HPV IN WOMEN AT RISK FOR CERVIX CANCER

MOLECULAR GENETIC ANALYSIS OF MYCOBACTERIUM TUBERCULOSIS

GENERATION OF A COMPLETE SET OF PRECISE NULL BAR-CODED DELETION MUTANTS OF MYCOBACTERIUM TUBERCULOSIS

CONTROL OF VESICULAR TRAFFICKING IN THE HEPATOCYTE.

A SYSTEMS BIOLOGY APPROACH TO THE MODEL APICOMPLEXAN TOXOPLASMA GONDII

MECHANISM OF MICROTUBULE DYNAMICS REGULATION BY KINESINS

ATOMS-TO-ANIMALS: STRUCTURAL GENOMICS OF IMMUNITY

CLINICAL AND TRANSLATIONAL SCIENCE AWARD (UL1)

SUPPORT FOR THE ROSE F. KENNEDY IDD RESEARCH CENTER

MOLECULAR GENETIC ANALYSIS OF MYCOBACTERIUM TUBERCULOSIS

EPIDEMIOLOGIC DETERMINANT OF CARDIAC STRUCTURE AND FUNCTION AMONG HISPANICS

BRONX CENTER TO REDUCE AND ELIMINATE ETHNIC AND RACIAL HEALTH DISPARITIES

ENHANCING PATHOGEN-SPECIFIC MEMORY CD8+ T CELL RESPONSES IN VIVO

VASCULAR DETERMINANTS OF STAGE B HF AMONG HISPANICS: THE ROLE OF THE HEART-VASCULAR INTERACTION - PROJECT SUMMARY AORTIC STIFFNESS INCREASES MARKEDLY WITH AGE AND IS ASSOCIATED WITH HYPERTENSION, HEART FAILURE (HF) AND ACCELERATED BRAIN AGING. ABNORMAL HEMODYNAMIC COUPLING BETWEEN LEFT VENTRICLE AND AORTA CONTRIBUTES TO PATHOGENESIS OF TARGET ORGAN DAMAGE, PARTICULARLY HF. HISPANICS/LATINOS HAVE A HIGHER INCIDENCE OF HF COMPARED TO NON-HISPANIC WHITES AND PRESENT YOUNGER WITH HF WITH MORE CO-MORBIDITIES AND A LOWER LEFT VENTRICULAR (LV) EJECTION FRACTION. FURTHERMORE, THE COMMUNITY-BASED ECHOCARDIOGRAPHIC STUDY OF LATINOS (ECHO-SOL [ES]; R01 PI: RODRIGUEZ) HAS FOUND THAT COMPARED TO PUBLISHED ESTIMATES IN NON-HISPANIC WHITES, HISPANICS HAVE A HIGHER HF RISK FACTOR BURDEN, WORSE DIASTOLIC FUNCTION AND LV STIFFNESS THUS SIGNALING HISPANICS AT HIGH RISK FOR HF WITH PRESERVED EF (HFPEF). ECHO-SOL 2 (ES2) (PI: RODRIGUEZ) OBTAINED SERIAL ECHOS SHOWING SIGNIFICANTLY WORSENING OF ECHO PARAMETERS OVER AN AVERAGE OF 4.3 YEARS OF FOLLOW-UP. MECHANISM(S) FOR THE SUSCEPTIBILITY OF HISPANICS TO HF ARE NOT WELL-ACCOUNTED FOR BY STANDARD HF RISK FACTORS. WE HYPOTHESIZE THAT VASCULAR FUNCTION AND VENTRICULAR-ARTERIAL COUPLING SIGNIFICANTLY CONTRIBUTES TO HF PATHOGENESIS AND HF RISK IN HISPANICS. BECAUSE THE HEART AND VASCULATURE ARE INTIMATELY COUPLED, LV STROKE VOLUME DEPENDS ON THE IMPORTANT INTERACTION OF MYOCARDIAL CONTRACTILITY WITH LOADING CONDITIONS FROM ARTERIAL SYSTEM COMPLIANCE. THERE HAS BEEN NO STUDY OF COMPREHENSIVE VASCULAR FUNCTION AND VENTRICULAR- ARTERIAL COUPLING ASSESSMENT CONCOMITANT WITH A DETAILED ECHOCARDIOGRAPHIC EXAM IN HISPANICS. THUS, WE PROPOSE LEVERAGING THE RESOURCES OF HCHS/SOL, ES AND ES2 WITH LONGITUDINAL DATA ON CARDIAC PHENOTYPING AS WELL AS CLINICAL, SOCIOCULTURAL, AND PSYCHOSOCIAL RISK FACTORS TO COMPREHENSIVELY CHARACTERIZE VASCULAR FUNCTION IN ES PARTICIPANTS FOCUSING ON KEY PRIMARY PRESSURE-FLOW PHENOTYPES: CAROTID-FEMORAL PULSE WAVE VELOCITY, CENTRAL PULSE PRESSURE, CHARACTERISTIC IMPEDANCE AND ENDOTHELIAL FUNCTION [FLOW MEDIATED DILATATION / HYPEREMIC BRACHIAL FLOW VELOCITIES] CONCOMITANT WITH A DETAILED ECHOCARDIOGRAPHIC ASSESSMENT INCLUDING 2D, COLOR, SPECTRAL / TISSUE DOPPLER AND SPECKLE TRACKING. OUR APPLICATION IS FOCUSED ON VASCULAR DYSFUNCTION AND ITS INTERACTION / EFFECTS ON THE HEART. IMPAIRED MECHANICAL COUPLING CONTRIBUTES TO COMBINATION OF RIGHT AND LEFT HEART ABNORMALITIES LIMITS CARDIAC OUTPUT AND CONTRIBUTES TO THE STAGE B HF (NOW TERMED PRE-HF) TO SYMPTOMATIC HF, PARTICULARLY HFPEF. OUR GOAL IS TO COMPREHENSIVELY DESCRIBE VASCULAR FUNCTION PRESSURE-FLOW RELATIONS AND ITS DETERMINANTS IN HISPANICS/LATINOS. (AIM 1) THEN, DETERMINE HOW VASCULAR FUNCTION RELATES TO CARDIAC STRUCTURAL AND FUNCTIONAL ABNORMALITIES (INCLUDING MYOCARDIAL STRAIN) TO TEST THE HYPOTHESIS THAT AORTIC STIFFNESS IMPAIRS MECHANICAL COUPLING. (AIM 2) BECAUSE OBTAINING AN ECHO EXAM IS A NATURAL COMPONENT OF OUR PRIMARY FOCUS, WE WILL HAVE THE BENEFIT OF LEVERAGING ~12 YEARS OF EXISTING ES AND ES2 LONGITUDINAL DATA TO IDENTIFY CARDIAC TRAJECTORIES, ASSESS THE DETERMINANTS OF EACH TRAJECTORIES AND THE INDEPENDENT ASSOCIATION WITH OUTCOMES SUCH AS VASCULAR PHENOTYPES OVERALL MORTALITY AND HF. (AIM 3) LASTLY, WE WILL LINK OUR DATASET WITH OTHER NIH-FUNDED COHORTS WITH EXISTING VASCULAR FUNCTION DATA TO PERFORM POOLED COHORT ANALYSES OF VASCULAR FUNCTION OF HISPANICS/LATINOS WITH NON-HISPANIC WHITES AND BLACKS FROM THE FRAMINGHAM HEART STUDY AND JACKSON HEART STUDY RESPECTIVELY, TO IDENTIFY AND ADDRESS VASCULAR DISPARITIES AMONG RACIAL-ETHNIC MINORITIES. (AIM 4) OUR LARGE-SCALE STUDY REPRESENTS AN INNOVATIVE AND COST-EFFECTIVE (LEVERAGING EXISTING RESOURCES) APPROACH TO ADVANCING OUR UNDERSTANDING OF THE VENTRICULAR-VASCULAR INTERACTION ON HF PROGRESSION IN AN UNDERREPRESENTED AND VULNERABLE POPULATION. IDENTIFICATION OF HISPANICS WITH PRE-HF AND ABNORMAL VASCULAR FUNCTION MAY HELP TO DIFFERENTIATE THOSE WHO ARE AT THE HIGHE

THE ROLES OF LIPID METABOLISM IN THE MAINTENANCE OF HEMATOPOIETIC STEM CELLS

SUPPORT FOR THE ROSE F KENNEDY IDDRC P50 - PROJECT SUMMARY/ABSTRACT (OVERALL) THE OVERARCHING PURPOSE OF THE ROSE F. KENNEDY INTELLECTUAL AND DEVELOPMENTAL DISABILITIES RESEARCH CENTER (RFK IDDRC) IS TO IMPROVE THE LIVES OF CHILDREN WITH INTELLECTUAL AND DEVELOPMENTAL DISABILITIES (IDDS). FIFTY- PLUS YEARS OF DISTINGUISHED PROGRESS IN BASIC, TRANSLATIONAL AND CLINICAL RESEARCH AS ONE OF NICHD’S FLAGSHIP IDDRCS, COUPLED WITH IMPORTANT RECENT FACULTY RECRUITMENTS AND AN HISTORIC MERGER BETWEEN THE ALBERT EINSTEIN COLLEGE OF MEDICINE AND ITS UNIVERSITY-AFFILIATED HOSPITAL, MONTEFIORE MEDICAL CENTER, OFFER A SOLID PLATFORM FOR CONTINUING EXCELLENCE IN OUR COMMITMENT TO IDD RESEARCH. THE CENTER’S 4 HIGHLY INTEGRATED SCIENTIFIC CORES CONSIST OF: 1) OUR CLINICAL TRANSLATIONAL CORE KNOWN AS THE HUMAN CLINICAL PHENOTYPING (CORE B, HCP), WHICH SERVES TO FACILITATE BOTH ACCESS TO AND CHARACTERIZATION OF PARTICIPANTS FOR IDD RELEVANT RESEARCH; 2) A NEUROGENOMICS FACILITY (CORE C, NGEN) THAT PROVIDES CUTTING EDGE EPIGENETIC AND GENOMIC PROCESSING AND ANALYSES ON BOTH HUMAN AND ANIMAL TISSUES; 3) A NEURAL CELL ENGINEERING AND IMAGING FACILITY (CORE D, NCEI) THAT PROVIDES STATE-OF-THE-ART APPROACHES TO BRAIN CELL MANIPULATION AND VISUALIZATION; AND 4) AN ANIMAL PHENOTYPING FACILITY (CORE E, AP) FOR EVALUATION OF ANIMAL BEHAVIOR, METABOLISM AND IMAGING IN A MANNER WITH STRONG PARALLELS TO APPROACHES TAKEN IN PATIENTS ACCESSED THROUGH HCP. EACH OF OUR SCIENTIFIC CORES IS CAREFULLY OVERSEEN AND MONITORED BY THE ADMINISTRATIVE CORE (CORE A, ADM), WHICH ALSO SERVES AS THE HEAD GANGLION OF THE ENTIRE IDDRC IN ITS SUBSTANTIAL OUTREACH PROGRAMS TO EINSTEIN/MONTEFIORE, THE BRONX COMMUNITY AS WELL AS NATIONALLY. EACH SCIENTIFIC CORE HAS AN ESSENTIAL CONNECTION TO OUR SIGNATURE RESEARCH PROJECT WHICH BRINGS TOGETHER A MULTIDISCIPLINARY TEAM OF INVESTIGATORS FOCUSED ON MECHANISMS OF IDD IN CHILDREN WITH MUTATIONS IN THE TRANSCRIPTIONAL REGULATOR LYSINE DEMETHYLASE 5C GENE, KDM5C. A CENTRAL FUNCTION OF THE RFK IDDRC IS TO PROMOTE THE SUBSTANTIVE LINKS BETWEEN EINSTEIN RESEARCH LABORATORIES AND CLINICS AT THE CHILDREN'S EVALUATION AND REHABILITATION CENTER (CERC) AND THE CHILDREN’S HOSPITAL AT MONTEFIORE (CHAM). TOGETHER, OUR CORES AND RESEARCH PROJECT FORM A DYNAMIC NETWORK – A COMMUNITY – OF IDD-FOCUSED PROGRAMS AND PRACTICES THAT INTERLINK 18 DIFFERENT ACADEMIC DEPARTMENTS, >100 IDDRC MEMBERS AND 20-PLUS IDD-RELEVANT CLINICS AT EINSTEIN AND MONTEFIORE. THE LATTER INCLUDE 22Q11.2DS, RETT AND WILLIAMS SYNDROMES, TUBEROUS SCLEROSIS, NEUROFIBROMATOSIS, WEST SYNDROME AND INFANTILE SPASMS, AUTISM SPECTRUM DISORDERS, AND A WIDE RANGE OF NEUROMETABOLIC DISORDERS. NEW INITIATIVES MOVING FORWARD AT THIS TIME INCLUDE OUR UNIQUE PRECISION MEDICINE/COMMUNITY OUTREACH PROGRAM WE CALL OPERATION IDD GENE TEAM, OUR GOAL TO FORTIFY TIES WITH OUR EINSTEIN CLINICAL PARTNER (CERC AND ITS AFFILIATED UCEDD AND LEND PROGRAMS) UNDER THE UMBRELLA OF THE ROSE F. KENNEDY CENTER AND A HEIGHTENED FOCUS ON TRAINING THROUGH OUR NEWLY ESTABLISHED T32 FOR IDD POSTDOCTORAL FELLOWS.

EINSTEIN/RWANDA/DRC CONSORTIUM FOR RESEARCH IN HIV/HPV/MALIGNANCIES

THE B7X PATHWAY IN THE TUMOR MICROENVIRONMENT

MOLECULAR MECHANISM OF THE CYTOPLAMIC DYNEIN-DYNACTIN MOTOR COMPLEX

CARRIER MEDIATED ANTIFOLATE TRANSPORT AND RESISTANCE

GEOGRAPHIC MEDICINE AND EMERGING INFECTIONS

BIOCHEMISTRY AND GENETICS OF CHROMATIN ASSEMBLY FACTORS IN DROSOPHILA

INTRACELLULAR SIGNALING BY THE INSULIN RECEPTOR KINASE

KERALA-EINSTEIN STUDY: HEALTHY LIFESTYLE, VASCULAR DISEASE, AND COGNITIVE DECLINE

MECHANISMS UNDERLYING THE HIV-HSV-2 SYNDEMIC

MAPPING AUTOIMMUNE DIABETES AND THYROIDITIS GENES

HPV & CERVIX NEOPLASIA IN A LARGE, LONG-TERM HIV+ COHORT

ROLE OF EXCEPTIONAL LONGEVITY GENOTYPES IN PROTECTION AGAINST FRAILTY IN AGING

MULTICULTURAL HEALTHY DIET TO REDUCE COGNITIVE DECLINE & ALZHEIMER DISEASE RISK

MULTIPLEX IMAGING OF SIGNALING PATHWAYS IN CELL MOTILITY

REST-ACTIVATED PROGRAM OF GENE EXPRESSION IN ISCHEMIA

HEPATIC ORGANIC ANION UPTAKE TRANSPORT

MOLECULAR AND CELLULAR REGULATION OF PRE-LEUKEMIC STEM CELLS AND THEIR THERAPEUTIC TARGETING - ABSTRACT CLINICAL OUTCOME IN MDS AND AML HAS NOT SIGNIFICANTLY IMPROVED OVER THE PAST 50 YEARS AND CURE RATES REMAIN BELOW 15% IN THE MAJORITY OF PATIENTS (~85%) WHICH ARE >55 YEARS OF AGE. FUNDAMENTALLY NOVEL APPROACHES ARE URGENTLY NEEDED TO IMPROVE OUR UNDERSTANDING OF DISEASE PATHOGENESIS AND TO ENABLE MORE EFFECTIVE THERAPEUTIC INTERVENTION. EVIDENCE OVER THE PAST 10 YEARS HAS SHOWN THAT MDS AND AML ARISE FROM PRELEUKEMIC STEM CELLS (PREL-SC), PRECEDING THE FORMATION OF FULLY TRANSFORMED LEUKEMIA STEM CELLS (LSC). RECENT WORK HAS UNCOVERED CONSIDERABLE SUBCLONAL HETEROGENEITY OF PREL-SC IN MDS AND AML AND HAS INDICATED THAT STEM CELL SUBCLONAL COMPLEXITY PLAYS A KEY ROLE IN PATHOGENESIS, PROGRESSION, AND THERAPEUTIC RESISTANCE. HOWEVER, THE MOLECULAR AND CELLULAR MECHANISMS GOVERNING THESE PROCESSES ARE STILL LARGELY UNKNOWN. TRANSCRIPTION FACTORS (TF) HAVE LONG BEEN RECOGNIZED AS CRITICAL REGULATORS OF NORMAL AND MALIGNANT HEMATOPOIESIS. SPECIFICALLY, IN MDS AND AML TRANSCRIPTIONAL DYSREGULATION IS KEY TO CONFER THE PATHOGNOMONIC FEATURES OF CELLULAR DYSPLASIA AND A MYELOID DIFFERENTIATION BLOCK. CELL FATE AND DIFFERENTIATION DECISIONS AS WELL AS THE INDUCTION OF A MYELOID BIAS AT THE STEM CELL AND MULTIPOTENT PROGENITOR LEVEL, WHICH IS ONE OF THE EARLIEST CELLULAR PROPERTIES DETECTED IN PREL-SC, ARE GOVERNED BY TRANSCRIPTION FACTORS. IN ADDITION, OUR RECENT WORK HAS DISCOVERED AN UNEXPECTED DEGREE OF TRANSCRIPTION DYNAMICS AND PLASTICITY IN HEMATOPOIETIC STEM AND PROGENITORS, AND THAT BOTH TRANSCRIPTIONAL PLASTICITY AND TRANSCRIPTIONAL MEMORY ARE DYSREGULATED IN PREL-SC AND LSC. OUR MAJOR RESEARCH QUESTIONS/GOALS ARE TO UNDERSTAND STEM CELL SUBCLONAL DYNAMICS AND THEIR REGULATION IN THE INITIATION AND PROGRESSION OF MDS AND AML, TO IDENTIFY AND STUDY MECHANISMS OF TRANSCRIPTIONAL COOPERATIVITY IN PRE-LEUKEMIC STEM CELLS AND THEIR THERAPEUTIC TARGETING, AND TO STUDY TRANSCRIPTION DYNAMICS AND PRE-LSC FATE DYSREGULATION AT A SINGLE-CELL AND SINGLE-MOLECULE RESOLUTION. TO ACCOMPLISH THESE GOALS WE WILL UTILIZE NOVEL TOOLS FOR STEM CELL SUBCLONAL ANALYSIS IN PATIENTS, AS WELL AS NEWLY DEVELOPED LONGITUDINAL MOUSE GENETIC MODELS OF PREL-SC PROGRESSION TO MDS AND AML. IN ADDITION, WE WILL LEVERAGE RECENT ADVANCES IN OUR ABILITY TO DIRECTLY TARGET KEY TRANSCRIPTION FACTORS BY NOVEL FIRST-IN-CLASS PHARMACOLOGICAL INHIBITORS, AS WELL AS NOVEL EXPERIMENTAL TOOLS FOR THE STUDY OF TRANSCRIPTION DYNAMICS AT A SINGLE-MOLECULE LEVEL IN PRIMARY STEM/PROGENITOR CELLS FROM MURINE MODELS AND PATIENTS. OVERALL, OUR RESEARCH WILL DELINEATE THE MOLECULAR REGULATION OF PRE-CANCEROUS CELL STATES IN MDS AND AML PATHOGENESIS. THIS WILL ENABLE THEIR THERAPEUTIC TARGETING, IN ADDITION TO THE ELIMINATION OF THE FULLY-TRANSFORMED LEUKEMIC CLONES. SUCH AN APPROACH HOLDS THE PROMISE OF ACHIEVING LASTING REMISSIONS AND POTENTIALLY CURE OF MDS AND AML. OUR LONG-TERM VISION IS THAT, ONCE WE UNDERSTAND THE EARLY TRANSFORMATION-INITIATING MECHANISMS IN PRE-CANCEROUS STEM CELLS, IT MAY EVEN BE POSSIBLE TO TARGET SUCH PRE-CANCEROUS STATES BEFORE THE ONSET OF OVERT LEUKEMIA AND THUS PREVENT TRANSFORMATION.

CHARACTERIZATION OF BRAIN DYSFUNCTION DURING DEVELOPMENT IN SURVIVORS OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

MOLECULAR MECHANISMS OF ALPHAVIRUS ENTRY AND EXIT

UNDERSTANDING CELLULAR AND TRANSCRIPTIONAL REGULATORY CHANGES IN HUMAN AGING

HIV AIDS AND OPPORTUNISTIC INFECTIONS

AMPLIFYING AND REDIRECTING CMV-SPECIFIC CD8 T CELLS TO PROVIDE SUSTAINED CONTROL OF HIV INFECTION - THE IMMUNE SYSTEM OF HIV-INFECTED INDIVIDUALS IS UNABLE TO ELIMINATE LATENTLY INFECTED CELLS FOLLOWING REACTIVATION, RESULTING IN THE RECURRENCE OF VIREMIA AFTER STOPPING ANTIRETROVIRAL THERAPY, PREVENTING FUNCTIONAL CURE. THIS NECESSITATES LIFELONG ART FOR PEOPLE WITH HIV (PWH). NEW STRATEGIES ARE NEEDED TO MOBILIZE THE IMMUNE SYSTEM TO PREVENT THE EMERGENCE OF HIV FROM THE HIV RESERVOIR AFTER ART CESSATION. WE RECENTLY DEVELOPED SYNTACS, INFUSIBLE IMMUNOSTIMULATORY BIOLOGICS CONSISTING OF DIMERIC FC-DOMAIN SCAFFOLDS LINKING MHC MOLECULES AND VIRUS-DERIVED PEPTIDES (C-PMHC) CAPABLE OF DELIVERING ANTIGEN-SPECIFIC TCR-SIGNALS AND LIGANDS THAT SUPPLY DEFINED COSTIMULATORY SIGNALS. WE DEMONSTRATED THAT SYNTACS BEARING CMV-DERIVED PEPTIDES, AND ANTI-CD28 SCFV OR 4-1BBL SIGNALING MODULES, STIMULATED VIGOROUS AND SELECTIVE EX VIVO AND IN VIVO EXPANSION OF HIGHLY POLYFUNCTIONAL CMV-SPECIFIC CD8+ T CELLS IN PWH PBMC, WHICH DISPLAYED POTENT IN VIVO ANTI-CMV ACTIVITIES. WE ALSO RECENTLY DESCRIBED THE POTENT IN VITRO AND IN VIVO ANTI-HIV ACTIVITY OF CAR-T CELLS THAT USE A NOVEL TWO- MOLECULE DUOCAR ARCHITECTURE TO CO-EXPRESS TWO INDEPENDENT CARS, EACH RECOGNIZING A DISTINCT GP120 EPITOPE. HIV-SPECIFIC T CELL RESPONSES OR CAR-T CELL TREATMENTS FAIL TO PROVIDE SUSTAINED CONTROL OF HIV INFECTION BECAUSE OF THE EVENTUAL REDUCTION OR LOSS OF THEIR FUNCTIONAL ANTI-HIV ACTIVITY, EVEN IN THE ABSENCE OF MUTATIONAL IMMUNE ESCAPE. IN CONTRAST, CMV-SPECIFIC T CELL RESPONSES CONSIST OF EFFECTOR MEMORY CD8 T CELLS THAT MAINTAIN THEIR CAPACITY FOR CYTOKINE RELEASE, KILLING AND PROLIFERATION AND ACTUALLY EXPAND OVER TIME, A PHENOTYPE DESCRIBED AS MEMORY INFLATION. WE HYPOTHESIZE THAT COMBINING THE CAPACITY OF SYNTACS TO ACTIVATE AND MARKEDLY EXPAND CMV- SPECIFIC CD8 T CELLS WITH NOVEL STRATEGIES TO REDIRECT THEM TO ELIMINATE HIV-INFECTED CELLS, WOULD EXPLOIT THE HIGHLY FUNCTIONAL AND RESILIENT CMV-SPECIFIC CD8 T CELL RESPONSES TO PROVIDE IMPROVED IMMUNE CONTROL OF HIV INFECTION. WE PROPOSE TO COMBINE THE CAPACITY OF SYNTACS TO SELECTIVELY ACTIVATE AND MARKEDLY EXPAND CMV-SPECIFIC CD8 T CELLS WITH POTENT AND SUSTAINED ANTI-VIRAL ACTIVITY WITH THREE SPECIFIC AIMS (SA) TO REDIRECT THEM TO TARGET HIV- INFECTED CELLS. WE WILL EITHER CONVERT THE EXPANDED CMV CD8 T CELLS INTO HIV-SPECIFIC CAR T CELLS (SA 1), OR ANTI-HIV T CELLS (SA 2), OR MODIFY THE SYNTAC STRUCTURE TO LINK CMV-C-PMHC, GP120-BINDERS AND COSTIMULATORY LIGANDS, TO BOTH FULLY ACTIVATE AND DIRECT CMV CD8 T CELLS TO TARGET HIV-INFECTED CELLS (SA 3), THEREBY MOBILIZING AN IN VIVO IMMUNE RESPONSE THAT CONTROLS HIV INFECTION, ELIMINATES REACTIVATED LATENTLY INFECTED CELLS AND PROVIDES SUSTAINED ART-FREE REMISSION OF HIV INFECTION TO PWH. FURTHERMORE, WE WILL ALSO UTILIZE SYNTACS DELIVERING DEFINED COSTIMULATORY SIGNALS, TO EXTEND OUR KNOWLEDGE REGARDING THE CAPACITY OF DIFFERENT COSTIMULATORY SIGNALS TO GENERATE THE MOST POTENT CD8+ T CELLS AND CAR-T CELLS FOR ELIMINATING REACTIVATED LATENTLY INFECTED T CELLS.

DECREASED PROTEIN DEGRADATION IN AGING

DISSECTING THE CANONICAL AND NON-CANONICAL FUNCTIONS OF TET2 IN HEMATOPOIETIC STEM CELLS AND HEMATOLOGIC DISORDERS

DYSREGULATION OF MTOR SIGNALING IN FRAGILE X SYNDROME

THYROGLOBULIN PEPTIDE PRESENTATION BY HLA-DR IN THYROIDITIS

NEAR-INFRARED FLUORESCENT PROTEINS, BIOSENSORS AND OPTOGENETIC TOOLS

SOMATOTROPIC SIGNALING AND RESILIENCE TO AGING AND ALZHEIMER'S DISEASE

EPIDEMIOLOGY OF THE GUT MICROBIOME, PREDIABETES AND DIABETES IN LATINOS

A MULTIMODAL PARENT-FOCUSED INTERVENTION FOR VULNERABLE POPULATIONS IN THE BRONX - PROJECT SUMMARY / ABSTRACT IN RESPONSE TO PAR-20-237, “COMMUNITY INTERVENTIONS TO ADDRESS THE CONSEQUENCES OF THE COVID-19 PANDEMIC AMONG HEALTH DISPARITY AND VULNERABLE POPULATIONS,” WE PROPOSE TO STUDY A PARENT-FOCUSED MENTALIZING INTERVENTION WITH A SMARTPHONE HEALTH PLATFORM IN VULNERABLE POPULATIONS IN THE BRONX. THE BRONX—THE POOREST BOROUGH IN NEW YORK CITY (NYC) WITH 84% OF ITS POPULATION COMPRISED OF MINORITIES—HAS BEEN HIT DISPROPORTIONALLY BY THE COVID-19 PANDEMIC. FOR CAREGIVERS IN THE BRONX, THE PANDEMIC HAS CAUSED UNPRECEDENTED PSYCHOLOGICAL DISTRESS; IN ADDITION TO COMBATING SOCIAL DETERMINANTS OF HEALTH (SDOH), THESE FAMILIES NOW FACE GREATER FINANCIAL INSECURITY AND CHALLENGES RELATED TO THEIR SCHOOL-AGED CHILDREN. FURTHERMORE, SOCIAL DISTANCING REQUIREMENTS AND LIMITED TELEHEALTH RESOURCES FOR BRONX FAMILIES HAVE POSED GREATER BARRIERS TO HEALTHCARE. SUCH PARENTAL DISTRESS CONTRIBUTES TO HEIGHTENED RISK OF TRANSGENERATIONAL CYCLES OF PSYCHOLOGICAL STRESS, TRAUMA AND MALTREATMENT. ADDRESSING THESE CHALLENGES, WE PROPOSE A MULTIMODAL STUDY TACKLING BOTH PARENTAL VULNERABILITY AND HEALTHCARE ACCESS. A) TARGETING PARENTAL VULNERABILITY, WE PROPOSE TO BUILD UPON OUR 12-SESSION THERAPEUTIC CARE PROGRAM, WHICH UTILIZES MENTALIZATION BASED THERAPY AND DESIGNED FOR PARENTS OF CHILDREN IN TREATMENT IN A COMMUNITY PSYCHIATRY CLINIC IN OUR HEALTH SYSTEM. MULTIPLE RANDOMIZED CONTROLLED TRIALS (RCTS) OF ATTACHMENT-BASED PARENTING INTERVENTIONS, INCLUDING FROM OUR GROUP IN DISADVANTAGED COHORTS FROM THE BRONX. B) TARGETING HEALTHCARE ACCESS, WE PROPOSE TO UTILIZE THE HIPAA-COMPLIANT AND IRB-APPROVED VALERA HEALTH SMARTPHONE APPLICATION (“APP”), WHICH HAS BEEN STUDIED IN OUR HEALTH SYSTEM IN SELECTED COHORTS AND RESULTED IN GREATER ACCESS TO HEALTHCARE. BUILDING UPON OUR WORK AND CLINICAL INFRASTRUCTURE, WE HYPOTHESIZE THAT BOTH THE CARE PROGRAM AND THE VALERA APP WILL MITIGATE THE PSYCHOLOGICAL EFFECTS OF COVID-19 WHILE ENHANCING ACCESS TO HEALTHCARE IN THE BRONX. THE STUDY WILL TAKE PLACE AT MONTEFIORE MEDICAL CENTER (MMC), THE LARGEST HEALTH SYSTEM IN THE BRONX, WHICH SERVES PREDOMINANTLY RACIAL AND ETHNIC MINORITY INDIVIDUALS FROM UNDERSERVED FAMILIES. WE WILL FOCUS ON THREE HIGHLY VULNERABLE COHORTS: A) CAREGIVERS OF CHILDREN WITH PSYCHIATRIC CONDITIONS (N=130); B) CAREGIVERS OF CHILDREN WITH AUTOIMMUNE ILLNESSES (N=130), AND; C) CAREGIVERS WHO ARE FRONTLINE HEALTHCARE WORKERS AT MMC (N=100); ALL PRESENTING WITH MODERATE STRESS. A RCT WITH 4 ARMS (2 X 2 DESIGN) WILL TEST OUR HYPOTHESIS: A) CARE PROGRAM ALONE; B) CARE PROGRAM + VALERA APP; C) PARENT EDUCATION (PE) ALONE; D) PE + VALERA APP. SMARTPHONES AND CONNECTIVITY WILL BE PROVIDED AS NEEDED. SURVEYS AT STUDY ENROLLMENT, 6-, 12- AND 24-WEEKS WILL ASSESS PARENTAL STRESS, MENTALIZING CAPACITY (REFLECTIVE FUNCTIONING), ACCESS TO HEALTHCARE, MOOD AND ANXIETY AND ADDITIONAL PARENT AND CHILD CLINICAL MEASURES. MACHINE LEARNING APPROACHES WILL EXPLORE COMPLEX PATTERNS AS PREDICTORS OF OUTCOME INCLUDING COVID-19 ILLNESS/DEATHS, MEDICAL COMORBIDITY, HOUSING, POVERTY, PSYCHOPATHOLOGY, AGE, FAMILY FUNCTIONING, AND TRAUMA. IMPACT. THIS MULTIMODAL STUDY ADDRESSES KEY STRATEGIES TO MITIGATE THE PSYCHOLOGICAL AND HEALTH IMPACT OF COVID-19 IN VULNERABLE POPULATIONS.

A COMPUTATIONAL BIOMECHANICAL AIRWAY MODEL FOR OBESE CHILDREN AT RISK FOR OSAS

MICROSPORIDIA: INVASION APPARATUS

PROMOTING ASTHMA GUIDELINES AND MANAGEMENT THROUGH TECHNOLOGY-BASED INTERVENTION AND CARE COORDINATION (PRAGMATIC)

ANTIMICROBIAL PEPTIDES, GENITAL HSV & HIV CO-INFECTION

MECHANISMS OF OPIOID- MEDIATED HIV NEUROPATHOGENESIS

NOVEL BIOLOGICS DESIGNED TO MOBILIZE HIV-SPECIFIC CTL FOR SUSTAINED HIV REMISSION

GENE REGULATION OF RETINAL CELL DIFFERENTIATION

TMEM, MENACALC, AND MENAINV AS PROGNOSTIC AND PREDICTIVE MARKERS FOR BREAST CANCER METASTASIS

RISK ROLES AND RELATIONSHIPS: PROJECT PREPARED

TAXOL: MECHANISMS OF ACTION AND RESISTANCE

SWAN-STUDY OF WOMEN'S HEALTH ACROSS THE NATION-N.J.SITE

HIV/HPV CANCER PREVENTION, TREATMENT & PATHOGENESIS: RWANDA/EINSTEIN CONSORTIUM

ACTIVITY-DEPENDENT SYNAPTIC PLASTICITY EXPRESSED BY NMDA RECEPTORS

IMPACT OF ILLICIT DRUGS, HIV, AND ART ON NEUROINFLAMMATION AND BBB DISRUPTION

HIGH THROUGHPUT GENETIC ANALYSIS OF MYCOBACTERIUM TUBERCULOSIS

THE ROLE OF VIRAL AND CELLULAR PROTEINS IN EARLY EVENTS OF HIV-1 REPLICATION

CELL FATE CHOICES BY TBX1 IN FORMING THE MAMMALIAN HEART

MECHANISM OF RECEPTOR-MEDIATED ENTRY AND INFECTION BY FILOVIRUSES

ANDROGEN RECEPTOR ASSOCIATED PROTEINS IN PROSTATE CANCER

DEVELOPMENTAL IMPACT OF NICU EXPOSURES (DINE)

EINSTEIN POST-BACCALAUREATE RESEARCH EDUCATION PROGRAM

DNA MISMATCH REPAIR AND CANCER IN MURINE MODELS

TUMOR MICROENVIRONMENTS DETERMING MIGRATION, DISSEMINATION AND DORMANCY

ENDOSOMAL MICROAUTOPHAGY IN DROSOPHILA

CHARACTERISTICS AND PROTECTIVE EFFICACY OF HUMAN ANTIBODIES AGAINST M. TUBERCULOSIS

MTORC1-DEPENDENT REGULATION OF THE CYCC/CDK8 COMPLEX

DOES MEDICAL CANNABIS REDUCE OPIOID ANALGESICS IN HIV+ AND HIV- ADULTS WITH PAIN?

ROLE OF IKK-BETA/NF-KAPPAB IN HYPOTHALAMIC DYSREGULATION OF ENERGY BALANCE

A STRUCTURAL & FUNCTIONAL STUDY OF THE UPPER AIRWAY IN ADOLESCENT GIRLS WITH PCOS

NEW YORK CONSORTIUM FOR INTERDISCIPLINARY TRAINING IN KIDNEY, UROLOGICAL AND HEMATOLOGICAL RESEARCH (NYC TRAIN KUHR)

COGNITIVE INTERVENTION TO IMPROVE SIMPLE AND COMPLEX WALKING

INFLAMMATORY AND IMMUNE MECHANISMS OF ATHEROSCLEROSIS IN HIV-INFECTED WOMEN

MECHANISMS OF GATING AND PERMEATION IN GAP JUNCTIONS

CD138 REGULATES COMPETITION OF ANTIBODY SECRETING CELLS FOR SURVIVAL

EVALUATION OF THE ASTHMA MANAGEMENT PROGRAM TO PROMOTE ACTIVITY FOR STUDENTS IN SCHOOLS (ASTHMA-PASS) - PROJECT SUMMARY/ABSTRACT ASTHMA PREVALENCE IN BRONX, NY SCHOOLS IS 20-25%. PHYSICAL ACTIVITY (PA) IS AN IMPORTANT COMPONENT OF ASTHMA MANAGEMENT IN CHILDREN. STUDIES SHOW THAT PA IS ASSOCIATED WITH DECREASED SEVERITY OF ASTHMA SYMPTOMS, AS WELL AS IMPROVED DISEASE CONTROL AND QUALITY OF LIFE. HOWEVER, URBAN MINORITY CHILDREN WITH ASTHMA FACE BARRIERS TO PA ON MULTIPLE LEVELS. IN OUR PRIOR WORK (K23HD065742), WE IDENTIFIED SEVERAL BARRIERS TO PA IN URBAN MINORITY SCHOOLCHILDREN WITH ASTHMA. THESE BARRIERS INCLUDE: INADEQUATE ACCESS TO ASTHMA RESCUE MEDICATIONS IN SCHOOL, SUBOPTIMAL PRESCRIBING OF PREVENTIVE ASTHMA THERAPY BY PRIMARY CARE PHYSICIANS (PCPS), LACK OF SCHOOL PA OPPORTUNITIES, STIGMA ASSOCIATED WITH ASTHMA, PARENT/CHILD FEAR OF AN ASTHMA ATTACK WITH PA, AND LACK OF TEACHER CONFIDENCE IN ASSISTING STUDENTS WITH ASTHMA. WE DEVELOPED A NOVEL ASTHMA MANAGEMENT PROGRAM TO PROMOTE ACTIVITY FOR STUDENTS IN SCHOOLS (ASTHMA-PASS) IN COLLABORATION WITH STAKEHOLDERS TO ADDRESS THESE KEY BARRIERS. WE PILOT TESTED ASTHMA-PASS WITH 109 STUDENTS WITH ASTHMA FROM 4 BRONX ELEMENTARY SCHOOLS AND THEIR PARENTS TO DEMONSTRATE PROOF OF CONCEPT AND PRELIMINARY EVIDENCE OF INTERVENTION EFFECTIVENESS. RESULTS FROM THE PILOT STUDY DEMONSTRATED SIGNIFICANTLY GREATER INCREASE IN SYMPTOM-FREE DAYS (SFDS) (PRIMARY OUTCOME MEASURE) AND PA LEVELS. IN ADDITION, PRELIMINARY MEDIATION ANALYSES SUGGESTED VIGOROUS PA AND STEP COUNTS ARE MEDIATORS OF SFDS. WE NOW PLAN TO BUILD UPON THIS WORK AND EVALUATE IN A FULL-SCALE RANDOMIZED TRIAL WHETHER THE ASTHMA- PASS INTERVENTION REDUCES ASTHMA MORBIDITY AMONG HIGH-RISK URBAN SCHOOLCHILDREN. WE PROPOSE A CLUSTER- RANDOMIZED CONTROLLED TRIAL WITH 416 CHILDREN AGES 5-11 YEARS WITH PERSISTENT OR UNCONTROLLED ASTHMA FROM 26 BRONX SCHOOLS. SCHOOLS WILL BE STRATIFIED BY SIZE AND THEN RANDOMLY ASSIGNED TO EITHER (1) THE ASTHMA-PASS INTERVENTION (PCP COLLABORATION TO ENSURE OPTIMAL GUIDELINE-BASED PREVENTIVE ASTHMA CARE AND COMMUNITY HEALTH WORKERS TO FACILITATE RESCUE MEDICATION AVAILABILITY IN SCHOOL AND PROVIDE ASTHMA AWARENESS PROGRAMMING AND EDUCATION FOR CHILDREN, PARENTS AND SCHOOL PERSONNEL TO REDUCE STIGMA AROUND ASTHMA AND PA) OR (2) AN ASTHMA MANAGEMENT (AM) COMPARISON GROUP (PCP AND PARENT NOTIFICATION OF CHILD’S ASTHMA STATUS AND GENERAL ASTHMA EDUCATION). BOTH GROUPS WILL PARTICIPATE IN AN EXISTING DISTRICT-WIDE CLASSROOM-BASED DAILY ACTIVITY PROGRAM (‘MOVE TO IMPROVE’). WE WILL ASSESS THE EFFECTIVENESS OF ASTHMA-PASS IN REDUCING ASTHMA MORBIDITY (PRIMARY OUTCOME - SFDS), AND IMPROVING PA (SECONDARY OUTCOME) AS WELL AS ADDITIONAL CLINICAL AND FUNCTIONAL OUTCOMES. WE WILL MEASURE PA WITH ACCELEROMETERS USING PREVIOUSLY ESTABLISHED PROCEDURES. WE WILL ALSO IDENTIFY POTENTIAL MEDIATORS AND MODERATORS OF THE INTERVENTION EFFECT. WE WILL EVALUATE THE PROCESS OF INTERVENTION IMPLEMENTATION BY APPLYING THE RE-AIM FRAMEWORK. THIS PROPOSAL DIRECTLY BUILDS ON OUR PRIOR WORK IN SCHOOLS TO IMPROVE ASTHMA OUTCOMES AND REDUCE HEALTH DISPARITIES. IF ASTHMA-PASS SUCCESSFULLY REDUCES SYMPTOMS AND IMPROVES HEALTH, IT WILL PROVIDE A POWERFUL ARGUMENT FOR POLICY CHANGE IN SCHOOLS AND URBAN COMMUNITIES NATIONWIDE.

EFFECTS OF VITAMIN D AND FISH OIL ON THE KIDNEY IN HYPERTENSIVES

MOLECULAR BASIS OF EARLY CHILDHOOD OBESITY PROGRAMMING BY INTRAUTERINE GROWTH RESTRICTION

IN VIVO MULTIPHOTON BASED IMAGING OF COMPLEX CANCER CELL BEHAVIOR

MECHANISMS OF HYPOGLYCEMIA ASSOCIATED AUTONOMIC FAILURE

DEVELOPMENTAL NEPHROLOGY

LNCRNA MECHANISM OF HEART FAILURE

ROLES OF GLYCOSLYATION IN NOTCH SIGNALING

CELL-CELL INTERACTIONS IN DEVELOPING RETINA

TRAJECTORIES AND MODIFIABLE RISK FACTORS OF BRAIN, GAIT, AND COGNITIVE DECLINE IN AGING AND PRE-DEMENTIA

GATING OF PROTEIN CHANNELS IN LIPID BILAYER MEMBRANES

BUPRENORPHINE TREATMENT AT SYRINGE EXCHANGES TO REDUCE OPIOID MISUSE AND HIV RISK

STRUCTURE-BASED DESIGN OF BROAD FLAVIVIRUS IMMUNOGENS - SUMMARY DENGUE VIRUS IS A MOSQUITO-TRANSMITTED FLAVIVIRUS THAT CAUSES AN ESTIMATED 390 MILLION HUMAN INFECTIONS EACH YEAR. THERE ARE FOUR SEROTYPES OF DENGUE (DENV1-4) THAT CO-CIRCULATE IN HYPERENDEMIC REGIONS. PRIMARY INFECTION BY A SINGLE DENV SEROTYPE RESULTS IN FEBRILE ILLNESS AND SUBSEQUENT DURABLE IMMUNITY TO THAT SEROTYPE. SECONDARY INFECTIONS BY HETEROTYPIC SEROTYPES CAN LEAD TO SEVERE SHOCK SYNDROME AND DEATH. SEVERE DENGUE DISEASE IS CAUSED IN PART BY CROSS-REACTIVE ANTIBODIES ELICITED DURING PRIMARY INFECTION THAT CAN BIND HETEROLOGOUS DENV SEROTYPES BUT CANNOT NEUTRALIZE THEM. INSTEAD, THESE NON-NEUTRALIZING ANTIBODIES FACILITATE ENTRY AND INFECTION IN FC RECEPTOR-POSITIVE CELLS, THUS CAUSING "ANTIBODY-DEPENDENT ENHANCEMENT" (ADE) OF INFECTION. WHILE A LIVE-ATTENUATED FOUR-COMPONENT CHIMERIC VACCINE WAS RECENTLY DEPLOYED IN 19 COUNTRIES AND EUROPE, THIS VACCINE DOES NOT PROTECT NAÏVE INDIVIDUALS AGAINST SYMPTOMATIC OR SEVERE INFECTION, AND MAY EVEN EXACERBATE DISEASE IN SOME CASES. FURTHERMORE, THE GLOBAL EMERGENCE OF ZIKA VIRUS (ZIKV), AND THE POTENTIAL FOR ADE BETWEEN DENV AND ZIKV, RAISES CONCERNS FOR VACCINE STRATEGIES CONTAINING MOST OR ALL EPITOPES IN THE E GLYCOPROTEIN. NONETHELESS, THE ISOLATION AND CHARACTERIZATION OF PROTECTIVE AND, IN SOME CASES, BROADLY-NEUTRALIZING ANTIBODIES INDICATES THAT CERTAIN EPITOPES WITHIN THE E GLYCOPROTEIN MAY HAVE THE CAPACITY TO ELICIT BROADLY PROTECTIVE RESPONSES. HERE, WE UTILIZE INNOVATIVE PROTEIN ENGINEERING APPROACHES TO DEVELOP “IMMUNE-FOCUSED” ANTIGENS AS POTENTIAL VACCINE CANDIDATES, IN WHICH EPITOPES THAT INDUCE NON-NEUTRALIZING ANTIBODIES ARE MASKED BY ENGINEERED MUTATIONS OR GLYCOSYLATION. OUR HYPOTHESIS IS THAT MASKING OF THESE UNFAVORABLE EPITOPES WILL SKEW THE IMMUNE RESPONSE TOWARD A STRONGER NEUTRALIZING, PROTECTIVE, AND BROAD RESPONSE. AIMS 1 AND 2 FOCUS ON CRITICAL EPITOPES IN DENV AND ZIKV E DOMAIN III (EDIII), AND AIM 3 EXPLORES GLYCAN MASKING OF THE ZIKV E PREFUSION DIMER TO IMMUNE FOCUS ON THE E-DIMER EPITOPE (EDE). EDIII IS ATTRACTIVE FOR SUBUNIT VACCINE DESIGN BECAUSE IT IS THE TARGET OF POTENTLY NEUTRALIZING AND PROTECTIVE ANTIBODIES FOR BOTH DENV AND ZIKV. HOWEVER, IMMUNIZATION WITH WILD-TYPE EDIII PROTEIN RESULTS IN INDUCTION OF BOTH NEUTRALIZING AND NON-NEUTRALIZING ANTIBODIES THAT ENGAGE A VARIETY OF EPITOPES. WE HAVE USED PHAGE DISPLAY TO MASK UNPRODUCTIVE EPITOPES OF DENV AND ZIKV EDIIIS BY MUTATION, WHILE MAINTAINING NEUTRALIZING EPITOPES. THESE “RESURFACED EDIIIS” (RSDIIIS) WILL BE CONJUGATED TO PROTEIN NANOPARTICLES AND THEIR CAPACITY TO INDUCE NEUTRALIZING AND PROTECTIVE ANTIBODY RESPONSE IN MICE EVALUATED. TO IMMUNE FOCUS THE PREFUSION E DIMER ON THE EDE, WE HAVE DEVELOPED A MAMMALIAN DISPLAY SYSTEM THAT ALLOWS FOR RAPID EVALUATION OF E DIMER CONSTRUCTS FOR BINDING TO EDE MABS. WE WILL UTILIZE THIS SYSTEM TO SCREEN VARIANTS WITH MULTIPLE ENGINEERED GLYCOSYLATION SITES THAT MASK THE SURFACE OUTSIDE OF THE EDE. THE MOST PROMISING CANDIDATES WILL BE TESTED FOR THEIR CAPACITY TO INDUCE EDE-LIKE MABS IN MICE. THIS WORK WILL PROVIDE A PROOF-OF-CONCEPT FOR NOVEL SUBUNIT VACCINE CANDIDATES AGAINST DENV, ZIKV, AND POSSIBLY OTHER FLAVIVIRUSES OF GLOBAL CONCERN.

THE ROLE OF MACROH2A VARIANTS IN CANCER AND SENESCENCE

THE DYNAMIC MECHANISM OF NUCLEAR TRANSPORT VISUALIZED AT THE ATOMIC SCALE

SIGNAL TRANSDUCTION & ACTIN DURING AMOEBOID CHEMOTAXIS

ASTHMA SYMPTOM PERCEPTION FEEDBACK INTERVENTION FOR ETHNIC MINORITY ADOLESCENTS

ADAPTATION TO VISUAL MOTION

SMALL MOLECULE ACTIVATORS OF PRO-APOPTOTIC BAX FOR CANCER THERAPY

MONOCYTE CNS HIV ENTRY & NEURODEGENERATION: TRANSLATIONAL STUDIES IN THE CART ERA

COMPREHENSIVE APPROACH TO FAMILY WEIGHT MANAGEMENT

SAFETY, PHARMACOKINETICS, AND RESISTANCE TO BEDAQUILINE IN XDR TB AND HIV

OBESITY AND CARIES IN YOUNG SOUTH ASIAN CHILDREN: A COMMON RISK FACTOR APPROACH

ENERGY HOMEOSTASIS: GABAERGIC AND NON-GABAERGIC POMC NEURONS

RNA TRANSPORT AND LOCALIZATION IN YEAST IN SITU

ABSTINENCE REINFORCING CONTINGENCY MANAGEMENT TO SUPPRESS HIV VIRAL LOAD

HIV/ART, LOW BIRTH WEIGHT, AND MORTALITY IN HIV-EXPOSED UNINFECTED CHILDREN: A TRANSLATIONAL MECHANISTIC STUDY - ABSTRACT DESPITE THE RAPID SCALE-UP OF LIFELONG TRIPLE ANTIRETROVIRAL THERAPY (ART) AMONG PREGNANT WOMEN LIVING WITH HIV (WLH), CHILDREN BORN TO WLH CONTINUE TO HAVE AN INCREASED RISK OF LOW BIRTH WEIGHT (LBW), MORBIDITY, AND MORTALITY COMPARED TO INFANTS BORN TO WOMEN WHO ARE NOT LIVING WITH HIV. ALTHOUGH THE ASSOCIATION BETWEEN LBW AND DECREASED CHILD SURVIVAL HAS BEEN WELL STUDIED, THE BIOLOGICAL MECHANISMS LINKING HIV OR ART AND LBW ARE NOT WELL DESCRIBED. TO BETTER UNDERSTAND HOW HIV/ART INCREASES THE RISK OF LBW, WE LEVERAGE AN ONGOING, WELL-CHARACTERIZED COHORT OF WOMEN LIVING WITH HIV ENROLLED IN A TRIAL OF DATA-DRIVEN CONTINUOUS QUALITY INTERVENTION TO IMPROVE LONG TERM OUTCOMES OF ART IN KINSHASA, DEMOCRATIC REPUBLIC OF CONGO; OUR SPECIFIC FOCUS IS ON HIV-ASSOCIATED INFLAMMATION, IMMUNE ACTIVATION, AND MICROBIAL COMMUNITIES IN THE CONTEXT OF UNIVERSAL ART. A COHORT OF 600 WOMEN LIVING WITH HIV ON ART AND 600 HIV-NEGATIVE CONTROL ALONG WITH THEIR HIV-EXPOSED UN-INFECTED (HEU) AND HIV UNEXPOSED (HU) INFANTS WILL BE RECRUITED AND FOLLOWED UP THROUGH DELIVERY AND UP TO 12 MONTHS POSTPARTUM TO DETERMINE HOW HIV/ART-INDUCED PLACENTAL DYSFUNCTION (AIM 1) OR MICROBIAL DYSBIOSIS (AIM 2) MODULATE THE RISK OF LBW AND SUBSEQUENT INFANT MORTALITY. USING BIOLOGICAL SPECIMEN OBTAINED FROM THOSE WOMEN, WE WILL DOCUMENT HISTOPATHOLOGIC PLACENTAL ABNORMALITIES (E.G. NECROSIS) AND MEASURE LEVELS OF MARKERS OF INFLAMMATION, IMMUNE ACTIVATION, AND MICROBIAL TRANSLOCATION. WE WILL ALSO USE A CUTTING-EDGE MICROBIOME AND VIROME TOOLKIT WITH MACHINE LEARNING AND ECOSYSTEM MODELING APPROACHES TO EVALUATE ASSOCIATIONS BETWEEN THESE ENTITIES AND INFLAMMATION AND LBW, AS WELL AS IN SILICO TEST MYRIAD MECHANISTIC HYPOTHESES DERIVED FROM FUNCTIONAL ANALYSES. WE EXPECT THAT COMPLETION OF THESE COMPLEMENTARY AIMS WILL PROVIDE INSIGHT INTO THE BIOLOGICAL MECHANISM(S) ASSOCIATED WITH INCREASED RISK OF LBW AMONG HIV-EXPOSED INFANTS. THIS INSIGHT COULD ULTIMATELY IDENTIFY AN OPTIMAL HIV- TREATMENT OR CARE MODALITY FOR PREGNANT WLH: ONE WHICH PROMOTES MATERNAL HEALTH, PREVENTS HIV MOTHER-TO-CHILD TRANSMISSION, AND MAXIMIZES INFANT SURVIVAL.

POWER-UP: AN EFFECTIVENESS TRIAL OF THE DIABETES PREVENTION PROGRAM TAILORED FOR BLACK AND LATINO MEN