Beth Israel Deaconess Medical Center Inc

CONSORTIA FOR INNOVATIVE AIDS RESEARCH IN NONHUMAN PRIMATES

NOVEL HETEROLOGOUS ADENOVIRUS PRIME-BOOST HIV-1 VACCINE

DF/HCC RENAL CANCER SPORE

CONSORTIUM FOR AIDS VACCINE RESEARCH IN NONHUMAN PRIMATES

MECHANISMS OF STATE SWITCHING IN SLEEP AND SLEEP APNEA

I4C 2.0: IMMUNOTHERAPY FOR CURE - SUMMARY THE GOALS OF I4C 2.0 ARE TO ADVANCE OUR SCIENTIFIC UNDERSTANDING OF THE VIRAL RESERVOIR AND TO DEVELOP IMMUNOLOGIC STRATEGIES FOR HIV-1 REMISSION AND ERADICATION BY A HIGHLY COLLABORATIVE AND MULTIFACETED RESEARCH PROGRAM INVOLVING PARTNERSHIPS AMONG ACADEMIA, INDUSTRY, GOVERNMENT, AND THE COMMUNITY. OUR OVERALL HYPOTHESIS IS THAT MULTIPLE IMMUNOLOGIC STRATEGIES WILL NEED TO BE EXPLORED AND COMBINED TO ACHIEVE LONG-TERM, ART- FREE VIROLOGIC CONTROL OR COMPLETE VIRUS ERADICATION, WITH THE GOAL OF SELECTING COMBINATION REGIMENS TO ADVANCE INTO CLINICAL DEVELOPMENT BY THE END OF THE PROPOSED PERIOD OF SUPPORT. WE PROPOSE THREE RESEARCH FOCI, A MANAGEMENT AND OPERATIONS SECTION, AND A COMMUNITY ENGAGEMENT SECTION. FOCUS 1 (MECHANISTIC BASIS OF RESERVOIR TARGETING AND VIRAL PERSISTENCE) AIM 1. TO DEFINE A VIROLOGIC, IMMUNOLOGIC, AND TRANSCRIPTOMIC SIGNATURE OF VIRAL PERSISTENCE AND REBOUND AND TO DETERMINE HOW IMMUNOLOGIC STRATEGIES TARGET THE VIRAL RESERVOIR IN NHPS AND HUMANS AIM 2. TO DEFINE DRIVERS OF CLONAL EXPANSION AND PERSISTENCE OF THE REPLICATION-COMPETENT VIRAL RESERVOIR IN NHPS AND HUMANS TO ENHANCE RESERVOIR CONTROL AND ELIMINATION FOCUS 2 (NOVEL STRATEGIES FOR SUSTAINED VIRUS REMISSION) AIM 1. TO EVALUATE INNOVATIVE IMMUNE ENGINEERING STRATEGIES THAT PROVIDE LONG-TERM T CELL OR ENV-DIRECTED IMMUNE CONTROL, INCLUDING THERAPEUTIC VACCINES, CAR-T CELLS, AND ENGINEERED B CELLS AIM 2. TO COMBINE APPROACHES THAT AUGMENT HUMORAL AND CELLULAR IMMUNE RESPONSES TO ACHIEVE SUSTAINED IMMUNOSURVEILLANCE AND LONG-TERM ART-FREE VIROLOGIC CONTROL FOCUS 3 (NOVEL STRATEGIES FOR VIRUS ERADICATION) AIM 1. TO EVALUATE INNOVATIVE STRATEGIES FOR RAPID ELIMINATION OF THE MAJORITY OF THE VIRAL RESERVOIR, INCLUDING IMPROVED LRAS COMBINED WITH BNABS, ACTIVATED NK CELLS, AND CAR-T CELLS AIM 2. TO COMBINE THE MOST EFFECTIVE APPROACH TO RAPIDLY ELIMINATE THE MAJORITY OF THE VIRAL RESERVOIR WITH SUSTAINED IMMUNOSURVEILLANCE TO ELIMINATE THE RESIDUAL VIRAL RESERVOIR MANAGEMENT AND OPERATIONS (MO) SECTION COMMUNITY ENGAGEMENT (CE) SECTION

COMBINED IMMUNOLOGIC APPROACHES TO CURE HIV-1

ANDROGEN RECEPTOR ACTION IN CASTRATION RESISTANT PROSTATE CANCER

GENERATION OF A CELLULAR ATLAS OF ADIPOSE TISSUE IN MOUSE AND MAN

NOVEL AD/MVA AND AD/PROTEIN HIV-1 VACCINES

MECHANISMS OF SLEEP AND SLEEP APNEA

DEVELOPMENT OF AD26/ENV VACCINES FOR HIV

ENDOTHELIAL CELL PHENOTYPES IN HEALTH AND DISEASE

STATINS USE IN INTRACEREBRAL HEMORRHAGE PATIENTS (SATURN)

SLAM GENE FAMILY CONTROLLED PATHWAYS TO SLE

PROTEIN DISULFIDE ISOMERASES: A NEW CLASS OF ANTITHROMBOTIC TARGETS

DAMP-MEDIATED INNATE IMMUNE FAILURE AND PNEUMONIA AFTER TRAUMA

THE MODERATE ALCOHOL AND CARDIOVASCULAR HEALTH TRIAL

HARVARD MEDICAL SCHOOL AIDS INITIATIVE IN VIETNAM (HAIVN)

METABOLOMIC PREDICTORS OF INSULIN RESISTANCE AND DIABETES

AD26 BASED THERAPEUTIC VACCINES FOR HIV

PRIMARY IMMUNO-DEFICIENCIES AFFECTING SPECIFIC STAGES OF THE IMMUNE RESPONSE

THROMBUS FORMATION IN VIVO

IP24-045, A PROSPECTIVE OBSERVATIONAL STUDY OF RESPIRATORY VIRUS EPIDEMIOLOGY IN THE GREATER BOSTON AREA

FUTILITY STUDY OF DEFEROXAMINE MESYLATE IN INTRACEREBRAL HEMORRHAGE (HI-DEF)

DATA-DRIVEN SLEEP BIOMARKERS OF BRAIN HEALTH, HEART HEALTH, AND MORTALITY - ABSTRACT: DATA-DRIVEN SLEEP BIOMARKERS OF BRAIN HEALTH, HEART HEALTH, AND MORTALITY SLEEP STATE SIGNALS ENCODE CRITICAL BIOLOGICAL INFORMATION ABOUT BRAIN AND CARDIOVASCULAR HEALTH. HOWEVER, PRESENT APPROACHES TO POLYSOMNOGRAPHY DATA (“SLEEP STUDIES”) DISCARD MOST OF THE COLLECTED INFORMATION, INSTEAD PROVIDING, USING VISUAL ANALYSIS AND RULES FROM THE 1960S, RELATIVELY UNSOPHISTICATED METRICS (E.G., 30-SECOND SLEEP STAGES, APNEA-HYPOPNEA INDEX). VISUAL SCORING IS ALSO LIMITED BY INTERSCORER INCONSISTENCIES. RECENT ADVANCES IN COMPUTATIONAL SCIENCE AND MACHINE LEARNING (ML) / ARTIFICIAL INTELLIGENCE (AI) OPEN THE WAY FOR 1) STANDARD SCORING WITH UNPARALLELED PRECISION AND CONSISTENCY; 2) NEW DATA-DRIVEN, QUANTITATIVE MEASURES. THERE IS A CRITICAL UNMET NEED FOR NEW TOOLS, ALGORITHMS AND DATASETS THAT LEVERAGE RECENT ADVANCES IN DATA SCIENCE TO DEVELOP ROBUST SLEEP-BASED BIOMARKERS OF BRAIN AND CARDIOVASCULAR HEALTH. WE PROPOSE TO CREATE A COMPLETE AI SLEEP REPORT (CAISR) ALGORITHM FOR ALL STANDARD SLEEP MEASURES, AND A PROGRESSIVELY ACCUMULATING LIBRARY OF NOVEL ANALYTICS. WE ARE IDEALLY POSITIONED TO CLOSE THIS GAP. WE WILL ASSEMBLE BETWEEN OUR SIX COLLABORATING INSTITUTIONS SLEEP DATA FROM >200K PATIENTS (35,000 ALREADY ASSEMBLED), WE HAVE EXPERIENCE CURATING LARGE CLINICAL PHYSIOLOGY AND ELECTRONIC MEDICAL RECORDS DATA FOR RESEARCH; WE HAVE PROGRESS ALREADY UNDERWAY WITH BUILDING A SCALABLE PUBLIC DATA SHARING PORTAL; WE HAVE DEEP EXPERTISE IN BASIC AND TRANSLATIONAL SLEEP SCIENCE; AND WE HAVE AN ESTABLISHED RECORD OF SUCCESSFULLY DEVELOPING AND VALIDATING NOVEL DEEP LEARNING TOOLS AND ALGORITHMS TO ANALYZE SLEEP DATA. OUR LONG-TERM GOAL IS TO INCREASE THE VALUE OF SLEEP PHYSIOLOGY DATA BY REPLACING MANUAL ANALYSIS BY OPEN- SOURCE DATA-DRIVEN AI APPROACHES. OUR CENTRAL HYPOTHESIS IS THAT SLEEP SIGNALS CARRY MEASURABLE LATENT INFORMATION ABOUT MORTALITY AND BRAIN AND HEART HEALTH. OUR SPECIFIC AIMS ARE: 1) CREATE AN ONLINE PUBLIC PORTAL WITH DE-IDENTIFIED POLYSOMNOGRAMS (PSG) AND CROSS-SECTIONAL AND LONGITUDINAL ELECTRONIC HEALTH RECORDS (EHR) DATA FOR >200K ADULT AND PEDIATRIC PATIENTS; 2) IMPLEMENT CAISR AND VALIDATED THAT IT GENERALIZES ACROSS AGE, SEX, AND RACE. CAISR WILL ALSO BE EXTERNALLY VALIDATED ON >13,000 PSGS FROM PUBLIC RESEARCH COHORTS; 3) DEVELOP AI ALGORITHMS THAT A) DIFFERENTIATE PATIENTS WITH VS. WITHOUT EXISTING BRAIN AND HEART DISEASE; B) PREDICT PRIMARY OUTCOMES OF ALL CAUSE AND CARDIOVASCULAR MORTALITY, AND SECONDARY OUTCOMES OF HEART DISEASE (CORONARY ARTERY DISEASE, MYOCARDIAL INFARCTION, CONGESTIVE HEART FAILURE, ATRIAL FIBRILLATION, HYPERTENSION); AND BRAIN DISEASE (DEMENTIA, STROKE, INTRACRANIAL HEMORRHAGE). COMPLETING THESE AIMS WILL LEAD TO THESE EXPECTED OUTCOMES: (1) SLEEP DATA ACROSS THE LIFESPAN, (2) SLEEP SCORING AI ALGORITHMS VALIDATED ACROSS AGE, SEX, AND ETHNICITY; (3) PREDICTORS OF MORTALITY AND BRAIN AND HEART HEALTH. THESE OUTCOMES WILL LEAD TO NEW TESTABLE HYPOTHESES, MAKE SLEEP DIAGNOSTICS MORE ACCESSIBLE TO SOCIALLY AND BIOLOGICALLY UNDERSERVED GROUPS, AND STIMULATE PROGRESS IN DATA-DRIVEN SLEEP RESEARCH.

THE ROLE OF PTEN AND THE PI3K PATHWAY IN PROSTATE CANCER

HARVARD-LONGWOOD RESEARCH TRAINING IN VASCULAR SURGERY

VULNERABILITY TO PROGRESSION SCHIZOPHRENIA

METABOLIC SYNDROME, INFLAMMATION AND VASCULAR REMODELING

SPATIAL AND TEMPORAL REGULATION OF ANGIOGENESIS

INTEGRATING LARGE SCALE GENOMICS AND FUNCTIONAL STUDIES TO ACCELERATE FSGS/NS DISCOVERY

PROGRAM IN BLOOD COAGULATION AND VASCULAR BIOLOGY

SCHEDULED PROPHYLACTIC 6-HOURLY IV ACETAMINOPHEN TO PREVENT POSTOPERATIVE DELIRIUM IN OLDER CARDIAC SURGICAL PATIENTS

HEMATOPOIETIC STEM CELL COMMITMENT

STRENGTHENING VIETNAM'S HIV TECHNICAL ASSISTANCE CAPACITY

PRECISION MICRORNA MEDICINE IN CANCER

NOVEL ADENOVIRUS VECTOR-BASED VACCINES FOR HIV-1

AGRP NEURONS. NMDARS, SPINES, SOURCE OF EXCITATORY INPUT AND DOWNSTREAM EFFECTORS

MECHANISMS OF REGULATION BY RNA IN ACUTE MYELOID LEUKEMIA

SENSORY PHENOTYPING TO ENHANCE NEUROPATHIC PAIN DRUG DEVELOPMENT - PROJECT SUMMARY / ABSTRACT DESPITE THE HIGH PREVALENCE AND IMPACT OF NEUROPATHIC PAIN (NP), PATIENTS HAVE ONLY A 30% PROBABILITY OF MEANINGFUL RESPONSE TO ANY SINGLE MEDICATION. FURTHERMORE, IT IS NOT KNOWN WHICH PATIENTS WILL RESPOND TO WHICH MEDICATION. PRECISION PAIN MEDICINE (PPM) CONSIDERS INDIVIDUAL VARIATION IN PATIENT PHENOTYPE AND GENOTYPE TO OPTIMIZE PAIN TREATMENT OUTCOMES. A CRITICAL FIRST STEP TO ADVANCE PPM IS THE IDENTIFICATION OF BIOMARKERS THAT REPRESENT UNDERLYING PAIN MECHANISMS, WHICH CAN THEN BE MATCHED TO DRUG MECHANISMS. BASED ON THE CONSISTENT FINDING THAT DIFFERENT PAIN CONDITIONS HAVE COMMON PHENOTYPES, AND PRELIMINARY EVIDENCE THAT PAIN PHENOTYPE PREDICTS TREATMENT OUTCOME, OUR OVERARCHING HYPOTHESIS IS THAT THE PAIN PHENOTYPE IS A CLINICAL REPRESENTATION OF THE UNDERLYING PAIN MECHANISM THAT WILL PERMIT MECHANISM-BASED, RATHER THAN DISEASE-BASED TREATMENT (I.E., IT CAN BE USED AS A PREDICTIVE BIOMARKER TO ENHANCE THE LIKELIHOOD OF THERAPEUTIC SUCCESS). QUANTITATIVE SENSORY TESTING (QST) IS A PROMISING TECHNIQUE TO CREATE A SENSORY BIOSIGNATURE THAT CAN BE USED AS A PREDICTIVE BIOMARKER IN NP. LABORATORY-BASED QST CAN QUANTIFY THE SEVERITY OF POSITIVE AND NEGATIVE SENSORY PHENOMENA, AND HAS BEEN BROADLY USED TO ESTABLISH SENSORY PHENOTYPES THAT ROBUSTLY CATEGORIZE INTER- PATIENT VARIABILITY IN THE SENSORY FEATURES OF NP. PRELIMINARY DATA SUGGEST THAT SPECIFIC SENSORY PHENOTYPES MAY PREDICT RESPONSE TO SPECIFIC DRUGS, BUT THESE STUDIES ARE MOSTLY SMALL, SINGLE-CENTER, RETROSPECTIVE, AND USE THE RESOURCE-INTENSIVE LABORATORY-BASED QST. TO ENHANCE THE UTILITY OF QST WE HAVE DEVELOPED A BRIEF, CONVENIENT, INEXPENSIVE, “BEDSIDE” QST BATTERY WITH RELIABILITY AND VALIDITY EQUAL TO LABORATORY-BASED QST THAT CAN BE USED TO RAPIDLY CLASSIFY PATIENTS OR STUDY PARTICIPANTS INTO SENSORY PHENOTYPES (E.G., “IRRITABLE” AND “NON-IRRITABLE” NOCICEPTOR). HEREIN, WE PROPOSE TO DEVELOP A BEDSIDE QST-BASED PHENOTYPING BIOSIGNATURE AND RIGOROUSLY TEST ITS ABILITY TO PREDICT TREATMENT RESPONSE TO TWO KNOWN ANALGESICS WITH DIFFERENT MECHANISMS. WE ALSO EXPLORE WHETHER PROTEOMIC BLOOD-BASED BIOMARKERS ALONE OR IN CONJUNCTION WITH QST PHENOTYPES CAN PREDICT RESPONSE TO TREATMENTS. IN AIM 1, WE WILL ESTABLISH A HIGHLY-TRAINED, 5-SITE NETWORK THAT CAN RELIABLY PERFORM THE BEDSIDE QST BATTERY, COLLECT DATA FROM PATIENTS WITH NP, AND USE THOSE DATA TO DEVELOP CLUSTER ANALYSIS-BASED ALGORITHM(S) FOR CLASSIFYING NP SENSORY PHENOTYPES. IN AIM 2, WE MEET THE SCIENTIFIC MILESTONES AND FEASIBILITY REQUIREMENTS TO DESIGN AND COMPLETE THE START-UP PHASE OF A 5-SITE CROSSOVER RCT IN NP PATIENTS (E.G., OBTAIN IRB APPROVALS, TRAIN STAFF, CREATE A DATA MANAGEMENT SYSTEM). IN AIM 3, WE TEST THE ABILITY OF THE BEDSIDE QST- DERIVED PHENOTYPES TO PREDICT RESPONSE TO NP MEDICATIONS IN A 3-PERIOD CROSS-OVER TRIAL OF PREGABALIN, DULOXETINE, AND PLACEBO IN PATIENTS WITH NP. AIM 4 WILL DETERMINE RELATIONSHIPS BETWEEN PROTEOMIC BIOMARKERS AND QST PHENOTYPES AND THE PREDICTIVE ABILITY OF THOSE BIOMARKERS ALONE OR IN COMBINATION. THIS STUDY WILL DETERMINE WHETHER AN INEXPENSIVE AND SCALABLE QST-BASED BIOSIGNATURE CAN PREDICT RESPONSE TO PREGABALIN AND DULOXETINE AND POTENTIALLY IDENTIFY NOVEL PROTEOMIC-BASED BIOMARKERS THAT CAN AUGMENT QST-BASED PREDICTIONS.

CONSORTIUM FOR AIDS VACCINE RESEARCH IN NONHUMAN PRIMATES

GENETIC ENGINEERING OF VEIN BYPASS GRAFTS IN VASCULAR AND CARDIOVASCULAR SURGERY

NATIONAL CENTER FOR FUNCTIONAL GLYCOMICS

EXPANDED DOUBLE NEGATIVE T CELLS IN SLE

A GENETIC-NEUROANATOMIC DISSECTION OF MC4R FUNCTION

ARYL HYDROCARBON RECEPTOR INNATE IMMUNE MODULATORS FOR TREATMENT OF INFLAMMATORY BOWEL DISEASE

RESEARCH TRAINING: COMPLEMENTARY & INTEGRATIVE MEDICINE

ALCOHOL AND MONOCYTE SIGNALING

APTAMER PROTEOMICS OF CARDIOMETABOLIC AND RENAL TRAITS IN AFRICAN AMERICANS

LUPUS NEPHRITIS: NOVEL INSIGHTS IN THE PATHOGENESIS AND TREATMENT - OVERALL ABSTRACT LITTLE IS KNOWN ABOUT THE PATHOGENESIS OF LUPUS NEPHRITIS (LN), PARTICULARLY AS IT RELATES TO THE INITIATION AND PROPAGATION OF THE INFLAMMATORY RESPONSE WHICH ACCOUNTS FOR THE DEVELOPMENT OR END STAGE RENAL DISEASE. LN MAY COMPLICATE UP TO TWO THIRDS OF PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS WITH HIGHER RATES COMMONLY SEEN AMONG MINORITIES AND CHILDREN. BESIDES THE NEEDLE KIDNEY BIOPSY, WE LACK TOOLS THAT REFLECT TISSUE PATHOLOGY WITH FIDELITY. ALTHOUGH TWO DRUGS HAVE BEEN RECENTLY APPROVED TO TREAT PATIENTS WITH LN, ALL TREATMENT PROTOCOLS INVOLVE SYSTEMIC ADMINISTRATION OF DRUGS OR BIOLOGICS WHICH ARE LADEN WITH SIDE EFFECTS AND LIMITED CLINICAL EFFICACY. AMPLE EVIDENCE HAS REVEALED THAT KIDNEY RESIDENT CELLS AND NEWLY FORMED HIGH ENDOTHELIAL VENULES IN THE PRESENCE OF AN AUTOINFLAMMATORY ENVIRONMENT, UPREGULATE MOLECULES WHICH ACCOUNT FOR THE ENSUING INFLAMMATION AND CELL DAMAGE, WHILE IN THEIR ABSENCE, KIDNEY DAMAGE IS AVERTED. THESE MOLECULAR CHANGES CAN BE RECORDED IN PARALLEL IN PODOCYTES AND TUBULAR EPITHELIAL CELLS IN THE URINE. THIS PROPOSAL WILL TEST THE HYPOTHESIS THAT INTERACTION OF CONSTITUENTS OF THE IMMUNE SYSTEM WITH KIDNEY RESIDENT CELLS AND THE ECTOPICALLY FORMED HIGH ENDOTHELIAL VENULES, DETERMINES THE DEVELOPMENT OF INFLAMMATION AND INJURY IN THE SETTING OF LN. COROLLARIES OF THIS HYPOTHESIS ARE THAT KIDNEY RESIDENT CELLS CAN SERVE AS GATEWAYS FOR THE ADMINISTRATION OF TARGETED THERAPEUTICS FOR THE TREATMENT OF LN AND THAT KIDNEY TISSUE PATHOLOGY CAN BE RECORDED WITH HIGH FIDELITY IN THE URINE CELLS OF PATIENTS WITH LN. THERE ARE 2 PROJECTS IN THIS PROPOSAL: 1) INTERPLAY BETWEEN AUTOIMMUNE EFFECTORS AND KIDNEY RESIDENT CELLS IN LUPUS NEPHRITIS AND 2) NEWLY FORMED HIGH ENDOTHELIAL CELLS IN THE KIDNEY- PATHOGENESIS AND IMPLICATIONS IN LUPUS NEPHRITIS. THE PROPOSAL WILL BE SUPPORTED BY 3 CORES: THE ADMINISTRATIVE CORE WILL BE RESPONSIBLE FOR REGULATORY COMPLIANCE, BUDGET MANAGEMENT, SCHEDULING MEETINGS. THE NANOPARTICLE IMMUNE DELIVERY CORE WILL BE RESPONSIBLE FOR THE CONSTRUCTION OF NANOPARTICLES LOADED WITH DRUGS AND BIOLOGICS AND TAGGED WITH ANTIBODIES FOR CELL-SPECIFIC DELIVERY. THE SINGLE CELL, SPATIAL TRANSCRIPTOMICS AND BIOINFORMATICS CORE WILL PERFORM SINGLE CELL TRANSCRIPTOMICS STUDIES AND WILL PROVIDE STATISTICAL AND BIOINFORMATICS SUPPORT. THIS PROPOSAL THROUGH EXTENSIVE SYNERGISTIC PLANS BETWEEN THE PROJECT LEADERS BRINGS FORWARD NOVEL AND SIGNIFICANT ELEMENTS IN THE STUDY OF THE PATHOGENESIS, TREATMENT AND BIOMARKER DEVELOPMENT IN PATIENTS WITH LN.

MECHANISMS OF PROSTHETIC ARTERIAL GRAFT FAILURE

REGULATION OF THE BIOSYNTHESIS OF A NOVEL CLASS OF ANTI-DIABETIC LIPIDS

3/8 - PREDICTORS AND MECHANISMS OF CONVERSION TO PSYCHOSIS

NEUROMODULATORY MECHANISMS UNDERLYING VAGUS NERVE STIMULATION THERAPY FOR ALZHEIMER'S DISEASE

CARDIAC MR CHARACTERIZATION OF ARRHYTHMOGENIC SCAR IN PATIENTS WITH MYOCARDIAL INFARCTION

STATE DEPENDENT ASPECTS OF COGNITION

BIOLOGICAL MECHANISM OF INF2-MEDIATED FSGS

USE OF REGISTRIES, CLAIMS AND HEALTH SYSTEM DATA TO ENHANCE THE EVALUATION OF CARDIOVASCULAR THERAPIES IN CLINICAL TRIALS

ESTABLISHING SLEEP APNEA AS A NON-COGNITIVE PHENOTYPE OF BRAINSTEM ADRD PATHOLOGIES IN OLDER ADULTS - PROJECT SUMMARY ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD) AND SLEEP APNEA ARE COMMON AGING PHENOTYPES. SLEEP APNEA MAY ALSO BE AN AD PHENOTYPE, AS ADRD PATHOLOGIES MAY DISRUPT NEURAL CIRCUITS SUBSERVING BREATHING IN SLEEP. YET, NO STUDY HAS EXAMINED IF ADRD PATHOLOGIES IN “SLEEP APNEA” CIRCUITS ARE RELATED TO SLEEP APNEA. LIKE OTHER ADRD PHENOTYPES SUCH AS COGNITION OR MOBILITY, SLEEP APNEA IS MULTI-DIMENSIONAL. DEFECTS IN 3 KEY DIMENSIONS CAN LEAD TO SLEEP APNEA: A) FAILURE TO MAINTAIN AIRWAY PATENCY, B) INEFFICIENT RESPIRATORY DRIVE, AND C) ABERRANT APNEA TERMINATION BY AROUSAL. IN MODEL ORGANISMS, INTERCONNECTED, NEUROCHEMICALLY AND SPATIALLY DISTINCT BRAINSTEM CIRCUITS CONTROL THESE KEY DIMENSIONS. HOWEVER, THE ROLE OF ADRD PATHOLOGIES IN HUMAN SLEEP APNEA IS UNKNOWN, AS MULTI-DIMENSIONAL SLEEP APNEA STUDIES WITH COLLECTION OF CNS TISSUES ARE RARE, AND ADRD STAGING DOES NOT ASSESS SITES OF UNDERLYING CIRCUITS. IN PILOT STUDIES, 3 KEY DIMENSIONS WERE MEASURED TO OBTAIN SLEEP APNEA PHENOTYPES FROM OLDER ADULTS IN THE COMMUNITY USING NOVEL SENSORS. FEW OLDER ADULTS WITH SLEEP APNEA IN THE RUSH MEMORY AND AGING PROJECT (MAP, R01AG17917) WERE OBESE, SUGGESTING A MINOR STRUCTURAL AND AN IMPORTANT NEUROGENIC CONTRIBUTION. WE DOCUMENTED MIXED ADRD PATHOLOGIES IN POSTMORTEM BRAINSTEM TISSUES OF 3 “SLEEP-APNEA” CIRCUITS THAT SERVE EACH OF THE 3 KEY DIMENSIONS IN MAP ADULTS WITH SLEEP APNEA. THUS, TESTING IF ADRD DEGENERATIVE CHANGES MAY LEAD TO SLEEP APNEA IN OLD AGE IS FEASIBLE. THIS INNOVATIVE CLINICAL-POSTMORTEM PROPOSAL WILL LEVERAGE UNIQUE CLINICAL, PATHOLOGICAL AND BIOSPECIMEN RESOURCES FROM OLDER ADULTS FROM MAP, A COMMUNITY-BASED COHORT STUDY WITH BRAIN DONATION. THIS STUDY WILL I) OBTAIN COMPREHENSIVE SLEEP APNEA PHENOTYPING OF 3 KEY SLEEP APNEA DIMENSIONS USING A NOVEL SENSOR AND MRI TO QUANTIFY UPPER AIRWAY STRUCTURE IN OLDER ADULTS WITH AND WITHOUT ADRD, AND II) QUANTIFY DEGENERATIVE CHANGES IN BRAINSTEM “SLEEP APNEA” CIRCUIT NODES BY STAINING FOR BOTH PATHOLOGY MARKERS AND CELL TYPE SPECIFIC MARKERS AND INTEGRATE THESE NOVEL DATA. AIM 1 WILL TEST THE HYPOTHESIS THAT DEMOGRAPHIC AND CLINICAL PREDICTORS ARE DIFFERENTIALLY ASSOCIATED WITH THREE KEY PHYSIOLOGICAL DIMENSIONS OF SLEEP APNEA. AIMS 2&3 WILL TEST THE HYPOTHESES THAT DEGENERATIVE CHANGES I.E. ADRD PATHOLOGIES (AIM 2) AND SUBTYPE SPECIFIC NEURONAL LOSS (AIM 3) WITHIN THE 3 “SLEEP APNEA” CIRCUITS ARE RELATED TO THESE KEY SLEEP APNEA DIMENSIONS. AIM 4 WILL TEST THE HYPOTHESES THAT AD PATHOLOGY IS PRESENT IN “SLEEP APNEA” CIRCUITS OF OLDER ADULTS WITHOUT CLINICAL AD DEMENTIA, AND THAT CIRCUIT ADRD PATHOLOGIES IN THESE INDIVIDUALS IS ASSOCIATED WITH SLEEP APNEA AND ITS KEY DIMENSIONS. SHOWING THAT SLEEP APNEA IS A COMMON AND EARLY NON-COGNITIVE PHENOTYPE OF AD, MUCH AS REM SLEEP BEHAVIOR DISORDER IS AN EARLY MARKER OF PD, WILL DRIVE A PARADIGM SHIFT IN OUR CONCEPT OF THE RELATION BETWEEN ADRD AND SLEEP APNEA. SHOWING THAT SLEEP APNEA IS A CONSEQUENCE OF AD MAY BE USED TO IDENTIFY OLDER ADULTS AT RISK OF AD DEMENTIA AND FACILITATE ITS PREVENTION. CELL-SPECIFIC DATA WILL DRIVE DRUG DISCOVERY OF TARGETED SLEEP APNEA TREATMENTS FOR OLDER ADULTS WITH ADRD AND SLEEP APNEA UNRESPONSIVE TO CURRENT TREATMENTS.

NEURAL BASIS FOR LEPTIN CONTROL OF ENERGY BALANCE

INFLAMMATION AND T CELL MEMORY: INTER-RELATED BARRIERS TO ALLOGRAFT TOLERANCE

MULTI-OMICS ANALYSIS OF BROADLY NEUTRALIZING ANTIBODIES AND THERAPEUTIC VACCINATION - SUMMARY THE GOAL OF THIS P01 PROGRAM IS TO DEFINE MECHANISMS OF EFFICACY OF BROADLY NEUTRALIZING ANTIBODIES (BNABS) AND THERAPEUTIC VACCINES FOR HIV-1 IN A HIGHLY COLLABORATIVE AND MULTIFACETED RESEARCH PROGRAM. OUR OVERALL HYPOTHESIS IS THAT IMMUNOLOGIC STRATEGIES FOR HIV-1 CURE DELAY VIRAL REBOUND BOTH BY TARGETING THE VIRAL RESERVOIR AND BY INCREASING HOST ANTIVIRAL IMMUNITY. WE WILL EVALUATE MECHANISMS OF THERAPEUTIC EFFICACY IN BOTH HUMANS AND NONHUMAN PRIMATES (NHPS) USING COORDINATED VIROLOGIC, IMMUNOLOGIC, AND MULTI-OMIC APPROACHES WITH THE GOAL OF DEVELOPING IMPROVED NEXT GENERATION HIV-1 CURE STRATEGIES. WE WILL APPLY CUTTING- EDGE, HIGH-THROUGHPUT, MULTI-OMIC PROFILING PLATFORMS AND INTEGRATE THESE DATA SETS TO GENERATE A COMPREHENSIVE TISSUE LANDSCAPE AND REGULATORY NETWORK OF THE VIRAL RESERVOIR AND HOST IMMUNE RESPONSES. THIS PROGRAM BUILDS ON OUR EXISTING STUDIES OVER THE PAST SEVERAL YEARS IN BOTH HUMANS AND NHPS EVALUATING THE ABILITY OF BNABS AND THERAPEUTIC VACCINES TO DELAY VIRAL REBOUND FOLLOWING DISCONTINUATION OF ANTIRETROVIRAL THERAPY (ART). WE WILL FIRST UTILIZE EXISTING SAMPLES FROM THESE STUDIES TO GENERATE HYPOTHESES REGARDING CORRELATES OF DELAYED VIRAL REBOUND. WE WILL THEN PERFORM NEW INTERVENTIONAL STUDIES IN NHPS WITH SPATIAL MULTI- OMIC ANALYSES IN LYMPH NODES AND GASTROINTESTINAL MUCOSAL TISSUES TO TEST HYPOTHESES IN ORDER TO DEFINE MECHANISMS OF RESERVOIR TARGETING BY BNABS AND THERAPEUTIC VACCINES. THE SIGNIFICANCE OF THIS PROGRAM IS THE POTENTIAL TO DEFINE THE BIOLOGIC PATHWAYS THAT LEAD TO DELAYED VIRAL REBOUND FOLLOWING ART DISCONTINUATION. AN IMPROVED UNDERSTANDING OF PARTIALLY EFFECTIVE BNABS AND THERAPEUTIC VACCINES IN HUMANS AND NHPS WILL LEAD TO BASIC RESEARCH ADVANCES THAT WILL ALLOW THE DEVELOPMENT OF IMPROVED NEXT GENERATION HIV-1 CURE APPROACHES. TO ACCOMPLISH THE GOALS OF THIS P01 PROGRAM, WE PROPOSE THE FOLLOWING PROJECTS AND CORES: PROJECT 1. MULTI-OMICS CORRELATES OF BROADLY NEUTRALIZING ANTIBODY EFFICACY PROJECT 2. MULTI-OMICS CORRELATES OF THERAPEUTIC VACCINE EFFICACY CORE A. ADMINISTRATIVE CORE CORE B. MULTI-OMICS CORE CORE C. COMPUTATIONAL ANALYSIS CORE CORE D. NHP CORE

ADVANCING THE UNDERSTANDING OF POSTOPERATIVE DELIRIUM MECHANISMS VIA MULTI-OMICS

DETERMINANTS AND CARDIOVASCULAR CONSEQUENCES OF DIABETES IN OLDER ADULTS

RESEARCH RESOURCE FOR COMPLEX PHYSIOLOGIC SIGNALS

DISCOVERY, REGULATION AND FUNCTION OF THE PI 3-KINASE AND AKT PATHWAY IN CANCER

RESEARCH RESOURCE FOR COMPLEX PHYSIOLOGIC SIGNALS

COSTIMULATION AND CYTOKINES IN TOLERANCE

MULTI-SCALE SPATIAL MAPPING OF HUMAN LYMPHATIC VESSELS - ABSTRACT: LYMPHATIC DISEASE AFFECTS OVER 10 MILLION PATIENTS IN THE UNITED STATES AND ARE GROSSLY UNDERSTUDIED. LYMPHEDEMA, THE MOST COMMONLY OCCURRING LYMPHATIC DISEASE, IS CONSIDERED ONE ON OF THE MOST SIGNIFICANT CANCER SURVIVORSHIP ISSUES IN THE UNITED STATES. OF SIGNIFICANT NOTE, OUR PRIMARY UNDERSTANDING AND MAPPING OF THE LYMPHATIC SYSTEM COME FROM ANIMAL MODELS. A COMPREHENSIVE ANATOMIC REFERENCE FROM THE HUMAN LYMPHATIC SYSTEM DOES NOT CURRENTLY EXIST. WE PROPOSE THE DEVELOPMENT OF A LYMPHATIC TISSUE MAPPING CENTER (TMC) AS A PART OF THE NIH HUMAN BIOMOLECULAR ATLAS PROGRAM (HUBMAP). SPECIFICALLY, THROUGH A CONSORTIUM OF INSTITUTIONS INCLUDING THE BETH ISRAEL DEACONESS MEDICAL CENTER, UNIVERSITY OF SOUTHERN CALIFORNIA, UNIVERSITY OF PENNSYLVANIA, STANFORD UNIVERSITY, AND INDIANA UNIVERSITY, WE WILL ACQUIRE BOTH LYMPHATIC COLLECTORS AND LYMPHATIC CAPILLARIES IN HEALTHY INDIVIDUALS ACROSS THE ENTIRE HEALTH SPECTRUM AND REGISTER EACH OF THESE SAMPLES TO THE ASSOCIATED ANGIOSOME THEREBY ALLOWING COORDINATION WITH HUBMAP. THESE SAMPLES WILL UNDERGO SPATIAL TRANSCRIPTOME ANALYSIS. MOREOVER, WE WILL PERFORM 3D RADIOLOGIC IMAGING OF LYMPHATIC COLLECTORS THROUGHOUT THE BODY. THE SPATIAL TRANSCRIPTOME ANALYSIS AND 3D IMAGING DATA WILL BE PROCESSED AND TRANSFERRED TO THE HUBMAP INTEGRATION, VISUALIZATION, AND ENGAGEMENT (HIVE) COLLABORATIVE. THE LYMPHATIC TISSUE MAPPING CENTER, ALONGSIDE HUBMAP, WILL PROVIDE FINE DETAIL ANATOMIC PRECISION OF THE LYMPHATIC SYSTEM BETTER INFORMING FUTURE SURGICAL INTERVENTIONS. THE SPATIAL TRANSCRIPTOME ANALYSIS WILL PROVIDE POTENTIAL TARGETS FOR FUTURE PHARMACOLOGIC THERAPEUTICS.

THIOL ISOMERASES IN HEMOSTASIS AND THROMBOSIS

NETWORK MEDIATION OF EXPERIENTIAL AND EXPRESSIVE DEFICITS IN PSYCHOTIC DISORDERS

INTEGRATED ENDOCRINE AND METABOLIC RESEARCH TRAINING

CORAL: DATA COORDINATING CENTER

UNDERSTANDING AND PREVENTING ADVERSE SAFETY EVENTS IN PEDIATRIC OUT-OF-HOSPITAL CARDIAC ARRESTS

MULTI FUNCTIONAL STUDIES OF CANDIDATE DYSLEXIA SUSCEPTIBILITY GENES IN THE RAT

MICRO-RNA'S IN ALCOHOLIC LIVER DISEASE

MOLECULAR CONTROL OF BROWN ADIPOSE CELL FATE AND ENERGY METABOLISM

BIPOLAR & SCHIZOPHRENIA CONSORTIUM FOR PARSING INTERMEDIATE PHENOTYPES

DECIPHERING THE PHYSIOLOGICAL ROLE AND INTERPLAY BETWEEN UBIQUITINATION AND PHOSPHORYLATION PATHWAYS TO GUIDE TARGETED CANCER THERAPIES

DEVELOPMENT OF THERAPEUTIC ANTIBODY FOR TRAUMATIC BRAIN INJURY

ROLE OF IRF3 IN ENERGY AND GLUCOSE HOMEOSTASIS

IMMUNE PRIVILEGE OF THE HEMATOPOIEITIC STEM CELL NICHE

PROTEIN-GLYCAN INTERACTION RESOURCE AT THE NATIONAL CENTER FOR FUNCTIONAL GLYCOMICS (NCFG)

METABOLIC ACTIONS OF FGF21

REGULATION OF BONE LOSS BY IL-23/IL-17A AXIS IN INFLAMMATORY ARTHRITIS

AN INTEGRATED MODEL OF CAPACITY BUILDING IN CLINICAL MENTORING

PREVENTING AVOIDABLE REHOSPITALIZATIONS: POST ACUTE CARE TRANSITIONS PROGRAM

IN VIVO OPTICAL DETECTION OF DYSPLASIA IN ESOPHAGUS

GENE TRANSCRIPTION IN SLE

CARDIOVASCULAR RESEARCH TRAINING PROGRAM

CIRCUITRY FOR CIRCADIAN RHYTHMS

ELECTRICAL IMPEDANCE MYOGRAPHY IN AN ANIMAL MODEL

ENDOSCOPIC FINE-NEEDLE POLARIZED SCANNING SPECTROSCOPY FOR PANCREATIC CYSTIC LESIONS DIAGNOSIS

BIOMECHANICS OF VERTEBRAL FRACTURE: THE FRAMINGHAM QCT STUDY

HARVARD HEPATITIS B CONSORTIUM

EPVENT 2-A PHASE II TRIAL ESOPHAGEAL PRESSURE GUIDED VENTILATION

TARGETING TUMOR SUPPRESSIVE PATHWAYS FOR CANCER THERAPY

SINGLE-CELL ANALYSIS OF THE HIV/SIV RESERVOIR

TARGETING PML FOR LEUKEMIA THERAPY.

HUMAN EOSINOPHILS: MECHANISMS OF FUNCTIONING

GENE TRANSCRIPTION IN SLE

PROGNOSTIC IMPLICATIONS OF HOME-BASED BLOOD PRESSURE MONITORING IN OLDER ADULTS - HYPERTENSION AFFECTS OVER 85% OF ADULTS OVER 75 YEARS OF AGE AND REPRESENTS ONE OF THE FEW MODIFIABLE RISK FACTORS TO PREVENT DEMENTIA AND CARDIOVASCULAR DISEASE (CVD) EVENTS IN OLDER ADULTS. HOWEVER, CURRENT PRACTICE GUIDELINES FOR HYPERTENSION SCREENING AND TREATMENT FOCUS HEAVILY ON BLOOD PRESSURE (BP) MEASUREMENTS OBTAINED IN CLINIC SETTINGS. THIS RELIANCE ON BRICK-AND-MORTAR OFFICES FOR BP MEASUREMENT REPRESENTS A SIGNIFICANT BARRIER FOR OLDER ADULTS, WHO OFTEN DEPEND ON OTHERS FOR TRANSPORTATION AND WHO ARE AT INCREASED RISK OF SEVERE MORBIDITY FROM THE CURRENT COVID-19 PANDEMIC. HOME BP MONITORING (HBPM) HAS SHOWN INCREDIBLE PROMISE FOR MORE EFFECTIVE AND TIMELY BP TREATMENT AND CONTROL. FURTHERMORE, THE CURRENT PANDEMIC HAS CATALYZED WIDESPREAD ADOPTION OF HBPM FOR HYPERTENSION SCREENING AND MANAGEMENT. HOWEVER, EVIDENCE FOR THIS PRACTICE IS SEVERELY LACKING IN OLDER ADULTS. IN FACT, THERE ARE VIRTUALLY NO HBPM COHORT STUDIES IN ELDERLY POPULATIONS IN THE UNITED STATES. THIS IS PARTICULARLY CONCERNING AS THE DISCORDANCE BETWEEN CLINIC AND HOME BP INCREASES WITH AGE, MAKING OLDER ADULTS ESPECIALLY SUSCEPTIBLE TO HARMS FROM EITHER OVERLY AGGRESSIVE OR DELAYED BP TREATMENT. IN THIS PROPOSED STUDY, WE APPLY OUR UNIQUE EXPERTISE WITH HBPM AND 24-HOUR AMBULATORY BLOOD PRESSURE MONITORING TO ONE OF THE MOST LONG-STANDING AND WELL-RESPECTED AMERICAN COHORTS OF COMMUNITY-DWELLING ADULTS, THE ATHEROSCLEROSIS RISK IN COMMUNITIES STUDY (ARIC). WHILE ARIC ALREADY RIGOROUSLY MEASURES BP IN THE CLINIC SETTING VIA AUTOMATED DEVICES, OUR PROPOSAL WILL ADDITIONALLY ASSESS 8 DAYS OF HBPM AND 24 HOURS OF AMBULATORY BP (ONCE EVERY 20 MINUTES) IN 2,142 RACIALLY DIVERSE ADULTS OVER AGE 80 YEARS, ESTABLISHING POSSIBLY THE LARGEST PROSPECTIVE STUDY OF HOME, AMBULATORY, AND CLINIC-BASED BP MEASUREMENT AMONG OLDER ADULTS IN THE WORLD. THIS PROPOSAL IS DESIGNED TO DIRECTLY INFORM CLINICAL PRACTICE WITH HBPM BY CHARACTERIZING ITS MEASUREMENT PERFORMANCE (BIAS AND VARIANCE), PREDICTIVENESS WITH RESPECT TO KEY LONG-TERM EVENTS (DEMENTIA AND CVD), AND INTERPRETATION (I.E. WHAT A HOME BP MEASURE EQUALS IN TERMS OF BP MEASURED BY ABPM OR IN CLINIC). THE ACCOMPLISHMENT OF THIS PROPOSAL WILL ADDRESS CRITICAL GAPS IN KNOWLEDGE RELATED TO AN INCREASINGLY UTILIZED FORM OF BP MEASUREMENT, IMPROVING ACCESS TO TIMELY HYPERTENSION CARE BY ESTABLISHING AN EFFICIENT PROTOCOL FOR PRECISE BP MEASUREMENT AT HOME. MOREOVER, BY INVESTING IN THE DIGITAL MONITORING PLATFORM OF THE ARIC STUDY, THIS PROPOSAL WILL LAY THE FOUNDATION FOR REMOTE COLLECTION OF A WIDE RANGE OF DETAILED, LONGITUDINAL, BIOSENSOR DATA THAT CAN BE LEVERAGED BY MANY INVESTIGATORS THROUGH SUBSEQUENT ARIC PROPOSALS IN YEARS TO COME. WITH CURRENT TRENDS IN BP CONTROL WORSENING AMONG OLDER ADULTS IN THE UNITED STATES, THERE HAS NEVER BEEN A GREATER NEED FOR RESEARCH ON INNOVATIVE TECHNOLOGIES TO IMPROVE ACCESS TO HIGH QUALITY BP MEASUREMENT. ULTIMATELY, OUR PROPOSAL DIRECTLY ANSWERS THE CALL BY NHLBI'S 2017 EXPERT PANEL ON BP MEASUREMENT FOR HIGH IMPACT RESEARCH THAT DETERMINES “THE ROLE OF ABPM AND HBPM IN THE DIAGNOSIS…OF HYPERTENSION” AND “THE OPTIMAL PROTOCOL FOR USING HBPM…TO DIAGNOSE AND ASSESS…HYPERTENSION.”

A CAUSAL ROLE FOR NUCLEAR RECEPTOR PATHWAYS IN INSULIN RESISTANCE

MITOCHONDRIAL METABOLITE COMPARTMENTALIZATION IN HEALTH AND DISEASE

ANGIOPOIETIN MECHANISMS IN SEPSIS

A PSYCHOBIOLOGICAL FOLLOW-UP STUDY OF TRANSITION FROM PRODROME TO EARLY PSYCHOSIS

BIOMARKERS AND MECHANISMS IN CANCER ASSOCIATED THROMBOSIS

EFFICACY OF OPEN-LABEL PLACEBO, DOUBLE-BLIND PLACEBO, AND PEPPERMINT OIL IN IBS

APOL1 VARIANTS: UNDERSTANDING THE BASIS OF DISPARITIES IN RATES OF KIDNEY DISEASE

NEUROBIOLOGICAL MECHANISMS OF ALTERED CORTICAL PLASTICITY IN TYPE-2 DIABETES MELLITUS - PROJECT SUMMARY NEARLY 25% OF AMERICANS AGED 65 AND OLDER HAVE TYPE-2 DIABETES MELLITUS (T2DM) AND MORE THAN HALF HAVE ELEVATED HEMOGLOBIN A1C INDICATING IMPAIRED GLUCOSE TOLERANCE, OR PREDIABETES. T2DM CAN AFFECT THE BRAIN THROUGH NEURONAL TOXICITY OF HYPER- AND HYPOGLYCEMIA EPISODES, MICROVASCULAR INSULTS, IMPAIRED GLUCOSE TRANSFER AND INSULIN RESISTANCE. THE NEUROLOGIC IMPACT OF T2DM IS WIDESPREAD AND CAN LEAD TO STRUCTURAL, FUNCTIONAL, AND METABOLIC BRAIN CHANGES. CLINICALLY, T2DM IS ASSOCIATED WITH FASTER COGNITIVE DECLINE AND A HIGHER RISK OF DEMENTIA, INCLUDING ALZHEIMER’S DISEASE (AD). THE LINK BETWEEN T2DM-ASSOCIATE BRAIN CHANGES AND COGNITIVE DECLINE IS NOT COMPLETELY UNDERSTOOD, RESULTING IN A PAUCITY OF TARGETS FOR THERAPEUTIC INTERVENTION. ONE POTENTIAL TARGET IS CORTICAL PLASTICITY ITSELF, THE MECHANISMS OF WHICH CAN BE ASSESSED IN VIVO IN HUMANS USING TRANSCRANIAL MAGNETIC STIMULATION (TMS). THIS APPROACH USES SINGLE-PULSE TMS TO INDEX CORTICAL EXCITABILITY AND A FORM REPETITIVE TMS CALLED INTERMITTENT THETA-BURST STIMULATION (ITBS) TO INDUCE NMDA- RECEPTOR DEPENDENT CHANGES IN CORTICAL EXCITABILITY THAT RESEMBLE THE SYNAPTIC MECHANISMS OF LONG-TERM POTENTIATION (LTP) PLASTICITY. IN A PREVIOUS NIH-FUNDED STUDY (R21 NS082870), WHICH SERVES AS THE FOUNDATION FOR THE CURRENT PROPOSAL, WE USED THIS TMS-ITBS APPROACH TO SHOW THAT OLDER ADULTS WITH T2DM HAD REDUCED LTP-LIKE PLASTICITY COMPARED TO HEALTHY CONTROLS. MOREOVER, PLASTICITY IN T2DM PATIENTS WAS ASSOCIATED WITH BOTH COGNITION AND CORTICAL GLUTAMATE METABOLISM AS ASSESSED BY MAGNETIC RESONANCE SPECTROSCOPY (MRS). WE PERFORMED THESE TMS AND MRS ASSESSMENTS IN THE MOTOR CORTEX (M1) USING ELECTROMYOGRAPHY TO RECORD THE OUTPUT OF TMS AS A MOTOR EVOKED POTENTIAL (MEP). THE CURRENT STUDY SEEKS TO EXTEND THESE FINDINGS TO BRAIN REGIONS MORE DIRECTLY INVOLVED IN COGNITION, INCLUDING THE DORSOLATERAL PREFRONTAL CORTEX (DLPFC) AND INFERIOR PARIETAL LOBULE (IPL). WE WILL COMBINE TMS WITH ELECTROENCEPHALOGRAPHY (EEG) AND USE THE TMS- EVOKED EEG POTENTIAL (TEP) TO INDEX CORTICAL EXCITABILITY AND ITS MODULATION BY ITBS. OUR PILOT DATA SUPPORTS THIS APPROACH BY SHOWING THAT ITBS TO M1 INDUCES CORRELATED CHANGES IN MEPS AND TEPS AND THAT THE ITBS- INDUCED MODULATION OF TEPS IN DLPFC AND IPL ARE ASSOCIATED WITH TESTS OF EXECUTIVE FUNCTION AND MEMORY, RESPECTIVELY. OUR HYPOTHESIS IS THAT COGNITIVE DYSFUNCTION IN T2DM IS ASSOCIATED WITH ABNORMAL GLUTAMATERGIC NEUROTRANSMISSION, WHICH CAN BE ASSESSED USING TMS AND MRS. WE WILL PERFORM THESE ASSESSMENTS IN NON- DEMENTED OLDER PATIENTS WITH T2DM AND DEMOGRAPHICALLY SIMILAR NON-DIABETIC PARTICIPANTS, DIVIDED INTO HEALTHY AND PREDIABETIC SUBGROUPS ON THE BASIS OF A1C LEVELS. WE WILL COLLECT STRUCTURAL MAGNETIC RESONANCE IMAGING (MRI) MEASURES OF CORTICAL ATROPHY AND COMPREHENSIVE NEUROPSYCHOLOGICAL TESTING, PLUS DATA ON KNOWN AD RISK FACTORS, SUCH AS APOLIPOPROTEIN-E4 STATUS AND PLASMA AMYLOID-BETA LEVELS. IF SUCCESSFUL, THIS STUDY WILL IDENTIFY NEUROPHYSIOLOGICAL MARKERS OF COGNITIVE IMPAIRMENT THAT ARE POTENTIALLY MODIFIABLE AND COULD THUS BE TRANSLATED INTO THERAPEUTIC TARGETS FOR INTERVENTIONS TO SLOW COGNITIVE AGING IN T2DM AND REDUCE THE RISK OF DEVELOPING AD.

TLR4 SIGNALING IN ALCOHOLIC LIVER DISEASE

EFFECTS OF DASH GROCERIES ON BLOOD PRESSURE IN BLACK RESIDENTS OF URBAN FOOD DESERTS - ELEVATED BLOOD PRESSURE (BP) AND HYPERTENSION ARE RAMPANT IN THE US, DISPROPORTIONATELY AFFECTING OVER HALF OF BLACK ADULTS. INTERVENTIONS THAT LOWER BP REDUCE RISK OF CARDIOVASCULAR DISEASE (CVD), STROKE, AND PREMATURE DEATH. THE DASH DIET, A BALANCED EATING PLAN THAT EMPHASIZES FRUITS, VEGETABLES, LOW FAT DAIRY, AND LEAN MEATS, IS EFFICACIOUS IN LOWERING BP AMONG BLACK ADULTS WITH HYPERTENSION. HOWEVER, UPTAKE AMONG BLACK ADULTS IS POOR. IN FACT, UNHEALTHY DIET IS THE MOST SIGNIFICANT DETERMINANT OF DISPARITIES IN HYPERTENSION MANAGEMENT AMONG BLACK ADULTS. DESPITE NUMEROUS EDUCATIONAL INITIATIVES ENCOURAGING ADULTS TO EAT 7-9 DAILY SERVINGS OF FRUITS AND VEGETABLES, AVERAGE CONSUMPTION OF FRUITS AND VEGETABLES BY ADULTS OF LOWER SOCIOECONOMIC STATUS HAS STAGNATED AT 1.3 SERVINGS DAILY. ACCESS, COST, AND CULTURAL DISSONANCE IN URBAN "FOOD DESERTS" HAVE BEEN CITED AS SIGNIFICANT BARRIERS TO HEALTHIER EATING. THUS, INNOVATIVE RESEARCH IS URGENTLY NEEDED TO DEVISE STRATEGIES THAT IMPROVE CONSUMPTION OF HEALTHY FOODS AND REDUCE HEALTH DISPARITIES AMONG BLACK ADULTS LIVING IN URBAN FOOD DESERTS. NOVEL INNOVATIONS IN GROCERY DELIVERY HAVE THE POTENTIAL TO OVERCOME BARRIERS TO HEALTHY EATING ON A MASSIVE SCALE. WITH THE ADVENT OF LARGE TECHNOLOGY-BASED COMPANIES, WHICH HAVE UNPRECEDENTED SOURCING AND DELIVERY CAPABILITIES, IT IS POSSIBLE TO OVERCOME TRADITIONAL BARRIERS AND FACILITATE CHOICE OF PALATABLE HEALTHY FOODS THROUGHOUT URBAN BLACK COMMUNITIES. HOWEVER, WHETHER VIRTUAL SUPERMARKETS WITH HOME DELIVERY CAN BE LEVERAGED TO MEANINGFULLY IMPROVE DIET AND BP IN AN URBAN FOOD DESERT HAS NEVER BEEN TESTED. WE WILL PERFORM A 12-WEEK INDIVIDUAL-LEVEL, RANDOMIZED TRIAL TO DETERMINE THE HEALTH EFFECTS OF COMPLETE DIETARY REPLACEMENT WITH HOME-DELIVERED, LOW-SODIUM, DASH-PATTERN GROCERIES ORDERED VIRTUALLY WITH DIETITIAN ASSISTANCE. OUR PROPOSAL REPRESENTS A PARTNERSHIP WITH COMMUNITY CLINICS SERVING URBAN COMMUNITIES IN CONSULTATION WITH LEADERS IN CULTURALLY SENSITIVE MEAL PREPARATION AND COMMUNITY-BASED PARTICIPATORY RESEARCH TO ENROLL BLACK ADULTS LIVING IN LOCAL URBAN FOOD DESERTS WITH ELEVATED BP OR HYPERTENSION. PARTICIPANTS WILL HAVE AUTONOMY TO CHOOSE THEIR OWN GROCERIES WEEKLY THROUGH AMAZONFRESH, FOLLOWING A PATTERN THAT PORTIONS FOOD GROUPS ACCORDING TO THE DASH FEEDING PLAN AT AN AMOUNT THAT EXCEEDS THEIR CALORIE NEEDS. AFTER 12 WEEKS, WE WILL ASSESS THE EFFECTS OF THE GROCERIES ON SYSTOLIC BP (PRIMARY OUTCOME) AND SECONDARILY ON CVD RISK FACTORS (CHOLESTEROL). OUR PROPOSAL ALSO INCLUDES 8 WEEKS OF DEDICATED OBSERVATION TO CHARACTERIZE FACILITATORS AND BARRIERS OF SUSTAINED DASH ADHERENCE VIA MIXED METHODS. THIS TRIAL WILL ESTABLISH A SCALABLE, PATIENT-ORIENTED SOLUTION THAT OVERCOMES POOR ACCESS TO HEALTHFUL FOODS AND ADDRESSES HEALTH DISPARITIES. KNOWLEDGE TO BE GAINED FROM THIS PROPOSAL IS DIRECTLY RELEVANT TO EVOLVING U.S. FOOD STAMP (SNAP) POLICY TOWARD E-COMMENCE GROCERIES AND WILL INFORM ITERATIVE INNOVATION ON INTERVENTIONS THAT REDUCE DIETARY DISPARITIES AMONG BLACK ADULTS. ULTIMATELY, OUR PROPOSAL ACCOMPLISHES A MAJOR STRATEGIC PRIORITY OF THE NIMHD FOR SCIENTIFIC RESEARCH TO “DEVELOP AND TEST INTERVENTIONS TO REDUCE HEALTH DISPARITIES.”

LYMPHOCYTE SIGNALING DEFECTS IN PATIENTS WITH LUPUS

TARGETING THE ENDOTHELIUM IN SEPSIS

GERIATRIC TRAINING PROGRAM FOR PHYSICIANS, DENTISTS, AND BEHAVIORAL AND MENTAL HEALTH PROFESSIONS

PERIPHERAL AND CENTRAL INTERACTIONS IN ENERGY BALANCE

MECHANISMS UNDERLYING THE BLOOD PRESSURE LOWERING EFFECT OF SLEEP EXTENSION.

TARGETING TUMOR SUPPRESSOR PHOSPHATASES FOR CANCER THERAPY

INHIBITION OF HIV AT THE IMMUNE SYNAPSE UTILIZING NOVEL LIGANDS AND RECEPTORS

THE CO-CLINICAL PROJECT: INFORMING CLINICAL TRIALS USING PRECLINICAL MOUSE MODELS

GLUCLOSE TRANSPORTER REGULATION IN OBESITY AND DIABETES

GLYCOPROTEOMICS AND THE GLYCOSYLATION CODE OF THE BRAIN IN ASYMPTOMATIC AND SYMPTOMATIC ALZHEIMER?S DISEASE

ULTRASENSITIVE C.DIFFICILE TOXIN MEASUREMENT FOR DIAGNOSIS AND OUTCOME PREDICTION

PATTERNS OF SLEEP RESTRICTION AND RECOVERY: THE INFLAMMATORY RESOLUTION PATHWAYS

MYOCARDIAL RADIOMICS AND MECHANICS IN THE PATHOLOGY AND PROGNOSIS OF CARDIOVASCULAR DISEASE - PROJECT SUMMARY THOUGH KNOWLEDGE ADVANCES HAVE BEEN MADE IN IDENTIFICATION AND TREATMENT OF RISK FACTORS, CARDIOVASCULAR DISEASE (CVD) REMAINS THE LEADING CAUSE OF DEATH IN THE U.S., AND HAS BEEN WORLDWIDE FOR THE PAST 15 YEARS. THE MECHANISMS OF THREE LEADING SOURCES OF CVD MORBIDITY, ISCHEMIC CORONARY ARTERY DISEASE, HEART FAILURE, AND ATRIAL FIBRILLATION, APPEAR ROOTED IN MYOCARDIAL PATHOPHYSIOLOGY OF THE LEFT VENTRICLE (LV), SUGGESTING THAT DEEPER PHENOTYPING OF THE LV MAY PROVIDE INSIGHT INTO THE DISEASES. THE DETECTION OF EARLIEST FORMS OF LV DYSFUNCTION HAS BEEN CHALLENGING: TRADITIONAL MEASURES OF LV STRUCTURE AND FUNCTION ASSOCIATED WITH POOR OUTCOMES, SUCH AS MASS AND EJECTION FRACTION, REFLECT ADVANCED STAGES OF DISEASE. HOWEVER, RECENT ADVANCES IN QUANTITATIVE IMAGING OF THE LV MYOCARDIUM USING CARDIOVASCULAR MAGNETIC RESONANCE (CMR) IMAGES MAY BRIDGE THIS GAP. MYOCARDIAL TEXTURE ANALYSIS IS A TYPE OF ‘RADIOMICS’, THE COMPUTATION OF MYOCARDIAL PIXEL INTENSITY AND PATTERNS, WHICH HAS SHOWN THE ABILITY TO DIFFERENTIATE PATHOLOGICAL PATTERNS IN LV HYPERTROPHY. ADDITIONALLY, ANALYSIS OF MYOCARDIAL MECHANICS INCLUDING STRAIN AND TORSION HAVE SHOWN PROGNOSTIC VALUE IN EVALUATION OF CARDIOMYOPATHIES. THUS, INCREASING EVIDENCE INDICATES ROLES FOR THESE TECHNOLOGICAL ADVANCES IN IMAGING ANALYSIS TO EVALUATE PATHOLOGICAL LV REMODELING IN SUBCLINICAL CARDIOVASCULAR DISEASE IN THE GENERAL POPULATION. WE HYPOTHESIZE THAT APPLICATION OF THESE NOVEL IMAGING ANALYTICS, CORRELATED WITH BIOLOGY, SUBCLINICAL DISEASE PHENOTYPING, AND OUTCOMES, WILL ENABLE MORE GRANULAR INSIGHT INTO SUBCLINICAL LV STRUCTURAL AND FUNCTIONAL CHANGES PREDATING OVERT CVD AND ITS FORMS. THE FRAMINGHAM AND JACKSON HEART STUDIES, COMMUNITY-BASED COHORTS OF WHITES AND AFRICAN AMERICANS WITH LONGITUDINAL FOLLOW UP, OFFER THE OPPORTUNITY TO GAIN INSIGHT IN CVD DEVELOPMENT THROUGH INTEGRATION OF ADVANCED SECONDARY IMAGING ANALYSIS WITH DETAILED AND BROAD PHENOTYPING AND GENOTYPING, AND CLINICAL END-POINTS. THUS, THE OBJECTIVES OF OUR PROPOSAL ARE THREEFOLD: 1) TO FIRST IDENTIFY MYOCARDIAL TEXTURE ANALYSIS AND MECHANICS PATTERNS ASSOCIATED WITH PREVALENT CVD AND RISK FACTORS, 2) TO DEFINE THE BIOLOGICAL AND GENETIC UNDERPINNINGS OF THESE PHENOTYPES, AND 3) TO UNDERSTAND THEIR INTER-ASSOCIATION BETWEEN STRUCTURE AND FUNCTION, AND THEIR JOINT RELATIONS WITH LONG-TERM PROGNOSIS. EXECUTION OF OUR AIMS WILL ELUCIDATE NOVEL PATTERNS, DETERMINANTS, AND PROGNOSIS OF UNDERLYING EARLY AND PROGRESSIVE MYOCARDIAL REMODELING AND DYSFUNCTION IN CVD IN A LARGE BI-RACIAL COHORT. ULTIMATELY, OUR GOAL IS FOR KNOWLEDGE GAINED FROM THIS STUDY TO ADVANCE PHENOTYPING OF LV REMODELING GROUPS, METHODS OF CARDIOVASCULAR RISK STRATIFICATION, AND DEVELOPMENT OF THERAPIES FOR PATIENT CARE.

IMPACT OF HIV ENVELOPE CONFORMATION ON IMMUNOGENICITY

STALLED REPLICATION FORK REPAIR IN CANCER PREDISPOSITION AND CANCERTHERAPY - PROJECT SUMMARY ERROR-FREE DNA REPAIR INITIATED AT THE SITES OF REPLICATION FORK STALLING IS CRITICAL FOR THE PREVENTION OF GENOMIC INSTABILITY IN CYCLING CELLS. DEFECTS IN STALLED FORK REPAIR HAVE BEEN DIRECTLY IMPLICATED IN CANCER PREDISPOSITION AND OTHER HUMAN DISEASES. THE CLINICAL BURDEN ASSOCIATED WITH FAILED STALLED FORK REPAIR MAY INCLUDE HEREDITARY BREAST AND OVARIAN CANCER (HBOC) PREDISPOSITION, IN LIGHT OF THE INVOLVEMENT OF BRCA1 AND BRCA2 IN REPAIR OF STALLED REPLICATION FORKS, AND FANCONI ANEMIA (FA)—A RARE, AUTOSOMAL RECESSIVE (OR X-LINKED) DISEASE CAUSED BY INACTIVATION OF ANY ONE OF SEVERAL FA GENES. OUR WORK PREVIOUSLY ESTABLISHED ROLES FOR BRCA1 AND BRCA2 IN REGULATING HR AT BOTH DOUBLE STRAND BREAKS (DSBS) AND IN STALLED FORK REPAIR. WE DEVELOPED INNOVATIVE TOOLS FOR QUANTIFYING HOMOLOGOUS RECOMBINATION (HR) AND OTHER REPAIR OUTCOMES AT STALLED MAMMALIAN REPLICATION FORKS AND, MORE RECENTLY, AT BROKEN REPLICATION FORKS. A MAJOR GOAL OF THIS PROPOSAL IS TO DEFINE THE FUNDAMENTAL MECHANISMS OF REPAIR OF STALLED FORKS. WE HAVE DEVELOPED AN ARRAY OF CUTTING-EDGE TOOLS TO SUPPORT THIS STUDY, INCLUDING UNIQUE, SOPHISTICATED HR REPORTERS THAT CAN DISTINGUISH BETWEEN ERROR-FREE “SHORT TRACT” HR AND ERROR- PRONE “LONG TRACT” HR—A REPLICATIVE RESPONSE ANALOGOUS TO BREAK-INDUCED REPLICATION IN YEAST. ONE UNUSUAL ABERRANT REPLICATIVE RESPONSE THAT WE OBSERVE AT STALLED FORKS SPECIFICALLY IN BRCA1 MUTANT CELLS IS THE FORMATION OF <10 KB NON-HOMOLOGOUS TANDEM DUPLICATIONS (TDS). IN A PARADIGM-SHIFTING DISCOVERY, WE FOUND THAT THESE HIGHLY SPECIFIC FORMS OF STRUCTURAL VARIATION ARE ALSO ABUNDANT IN THE HUMAN BRCA1-LINKED BREAST AND OVARIAN CANCER GENOME. A MAJOR GOAL OF THIS PROPOSAL IS TO DEFINE THE GENETIC REGULATION AND FULL MECHANISM OF TD FORMATION AT STALLED FORKS IN BRCA1 MUTANT CELLS. SUCCESS IN THIS PROJECT WILL REVEAL IN UNPRECEDENTED DETAIL THE MECHANISMS THAT REGULATE MAMMALIAN STALLED (OR BROKEN) FORK REPAIR AND THEIR RELATIONSHIP TO CANCER PREDISPOSITION. IN SUPPORT OF THIS, WE WILL DEVELOP NEW TECHNIQUES FOR ANALYZING DNA STRUCTURAL INTERMEDIATES, CHROMATIN RESPONSES TO FORK STALLING AND PROTEIN COMPOSITION OF THE STALLED MAMMALIAN REPLICATION FORK. THESE ANALYTICAL STUDIES MAY ALSO IDENTIFY NEW MOLECULAR TARGETS FOR THERAPY OF BREAST AND OVARIAN CANCER. INDEED, OUR RECENT WORK ON THE MECHANISMS UNDERLYING FORMATION OF BRCA1-LINKED TDS LED US TO DISCOVER A SYNTHETIC LETHAL INTERACTION BETWEEN BRCA1 AND FANCM LOSS-OF-FUNCTION MUTATIONS. FANCM IS A MOTOR PROTEIN AND, HENCE, AN ATPASE. WE FIND THAT ABLATION OF FANCM ATPASE ACTIVITY ALONE (LEAVING THE REST OF THE PROTEIN INTACT AND STABLE WITHIN THE CELL) IS SUFFICIENT TO CONFER LETHALITY ON BRCA1 MUTANT CELLS. THUS, FANCM MAY BE A “DRUGGABLE” TARGET FOR THERAPY IN BRCA1-LINKED CANCER. IN WORK PROPOSED HEREIN, WE WILL DEFINE THE THERAPEUTIC POTENTIAL OF THIS DISCOVERY. DURING THE FUNDING PERIOD, WE EXPECT TO MAKE IMPORTANT DISCOVERIES IN THIS FIELD AND TO OPEN THE DOOR TO NEW THERAPIES IN HBOC AND PERHAPS OTHER FORMS OF CANCER.

TAMING INFLAMMATION TO CREATE TRANSPLANT TOLERANCE

OBSTRUCTIVE SLEEP APNEA INCREASES CARDIOVASCULAR RISK IN TYPE 2 DIABETES

HARVARD MEDICAL SCHOOL VACCINE CLINICAL TRIALS UNIT

USE OF DE NOVO SYNTHESIS APPROACHES AND STRUCTURE-GUIDED DESIGN TO OPTIMIZE THERAPEUTIC PROPERTIES OF STREPTOTHRICIN CLASS ANTIMICROBIALS

RESEARCH TRAINING IN NEPHROLOGY

NOVEL REGULATION OF PI3K/AKT TO DIRECT TARGETED BREAST CANCER THERAPIES

ERK KINASE REGULATION OF INSULIN SIGNALING AND INFLAMMATION: HONING THE ANTIDIABETIC EFFECTS OF PPAR-GAMMA ACTIVATION

EFFECTS OF PGE2 ON RECONSTITUTION OF HEMATOPOIESIS AND IMMUNITY AFTER UCBT

PERFUSION MRI FOR MULTISITE STUDIES OF BRAIN FUNCTION

PHOSPHATASES IN HUMAN LUPUS

MEMORY ADVANCEMENT BY INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID)

REGULATION OF NUTRIENT HOMEOSTASIS BY IRF4

PREDICTING FRACTURE RISK IN PATIENTS TREATED WITH RADIOTHERAPY FOR SPINAL METASTATIC DISEASE

CARDIOPULMONARY EXERCISE MRI IN HEART FAILURE WITH PRESERVED EJECTION FRACTION - PROJECT SUMMARY CARDIOVASCULAR DISEASE (CVD) IS THE LEADING CAUSE OF MORBIDITY AND MORTALITY IN THE UNITED STATES, WITH THE PREVALENCE OF HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFPEF) RISING EVERY YEAR. CURRENTLY, THERE IS NO SINGLE NON-INVASIVE DIAGNOSTIC TEST FOR ACCURATE DIAGNOSIS OF HFPEF. HFPEF IS DIAGNOSED THROUGH A COMBINATION OF SYMPTOM ASSESSMENTS, PLASMA BIOMARKERS, AND CARDIAC IMAGING. WHEN PATIENTS ARE ACUTELY DECOMPENSATED, HFPEF CAN BE DIAGNOSED WITH HIGH CONFIDENCE. HOWEVER, AMONG STABLE OUTPATIENTS PRESENTING WITH DYSPNEA ON EXERTION AND AN INTERMEDIATE PRE-TEST PROBABILITY OF HFPEF, DIAGNOSIS IS EXTREMELY CHALLENGING. SINCE NON- INVASIVE TESTING HAS LIMITED DIAGNOSTIC SPECIFICITY, IN THESE CASES, INVASIVE HEMODYNAMIC CARDIOPULMONARY EXERCISE TESTING (ICPET) IS CONSIDERED THE GOLD STANDARD. HOWEVER, ICPET IS INVASIVE, CARRIES RISK, AND IS PERFORMED ONLY IN SPECIALIZED CENTERS. CARDIOVASCULAR MRI (CMR) CAN NON-INVASIVELY ASSESS HF-RELATED HEART AND VASCULAR ABNORMALITIES INCLUDING BIVENTRICULAR STRUCTURE/FUNCTION, MYOCARDIAL TISSUE COMPOSITION, CORONARY MICROVASCULAR FUNCTION, AORTIC DISTENSIBILITY/STIFFNESS, AND FAT ACCUMULATION. AS CARDIOVASCULAR AND PULMONARY SYMPTOMS OF HFPEF OCCUR WITH EXERTION, THE OBJECTIVE OF THIS PROPOSAL IS TO USE A SUPINE ERGOMETER MOUNTED ON THE MRI SCANNER TABLE TO EXAMINE HEART AND LUNG PATHOPHYSIOLOGY WITH EXERCISE OF INCREMENTALLY INCREASING RESISTANCE, FOLLOWED BY A CONVENTIONAL VASODILATOR STRESS IMAGING PROTOCOL. THE GOAL OF THIS STUDY IS TO USE OUR NOVEL CARDIOPULMONARY EXERCISE MRI PROTOCOL TO ACCURATELY DIAGNOSE “EARLY” HFPEF, TO ELIMINATE THE NEED FOR ICPET, AND TO IDENTIFY SPECIFIC PATHOPHYSIOLOGIES UNDERLYING HFPEF PROGRESSION AND PROGNOSTIC INFORMATION FOR ADVERSE CVD OUTCOMES. TO ACHIEVE THIS, WE WILL RECRUIT PATIENTS FROM THREE MEDICAL CENTERS TO CONDUCT A PROSPECTIVE STUDY USING CARDIOPULMONARY EXERCISE MRI IN SUSPECTED “EARLY” HFPEF PATIENTS WHO ARE CLINICALLY REFERRED FOR ICPET, WITH A FOLLOW-UP MRI SCAN 18 MONTHS LATER. OUR THREE SPECIFIC AIMS SEEK TO 1) INVESTIGATE NON-INVASIVE IMAGING CORRELATES AND DIAGNOSTIC PERFORMANCE OF CARDIOPULMONARY MRI FOR EARLY HFPEF DIAGNOSIS IN PATIENTS WITH NORMAL EJECTION FRACTION AND UNEXPLAINED DYSPNEA, USING ICPET AS A REFERENCE STANDARD; 2) INVESTIGATE THE RELATIONSHIP BETWEEN CARDIOPULMONARY EXERCISE MRI PARAMETERS AND CVD HEALTH OUTCOMES, INCLUDING CARDIOVASCULAR DEATH AND HOSPITALIZATION IN SUSPECTED EARLY HFPEF; 3) EXPLORE TEMPORAL CHANGES IN HEART AND LUNG STRUCTURE AND FUNCTION IN SUSPECTED EARLY HFPEF BY COMPLETING A SECOND CARDIOPULMONARY EXERCISE MRI 18 MONTHS AFTER THE INITIAL MRI EXAM. THIS INNOVATIVE CARDIOPULMONARY EXERCISE MRI PROTOCOL IS EXPECTED TO IMPROVE NON-INVASIVE DIAGNOSIS AND PROGNOSIS OF HFPEF, AND ULTIMATELY CONTRIBUTE TO IMPROVED TREATMENT STRATEGIES AND PREVENTATIVE CARE BY PROVIDING MORE ACCURATE DIAGNOSTIC CRITERIA AND A NON-INVASIVE METHOD OF MONITORING THE EFFICACY OF NEW TREATMENT STRATEGIES IN CLINICAL TRIALS.

MOLECULAR GENETICS OF INHERITED FOCAL GLOMERULEROSIS

GLUCOSE-SENSING BY NEURONS: ITS IMPORTANCE AND THE ROLE OF UCP2

IMMUNOLOGIC SIGNATURES OF SARS-COV-2 VACCINATION AND DISEASE

PERSONALIZED ADOPTIVE T-CELL THERAPY FOR AML - ABSTRACT/PROJECT SUMMARY THE DEVELOPMENT OF STRATEGIES TO EXPAND AND ACTIVATE AML SPECIFIC T CELLS IS OF CRITICAL IMPORTANCE. WE HAVE DEVELOPED A PERSONALIZED CANCER VACCINE IN WHICH PATIENT DERIVED TUMOR CELLS ARE FUSED WITH AUTOLOGOUS DENDRITIC CELLS (DCS), PRESENTING A BROAD ARRAY OF ANTIGENS THAT CAPTURE THE HETEROGENEITY OF THE LEUKEMIA CELL POPULATION, INCLUDING SHARED AND NEOANTIGENS. WE HAVE COMPLETED A PHASE II CLINICAL TRIAL IN WHICH PATIENTS THAT ACHIEVE REMISSION FOLLOWING CHEMOTHERAPY UNDERGO SERIAL VACCINATION WITH DC/AML FUSIONS. REMARKABLY, DESPITE A MEDIAN AGE OF 63, 71% REMAINED FREE OF DISEASE WITH A MEDIAN FOLLOW UP OF 5 YEARS. VACCINATION WAS ASSOCIATED WITH THE EXPANSION OF T CELLS TARGETING BOTH AUTOLOGOUS AML CELLS AND LEUKEMIA ASSOCIATED ANTIGENS. THE DC/AML VACCINE CAN BE USED AS A PLATFORM TO GENERATE ACTIVATED LEUKEMIA-SPECIFIC T CELLS EX- VIVO FOR ADOPTIVE IMMUNOTHERAPY. IN THIS WAY, EFFECTOR CELLS MAY BE GENERATED THAT ARE LEUKEMIA SPECIFIC, CAPTURE TUMOR HETEROGENEITY, AND ARE ACTIVATED EX VIVO TO ACHIEVE A FUNCTIONALLY COMPETENT PHENOTYPE. WE HAVE DEMONSTRATED THAT VACCINE STIMULATION IN THE CONTEXT OF IL7/IL-15 RESULTS IN ENHANCED LEVELS OF CENTRAL MEMORY CELLS CRITICAL FOR LONG TERM PERSISTENCE OF RESPONSE. WHILE THE GENERATION OF VACCINE STIMULATED LEUKEMIA SPECIFIC T CELLS EX VIVO REPRESENTS A PROMISING STRATEGY TO EFFECTIVELY TARGET AML CELLS IN VIVO, THE IMMUNOSUPPRESSIVE NATURE OF THE TUMOR MICROENVIRONMENT REMAINS A BARRIER TO THE DEVELOPMENT OF A MEMORY RESPONSE AND LONG-TERM PROTECTION. WE PERFORMED TRANSCRIPTOME ANALYSIS IN THE REMISSION BONE MARROW AT TIME OF VACCINATION TO IDENTIFY BIOMARKERS THAT WERE PREDICTIVE OF DURABLE RESPONSE AS COMPARED TO EARLY RELAPSE FOLLOWING VACCINATION WITH DC/AML FUSIONS. OF NOTE, DECREASED EXPRESSION OF TGF-SS IN THE BONE MARROW MICROENVIRONMENT WAS ASSOCIATED WITH DURABLE REMISSION. THESE RESULTS ARE CONSISTENT WITH PRIOR REPORTS SUGGESTING TGF-SS AS A NEGATIVE REGULATOR OF TUMOR IMMUNOGENICITY, T CELL ACTIVATION AND INFILTRATION INTO THE TUMOR BED. AS SUCH THERE IS STRONG RATIONALE TO TARGET TGFSS TO ENHANCE VACCINE EFFICACY. IN THE PRESENT STUDY, WE WILL CREATE A NOVEL STRATEGY FOR ADOPTIVE T CELL THERAPY GENERATED BY VACCINE MEDIATED STIMULATION, SELECTION OF ANTIGEN SPECIFIC T CELLS AND EX VIVO EXPANSION. FUNCTIONAL CHARACTERISTICS WILL BE EXAMINED IN AN IMMUNOCOMPETENT MURINE LEUKEMIA MODEL. WE WILL THEN EXAMINE THE EFFECT OF TGF-SS INHIBITION ON VACCINE RESPONSE AND TGF INHIBITION WITHIN VACCINE STIMULATED T CELLS BY SILENCING OF THE DOWNSTREAM EFFECTOR SMAD2. IN THE SECOND AIM, THE T CELL PRODUCT WILL BE CHARACTERIZED WITH RESPECT TO TARGETING OF SHARED AND NEO-ANTIGEN TARGETS, OLIGOCLONAL EXPANSION AND DIVERSITY OF THE REPERTOIRE, EXPRESSION OF MARKERS OF ACTIVATION, EXHAUSTION, SENESCENCE, AND CHEMOKINES NEEDED FOR MIGRATION INTO THE TUMOR BED. IN THE THIRD AIM, WE WILL CONDUCT A PHASE I STUDY IN WHICH PATIENTS WITH AML WHO ACHIEVE COMPLETE REMISSION WILL UNDERGO ADOPTIVE THERAPY WITH VACCINE STIMULATED T CELLS.

USING POLYGENIC RISK SCORES AND OMICS TO STUDY HOW SUBOPTIMAL SLEEP ACCELERATES COGNITIVE AGING IN DIVERSE POPULATIONS - PROJECT SUMMARY SUBOPTIMAL SLEEP, CHARACTERIZED BY PHENOTYPES SUCH AS INSOMNIA, SHORT SLEEP, AND OBSTRUCTIVE SLEEP APNEA, IS ASSOCIATED WITH REDUCED COGNITIVE PERFORMANCE AND INCREASED COGNITIVE DECLINE AND DEMENTIA RISK. THERE IS STRONG EVIDENCE OF SLEEP DISPARITIES BETWEEN RACE/ETHNIC AND GENDER MINORITIES, POTENTIALLY RELATING TO DOWNSTREAM DISPARITIES IN COGNITIVE AGING. HOWEVER, THE MECHANISMS BY WHICH SLEEP PHENOTYPES ACCELERATE COGNITIVE AGING ARE NOT WELL UNDERSTOOD. IDENTIFYING SPECIFIC BIOLOGICAL PATHWAYS AND BIOMARKERS OF SLEEP PHENOTYPES WILL ENABLE UNCONFOUNDED QUANTIFICATION OF THE EFFECT OF SLEEP PHENOTYPES ON COGNITIVE AGING, RISK STRATIFICATION, AND DEVELOPMENT OF POTENTIAL INTERVENTION TARGETS. WE WILL ESTABLISH A COLLABORATION ACROSS THREE LONGITUDINAL COHORT STUDIES REPRESENTING THE DIVERSE U.S. POPULATION: THE ATHEROSCLEROSIS RISK IN COMMUNITIES (ARIC) STUDY, THE HISPANIC COMMUNITY HEALTH STUDY/STUDY OF LATINOS (HCHS/SOL), AND THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), TO STUDY HOW SUBOPTIMAL SLEEP ACCELERATES COGNITIVE AGING. WE WILL STUDY THE ASSOCIATIONS OF SLEEP DISORDERS (INSOMNIA, SHORT AND LONG SLEEP, AND OBSTRUCTIVE SLEEP APNEA) WITH HARMONIZED, GLOBAL MEASURES OF COGNITIVE AGING. WE WILL DEVELOP POLYGENIC RISK SCORES (PRSS) FOR SLEEP PHENOTYPES USING NOVEL METHODOLOGY, THAT WILL APPROPRIATELY ACCOUNT FOR HETEROGENEOUS GENETIC ANCESTRY OF STUDY INDIVIDUALS, AND IDENTIFY SLEEP PHENOTYPES THAT ARE GENETICALLY STRONGLY ASSOCIATED WITH COGNITIVE AGING BASED ON PRSS. WE WILL USE OMICS (METABOLOMICS AND PROTEOMICS) TO EXPLAIN BIOLOGICAL PATHWAYS UNDERLYING THE SLEEP-COGNITIVE AGING ASSOCIATIONS. WE EXPECT THAT WE WILL IDENTIFY BIOMARKERS AND MEDIATORS OF THE SLEEP-RELATED EFFECTS ON COGNITIVE AGING, AND USING MENDELIAN RANDOMIZATION ANALYSES, WE WILL BE ABLE TO UNTANGLE SOME OF THE DIRECTIONAL ASSOCIATIONS. FINALLY, WE WILL STUDY RISK PREDICTION MODELS FOR COGNITIVE AGING THAT USE SLEEP-RELATED MEASURES. WE WILL STUDY WHETHER THE IDENTIFIED ASSOCIATIONS AND RISK PREDICTION MODELS GENERALIZE TO AD-SPECIFIC PHENOTYPES IN DATASETS OF TWO COHORTS FROM THE RUSH ALZHEIMER'S DISEASE CENTER. THIS WORK WILL RESULT IN THE IDENTIFICATION OF OMICS BIOMARKERS THAT MEASURE AND MEDIATE THE GENETIC RISK OF SLEEP PHENOTYPES ON COGNITIVE AGING, AND NEW RISK MODELS FOR COGNITIVE AGING BASED ON PRSS AND OMICS. IMPORTANTLY, OUR STUDY WILL INCLUDE INDIVIDUALS FROM DIVERSE U.S. POPULATIONS, AND OUR METHODOLOGY WILL ENSURE THAT THE FINDINGS AND MODELS ARE USEFUL ACROSS POPULATIONS. THIS WORK WILL GUIDE PRECISION MEDICINE INITIATIVES TO IMPROVE COGNITIVE HEALTH IN AGING INDIVIDUALS FROM DIVERSE GENETIC BACKGROUNDS.

THE FUNCTIONAL NEUROANATOMY OF THE HUMAN PHYSIOLOGICAL STRESS RESPONSE

BIOLOGICAL MECHANISM OF FSGS-1

LEVERAGING THE RICH GENETIC DIVERSITY OF VAGAL MOTOR NEURONS TO DECODE BRAIN-TO-GUT COMMUNICATION

PERSONALIZED VACCINE FOR PATIENTS WITH AML

OPTIMIZATION OF BROADLY NEUTRALIZING ANTIBODIES FOR HIV ERADICATION

COOPERATIVE REGULATION OF MECHANOTRANSDUCTION FOR LYMPHATIC VALVE DEVELOPMENT BY PROX1 AND NF-KB

GADOLINIUM FREE CARDIAC MR IMAGING OF SCAR AND FIBROSIS

ANALYSIS OF BRCA1 RECOMBINATION FUNCTIONS

(PQB5)MOLECULAR WIRING AND THERAPEUTIC TARGETING OF EGFR AND PDGFR SIGNALING NETW

IMAGING MARKERS OF SUBCLINICAL CARDIOTOXICITY IN BREAST CANCER

RESOURCE FOR NONHUMAN PRIMATE CELL DEPLETING ANTIBODIES

THE TRAJECTORIES AND CLINICAL EXPERIENCES OF ICD THERAPY (TRACER-ICD) STUDY - PROJECT SUMMARY / ABSTRACT X OVER 50,000 IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS (ICDS) ARE IMPLANTED ANNUALLY IN PATIENTS =65 YEARS OLD AT AN ESTIMATED COST OF >$2 BILLION. ICD GUIDELINES DRAW UPON TRIALS ENROLLING FEW OLDER PATIENTS, YET HALF OF THESE PATIENTS WILL EITHER BE DEAD OR ENROLLED IN HOSPICE WITHIN 5 YEARS OF IMPLANTATION. THOUGH MEDICARE NOW MANDATES SHARED DECISION-MAKING (SDM) FOR ICDS, FEW STUDIES HAVE INVESTIGATED QUESTIONS VITAL FOR OLDER PATIENTS, INCLUDING HEALTH STATUS TRAJECTORIES AND QUALITY OF LIFE. IMPROVED SDM FOR OLDER PATIENTS REQUIRES MOVING BEYOND AVERAGE TREATMENT EFFECT ESTIMATES TO INCORPORATE PRECISION MODELING OF THESE OUTCOMES. THERE IS THEREFORE A PRESSING NEED FOR LONGITUDINAL DATA TO SUPPORT PATIENT-CENTERED SDM FOR OLDER ADULTS. TO EXTEND OUR PRIOR WORK AND FURTHER IMPROVE SDM FOR OLDER ADULTS CONSIDERING AN ICD, WE PROPOSE THE TRAJECTORIES AND CLINICAL EXPERIENCES OF ICD THERAPY (TRACER-ICD) STUDY, A MULTI-CENTER PROSPECTIVE COHORT WITH THE GOAL OF BETTER DEFINING PATIENT-CENTERED GOALS AND EXPERIENCES IN OLDER PATIENTS UNDERGOING ICD IMPLANTATION. WE WILL PROSPECTIVELY COLLECT DATA ON GERIATRIC CONDITIONS AND QUALITY OF LIFE FROM PATIENTS AT 5 SITES, ENRICHED WITH REMOTE MONITORING DATA ON ARRHYTHMIAS AND PHYSICAL ACTIVITY, TO EVALUATE THEIR CLINICAL AND FUNCTIONAL TRAJECTORIES (AIM 1). THIS COHORT WILL SUPPORT FURTHER REFINEMENT OF OUR STATISTICAL MODEL TO PERSONALIZE PREDICTION OF TREATMENT OUTCOMES (AIM 2). LASTLY, WE WILL USE MIXED METHODS TO IDENTIFY OPTIMAL IMPLEMENTATION STRATEGIES FOR TRANSLATING THESE INDIVIDUALIZED PREDICTION PROFILES INTO SDM FOR ICDS (AIM 3).THIS PROPOSAL IS LED BY AN EARLY STAGE INVESTIGATOR WHOSE EXPERTISE IN CARDIAC ELECTROPHYSIOLOGY, GERIATRIC MEDICINE, AND OUTCOMES RESEARCH WILL BE COMPLEMENTED BY AN EXPERIENCED RESEARCH TEAM WITH A STRONG RECORD OF COLLABORATION. IMPACT: AS THE FIRST COMPREHENSIVE, PROSPECTIVE STUDY OF OLDER ICD PATIENTS, TRACER-ICD WILL GENERATE UNIQUE PATIENT-CENTERED AND PERSONALIZED DATA ESSENTIAL FOR CHARACTERIZING OUTCOMES OF THIS COMMON PROCEDURE IN A VULNERABLE POPULATION. MUCH LIKE OTHER LARGE COHORT STUDIES IN OLDER PERSONS, WE ANTICIPATE THE ROBUST DATA EMERGING FROM TRACER-ICD WILL SERVE AS A RICH RESOURCE THAT WILL IMPROVE CARE FOR MILLIONS OF PATIENTS CONSIDERING ICD IMPLANTATION, AND PROVIDE ESSENTIAL, EVIDENCE-BASED GUIDANCE FOR TRANSLATING PERSONALIZED OUTCOME PROFILING INTO THE SDM EXPERIENCE.

MECHANISMS OF INNATE MODULATION OF SIV RESERVOIRS AND OPPORTUNISTIC DISEASE IN THE ORAL CAVITY

A PLATFORM FOR CANCER BIOMARKER VALIDATION: IMAGE FUSION USING NIR FLUORESCENCE

ROCK1 SIGNALING IN GLUCOSE METABOLISM

SPECTRO-HOLOGRAPHIC INSTRUMENT FOR DYNAMIC SENSING OF CANCER PROGRESSION

INVESTIGATION OF THE AFFECTIVE DIMENSION OF DYSPNEA

THE IMPACT OF THE BONE MARROW NICHE'S IMMUNE PRIVILEGE ON PSORIATIC ARTHRITIS - ABSTACT: PSORIATIC ARTHRITIS (PSA) IS A CHRONIC, INFLAMMATORY, AND HETEROGENEOUS DISEASE THAT AFFECT VARIOUS DISTINCT ANATOMICAL SITES; INCLUSIVE OF THE JOINTS, SKIN, AND BONE MARROW (BM). THE ETIOLOGY OF PSA REMAINS TO BE ELUCIDATED. THE CLINICAL AND EXPERIMENTAL EVIDENCE FROM OUR GROUP AND OTHERS, HAVE FIRMLY DEMONSTRATED THAT BM PLAYS THE CRUCIAL ROLES IN THE PSA PATHOGENESIS. THIS R01 PROPOSAL INVESTIGATES THE ROLES OF THE HEMATOPOIETIC STEM CELL (HSC) MICROENVIRONMENT WITHIN THE BM, IN THIS PSA PATHOGENESIS. HSCS LOCALIZE AT THE SPECIALIZED, CONFINED MICROENVIRONMENTS WITHIN THE BM, TERMED NICHES. THE HSC NICHES HAVE BEEN EXTENSIVELY STUDIED AS SITES THAT REGULATE STEM CELL FATE OR FUNCTIONS. YET, IMMUNOLOGICAL ATTRIBUTES OF THE NICHE HAVE REMAINED LARGELY UNINVESTIGATED. IT IS FURTHER UNKNOWN WHETHER ANY POTENTIAL IMMUNOLOGICAL PROPERTIES OF THE HSC NICHES CAN IMPACT SYSTEMIC IMMUNITY OR INFLAMMATORY DISEASES; INCLUSIVE OF PSA. THE OVERALL HYPOTHESIS IS THAT THE HSC NICHE ACTS AS AN IMMUNOLOGICAL SANCTUARY FOR STEM CELLS, TERMED “IMMUNE-PRIVILEGED SITES”. THIS IMMUNE PRIVILEGE OF THE HSC NICHE LIMITS THE GENERATION OF BM INFLAMMATORY MYELOID CELLS AND OSTEOCLASTS REQUIRED FOR PSA DEVELOPMENT; WHEREAS THE BREAKDOWN OF THE IMMUNE PRIVILEGE ELICITS THE DISEASE DEVELOPMENT. IT WAS ORIGINALLY DEMONSTRATED IN 1950S THAT THE TESTIS AND PLACENTA SERVE AS IMMUNE PRIVILEGED SITES. WHILE IT HAD REMAINED LARGELY UNCLEAR WHETHER SOMATIC STEM CELL NICHES ARE BROADLY IMMUNOSUPPRESSIVE, OUR RECENT STUDIES HAVE INDICATED BM HSCS ARE IMMUNE PRIVILEGED. HSCS LOCALIZE AT POTENT FOXP3+ REGULATORY T CELLS (NICHE TREGS), RENDERING HSCS IMMUNE PRIVILEGED. OUR MOST RECENT MANUSCRIPT (NATURE) HAS FURTHER IDENTIFIED HIGHLY IMMUNE-PRIVILEGED NICHES, AMONGST BM SITES, COMPOSED OF THE DISTINCTIVE ENDOSTEUM CAPILLARIES NEAR THE EPIPHYSEAL LINE. THESE SPECIALIZED CAPILLARIES ARE CHARACTERIZED BY PRIMARY CILIA; AND MOLECULAR/PHENOTYPIC FEATURES OF “SPROUTING” BLOOD VESSELS. SUCH CILIATED CAPILLARIES SHIELD HIGHLY PRIMITIVE HSCS, AMONGST OTHER HSCS; AS IDENTIFIED BY HIGH LEVELS OF NITRIC OXIDE (NO). THE CILIATED CAPILLARIES FURTHER ACCOMMODATE UNIQUE NICHE TREG POPULATIONS; THAT EXPRESS HIGH LEVELS OF HSC DEFINITIVE GENES. THE CAPILLARIES MAINTAIN THE ABUNDANCE OF THESE “STEM CELL-LIKE TREGS”, ENABLING THE ROBUST IMMUNOPROTECTION OF THE NOHI HSCS. THESE STUDIES HAVE FIRMLY IDENTIFIED: (A) NOVEL STEM CELL-LIKE TREGS; (B) CILIATED, SPROUTING CAPILLARIES; AND (C) HIGHLY PRIMITIVE NOHI HSCS, AS THE THREE LINKED KEY PLAYERS INDUCING HIGH LEVELS OF IMMUNE PRIVILEGE. YET, LITTLE IS KNOWN ABOUT WHETHER THE IMMUNE PRIVILEGE AND THE ABOVE THREE SPECIFIC CELL POPULATIONS (A-C), CONTROL THE SYSTEMIC IMMUNITY AND WHETHER DYSFUNCTION PREDISPOSES TO PSA. THIS PROPOSAL ADDRESSES THESE QUESTIONS USING OUR PREVIOUSLY-ESTABLISHED APPROACHES: (I) PSA INDUCTION USING GENE TRANSFER; AND (II) THE TARGETED DELETIONS IN TREGS, HSCS, OR VESSELS TO DISRUPT THE IMMUNE PRIVILEGE. WE WILL FURTHER DEVELOP NEW THERAPEUTIC APPROACHES TO TRANSFER OR MODULATE: STEM CELL-LIKE TREGS; CILIATED CAPILLARY CELLS AND NOHI HSCS. SUCCESSFUL STUDIES WILL CREATE A NEW PARADIGM THAT THE NOVEL IMMUNE PRIVILEGE OF THE STEM CELL NICHE CONTROLS SYSTEMIC INFLAMMATION AND PSA.

TRAINING PROGRAM IN ANGIOGENESIS & INFLAMMATION

PROTEOMIC PATHWAY DISCOVERY IN CARDIOVASCULAR DISEASE

ROLE OF TAU CONFORMATIONS IN VASCULAR CONTRIBUTION TO COGNITIVE IMPAIRMENT AND DEMENTIA

NON-CODING RNAS IN RESILIENCE TO ALZHEIMER?S DISEASE - NON-CODING RNAS IN RESILIENCE TO ALZHEIMER’S DISEASE: PI’S HIDE, KIM, SLACK SUMMARY (30 LINES) THIS PROPOSAL IS A RESPONSE TO RFA-AG-23-010 NONCODING RNAS IN ALZHEIMER’S DISEASE AND RELATED DEMENTIAS. THE OVERARCHING GOAL OF THE PROPOSED STUDY IS TO DEFINE AND CHARACTERIZE KEY NONCODING RNA (NCRNA) REGULATORS OF MECHANISMS OF BIOLOGICAL RESILIENCE AGAINST COGNITIVE LOSS IN ALZHEIMER’S DISEASE (AD). AN INDIVIDUAL WHO IS RESILIENT TO AD-RELATED NEUROPATHOLOGY AND DOES NOT SHOW COGNITIVE DECLINE DESPITE THE PRESENCE OF AD-RELATED NEUROPATHOLOGY WILL BE LESS LIKELY TO DEVELOP DEMENTIA LATER IN LIFE. A STRIKING NATURAL SUBPOPULATION OF THE ELDERLY REMAIN COGNITIVELY INTACT WHILE CONTROLLING OR COMPENSATING FOR AD-RELATED PATHOLOGY. AS OF YET, DRUG INTERVENTIONS TARGETING SPECIFIC AD-RELATED PATHOLOGIES, SUCH AS SS-AMYLOID, NEUROFIBRILLARY TANGLES, OR NEUROINFLAMMATION, HAVE BEEN LARGELY INEFFECTIVE IN CONTROLLING AD PATHOLOGY-RELATED COGNITIVE DECLINE - AD RELATED DEMENTIA (AD/ADRD). A COMPELLING ALTERNATIVE IS TO FIND WAYS TO ENHANCE RESILIENCE AGAINST AD/ADRD. DURING AGING, THE FIDELITY OF TRANSCRIPTIONAL REGULATORY PROCESSES DECLINES WITH ASSOCIATED LOSS OF FUNCTION AND COGNITIVE DECLINE. PROPER CODING AND NONCODING GENE EXPRESSION REGULATION IS CRITICAL FOR MAINTAINING HOMEOSTASIS AND PREVENTING DISEASE PROCESSES. NCRNAS ARE INCREASINGLY RECOGNIZED AS POTENT, HIGHLY SPECIFIC REGULATORS OF GENE EXPRESSION AT ALL LEVELS. NCRNAS PLAY A CRITICAL ROLE IN CELL STRESS RESPONSE. GIVEN THE LARGE NUMBER OF MIRNA AND LNCRNA GENES AND GENE/LNCRNA/MIRNA INTERACTIONS AND THE OVERARCHING ROLE OF THESE RNAS IN NORMAL PROCESSES OF THE CELL, NCRNAS HAVE ENORMOUS POTENTIAL NOT ONLY AS THERAPEUTIC TARGETS AND BIOMARKERS FOR THE PATHOLOGIES OF AGING, BUT ALSO AS KEY INTERMEDIATE MECHANISM MARKERS - HELPING DEFINE MECHANISMS OF DISEASE RESPONSE THAT THEY REGULATE. WE WILL PERFORM THE FIRST STUDY THAT SYSTEMATICALLY IDENTIFIES AND CHARACTERIZES NOVEL NCRNA-REGULATED RESILIENCE MECHANISMS IN AD; DERIVED FROM HUMAN SUBJECT DATA. THIS PROJECT WILL ESTABLISH A SYSTEMATIC FRAMEWORK FOR IDENTIFICATION OF RESILIENCE PROCESSES, TO EXPLAIN THE ROLES OF NCRNAS IN RESILIENCE TO AD AT THE CELLULAR AND MOLECULAR LEVEL. OUR COMPREHENSIVE APPROACH WILL UNCOVER THE ROLE OF NCRNA FACTORS OF RESILIENCE TO COGNITIVE DECLINE. USING SYSTEMATIC ANALYSIS OF COGNITIVELY RESILIENT POPULATIONS AND POWERFUL TOOLS THAT IDENTIFY RESILIENCE LNCRNAS AND MIRNAS, WE WILL IDENTIFY AND CHARACTERIZE THE INTERACTIONS, FUNCTIONS AND TARGETS OF PRIORITIZED RESILIENCE- ASSOCIATED NCRNAS IN OUR IN VITRO NEURONAL/GLIAL CELL CULTURE MODELS AND ADVANCED THREE-DIMENSIONAL (3D) HUMAN NEURAL CELL CULTURE MODELS OF AD. THE TEAM BRINGS TOGETHER BROAD AND DEEP INTER-DISCIPLINARY EXPERTISE IN NCRNA BIOLOGY, SYSTEMS BIOLOGY AND ALZHEIMER’S DISEASE PATHOLOGY, WITH A SOLID BASIC AND TRANSLATIONAL SCIENCE BACKGROUND TO ADDRESS UNDERSTANDING OF NCRNA IN AGING (SLACK), NCRNA TARGETING (VLACHOS), SYSTEMS BIOLOGY OF COMPLEX DISEASE (HIDE) AND EXPERTISE IN 3D AD MODEL SYSTEMS (KIM) AND AD (TANZI).

ROLE OF PDZK1 IN LIPID METABOLISM AND ATHEROSCLEROSIS.

BRAIN VULNERABILITY IN DELIRIUM AND ALZHEIMER?S DISEASE AND RELATED DEMENTIAS: INTERSECTION OF POLYGENIC RISK AND INFLAMMATION - PROJECT SUMMARY/ABSTRACT THE GOAL OF THIS PROPOSAL IS TO TEST THE HYPOTHESIS THAT GENETIC RISK FOR ALZHEIMER’S DISEASE AND ALZHEIMER’S DISEASE-RELATED DEMENTIAS (AD/ADRD) IDENTIFIES INDIVIDUALS WITH A “VULNERABLE BRAIN,” WHO MAY BE PREDISPOSED TO BAD OUTCOMES, INCLUDING DELIRIUM, COGNITIVE DECLINE, AND AD/ADRD, IN THE PRESENCE OF AN INFLAMMATORY INSULT (E.G., SURGERY OR INFECTION). DELIRIUM AND AD/ADRD HAVE STRONG EPIDEMIOLOGICAL ASSOCIATIONS: AD/ADRD HAS LONG-BEEN RECOGNIZED AS A RISK FACTOR FOR DELIRIUM, AND RECENTLY DELIRIUM HAS BEEN IMPLICATED AS A RISK FACTOR FOR INCIDENT AD/ADRD. ALTHOUGH THIS POINTS TO A CLEAR LINK BETWEEN DELIRIUM AND AD/ADRD, THE SHARED PATHOPHYSIOLOGY UNDERLYING THESE RELATIONSHIPS REMAINS LARGELY UNKNOWN. GROWING EVIDENCE HIGHLIGHTS INFLAMMATION AS A COMMON BIOLOGICAL MECHANISM OF DELIRIUM AND AD/ADRD, BUT NOT ALL INDIVIDUALS WITH HIGH INFLAMMATION DEVELOP DELIRIUM AND/OR AD/ADRD. THEREFORE OTHER PREDISPOSING FACTORS (POSSIBLY GENETIC) LIKELY INFLUENCE THE EFFECT OF INFLAMMATION ON THE BRAIN. IN THE PROPOSED R01 SPECIFIC AIMS, WE WILL ADDRESS THIS GAP IN KNOWLEDGE AND SUBSTANTIALLY EXTEND OUR PRIOR STUDIES BY: 1) MOVING BEYOND SINGLE CANDIDATE GENE APPROACHES TO EXAMINE THE SYNERGISTIC EFFECTS OF MULTIPLE GENETIC LOCI (E.G., POLYGENIC RISK SCORES, SHOWN TO ENHANCE CLINICAL PREDICTION OF AD/ADRD), AND 2) CONSIDER HOW POLYGENIC RISK OF AD/ADRD AND INFLAMMATION INTERACT TO INCREASE RISK OF DELIRIUM, COGNITIVE DECLINE, AND AD/ADRD. THESE STUDIES WILL LEVERAGE THE CONSIDERABLE RESOURCES OF SIX DATASETS: (1 & 2) THE NIA-FUNDED PROGRAM PROJECT, THE SUCCESSFUL AGING AFTER ELECTIVE SURGERY STUDY (SAGES; P01AG031720) I AND ITS RENEWAL SAGES II, (3) INTUIT [INVESTIGATING NEUROINFLAMMATION UNDERLYING POSTOPERATIVE BRAIN CONNECTIVITY CHANGES, POSTOPERATIVE COGNITIVE DYSFUNCTION, DELIRIUM IN OLDER ADULTS; K76-AG057022 AND UH2/3 AG056925], (4) MADCO-PC [MARKERS OF ALZHEIMER’S DISEASE AND COGNITIVE OUTCOMES AFTER PERIOPERATIVE CARE], (5) MARBLE [MODULATING APOE SIGNALING TO REDUCE BRAIN INFLAMMATION, DELIRIUM, AND POSTOPERATIVE COGNITIVE DYSFUNCTION; R03AG050918]; AND 6) THE POPULATION-BASED UK BIOBANK, A LARGE COHORT OF OLDER ADULTS WHO HAVE ALREADY BEEN GENOTYPED. THIS PROPOSAL IS HIGHLY NOVEL IN EXAMINING POLYGENIC RISK SCORES AND THEIR RELATIONSHIP WITH INFLAMMATION IN MULTIPLE DATASETS WITH INFORMATION ON DELIRIUM AND AD/ADRD (UNAVAILABLE IN MOST STUDIES). IMPORTANTLY, THE RESULTS WILL INFORM TARGETED, PATHOPHYSIOLOGICALLY-BASED TREATMENTS TO PROVIDE NEUROPROTECTION FOR VULNERABLE OLDER ADULTS, THEREBY POTENTIALLY PREVENTING DELIRIUM AND REDUCING AD/ADRD, TWO MAJOR THREATS TO THE INDEPENDENCE AND QUALITY OF LIFE OF ALL OLDER ADULTS.

MICRORNAS IN AGING

ADVANCING TREATMENT OUTCOMES IN MALIGNANT GLIOMA BY INTEGRATING IMMUNOTHERAPY AND STANDARD OF CARE USING GENETICALLY ENGINEERED MICE THAT RECAPITULATE MOLECULAR FEATURE OF HUMAN GLIOMA

VASCULAR THIOL ISOMERASES IN THROMBOSIS

IMAGING OF AORTIC ATHEROSCLEROSIS AND INFLAMMATION IN THE METABOLIC SYNDROME

ROLE OF LRP1 IN ALZHEIMER?S DISEASE - ALZHEIMER’S DISEASE (AD) IS A SERIOUS PUBLIC HEALTH PROBLEM. AD IS THE MOST COMMON CAUSE OF DEMENTIA, WHICH IS PATHOLOGICALLY CHARACTERIZED BY THE ACCUMULATION OF AMYLOID PLAQUES AND TAU-CONTAINING NEUROFIBRILLARY TANGLES IN THE BRAIN. AD IS CLINICALLY MANIFESTED AS PROGRESSIVE MEMORY LOSS AND COGNITIVE IMPAIRMENT, LEADING TO PROLONGED DISABILITY AND EVENTUAL DEATH. YET, THE CELLULAR MECHANISMS UNDERLYING AD PATHOGENESIS ARE NOT FULLY UNDERSTOOD AND NO EFFECTIVE THERAPY IS CURRENTLY AVAILABLE FOR AD. OUR PRELIMINARY DATA POINT TO THE IMPORTANT ROLE OF LOW-DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 1 (LRP1) IN THE CHOROID PLEXUS (CHP) AND TANYCYTES THAT IS SIGNIFICANT IN THE OPTIMAL REGULATION OF AMYLOID-BETA (A) AND TAU EFFLUX. WE FOUND THAT DELETION OF LRP1 IN THE CHP LEADS TO A SIGNIFICANT DECREASE IN A CLEARANCE FROM THE CSF INTO CIRCULATION. INTERESTINGLY, WE ALSO FOUND THAT LRP1 IN TANYCYTES IS NECESSARY TO REGULATE TAU CLEARANCE FROM THE CSF TO THE BLOOD. IMPORTANTLY, LRP1 PHYSICALLY BINDS TO LEPTIN RECEPTOR (LEPR) IN RESPONSE TO A OR TAU. FURTHERMORE, WE OBSERVED THAT DIET-INDUCED OVERNUTRITION IMPAIRS A CLEARANCE FROM THE BRAIN AND OBESITY-RELATED METABOLIC PARAMETERS NEGATIVELY CORRELATE WITH SHORT-TERM MEMORY. WE THEREFORE HYPOTHESIZE THAT LRP1 IN THE CHP AND TANYCYTES IS ESSENTIAL FOR REGULATING A AND TAU CLEARANCE, WHICH IS COUPLED WITH THE LEPR TO EXERT TRANSCYTOSIS OF THESE PROTEINS FROM THE CSF TO CIRCULATION. THUS, AN IMPAIRED LRP1 ACTION CAUSES A AND TAU ACCUMULATION IN THE BRAIN, LEADING TO AD. OBESITY FURTHER AGGRAVATES LRP1-DEPENDENT A AND TAU EFFLUX, ACCELERATING COGNITIVE DECLINE. TO THIS END, WE WILL (I) ESTABLISH THE ROLE OF LRP1 IN CONTROLLING A EFFLUX IN THE CHOROID PLEXUS; (II) EXPLORE THE SIGNIFICANCE OF LRP1 IN REGULATING TAU TRANSPORT IN TANYCYTES. TO ACCOMPLISH THESE GOALS, WE WILL EMPLOY STATE-OF-THE-ART BIOCHEMICAL, MOLECULAR, CELLULAR, AND METABOLIC PHYSIOLOGICAL TECHNIQUES, INCLUDING GENETICALLY ENGINEERED TISSUE-SPECIFIC TRANSGENIC MOUSE MODELS, IN VIVO LIVE TWO-PHOTON IMAGING, AND CRE-INDUCIBLE AAV SYSTEM. THESE STUDIES WILL PROVIDE A UNIQUE OPPORTUNITY TO ESTABLISH A NOVEL MECHANISM IMPLICATING LRP1 AS A KEY DETERMINANT OF A AND TAU EFFLUX. THE DATA GENERATED FROM THESE TIMELY STUDIES MAY OFFER NEW INSIGHTS INTO THE UNDERLYING MECHANISMS OF LRP1-DEPENDENT A AND TAU CLEARANCE IN THE ETIOPATHOGENESIS OF AD AND PROVIDE NEW THERAPEUTIC TARGETS FOR AD AND RELATED DEMENTIA.

NATIONAL RESEARCH SERVICE AWARD

DEVELOPMENT OF SELECTIVE PIN1 INHIBITORS TO TARGET A COMMON ONCOGENIC MECHANISM

PROTEOMIC SIGNATURES OF DELIRIUM AND LONGTERM COGNITIVE DECLINE IN OLDER CARDIAC SURGICAL PATIENTS - PROJECT SUMMARY POSTOPERATIVE DELIRIUM FOLLOWING CARDIAC SURGERY IS CHARACTERIZED BY SUDDEN ONSET CONFUSION AND INATTENTION. IT INCURS SUBSTANTIAL COSTS AND CAN LEAD TO LONG-TERM COGNITIVE DECLINE, INCLUDING ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (AD/ADRD). ENHANCING OUR ABILITY TO IDENTIFY AT-RISK PATIENTS BEFORE SURGERY AND IMPLEMENTING TARGETED INTERVENTIONS BASED ON UNDERLING PATHOPHYSIOLOGY IS IMPORTANT. IN OUR DEXACET TRIAL, WHICH DEMONSTRATED THE EFFECTIVENESS OF INTRAVENOUS ACETAMINOPHEN IN REDUCING POSTOPERATIVE DELIRIUM AFTER CARDIAC SURGERY (JAMA 2019), WE CONDUCTED A SYSTEMATIC ANALYSIS OF PLASMA SAMPLES COLLECTED AT BASELINE AND ON POSTOPERATIVE DAY 2. UTILIZING THE SOMASCAN PLATFORM V 3.2 TO ANALYZE 1305 PROTEINS, WE DEVELOPED A MULTIVARIABLE RISK MODEL FOR PREDICTING PREOPERATIVE DELIRIUM, IDENTIFYING THREE NOVEL PROTEINS (TIMP1, ANGPT2, AND CCL5), AND HIGHLIGHTING OLDER AGE AND FEMALE GENDER AS ADDITIONAL RISK FACTORS. THESE PROTEINS INDICATE DISRUPTIONS IN IMMUNE FUNCTION, INFLAMMATORY RESPONSE, AND NEOVASCULARIZATION REGULATION. FURTHERMORE, INSIGHTS FROM PROTEOMICS RESEARCH IN THE SAGES I & II COHORTS SUGGEST, A SYSTEMIC PRE-INFLAMMATORY STATE PREDISPOSES TO A HYPERACTIVE INFLAMMATORY RESPONSE TO MAJOR SURGERY, RESULTING IN DELIRIUM IN THOSE WITH VULNERABLE BRAINS. THE DEXACET TRAIL LED TO A SUCCESSFUL NIA FUNDED PANDORA TRIAL TO EXAMINE THE IMPACT OF SCHEDULED 6-HOURLY INTRAVENOUS ACETAMINOPHEN OVER 48 HOURS IN 900 CARDIAC SURGICAL PATIENTS (760 RECRUITED, MAY 2024 FROM 12 CENTERS). LEVERAGING ON THE BANKED PLASMA SPECIMENS FROM THIS ONGOING TRIAL, WE WILL USE A STATE-OF-THE-ART SOMASCAN V5.0 PROTEOMICS PLATFORM THAT MEASURES 11,000 PROTEINS TO DERIVE (N=300, PLACEBO GROUP) AND VALIDATE (N=REMAINING 150 PLACEBO GROUP PATIENTS) A DELIRIUM PROTEIN SIGNATURE FOR CARDIAC SURGERY (AIM 1A). THE SOMASCAN-DERIVED TOP 10 PROTEINS WILL BE INDEPENDENTLY VALIDATED WITH STANDARD ANTIBODY-BASED METHODS (ELLA) IN ALL 450 PLACEBO GROUP PATIENTS (AIM1C). THIS MODEL WILL THEN BE PROBED WITH THE ACETAMINOPHEN GROUP (N=450, AIM1B). WE WILL COMBINE PROTEINS FROM THE AD/ADRD AND AGING PROTEOMIC SIGNATURES, ALONG WITH ADDITIONAL PROTEINS FROM THE 11,000 PROTEIN SOMASCAN V5.0 COVERING MANY BIOLOGICAL PATHWAYS, FOR A DEEP ETIOPATHOLOGICAL CHARACTERIZATION OF THE PLASMA PROTEOME FOR DELIRIUM AND 12-MONTH COGNITIVE DECLINE IN THE PANDORA COHORT (AIM 2). FURTHERMORE, LEVERAGING DATA FROM THE NIA-FUNDED SAGES I (N=560) & II (N=420) COHORTS, WE WILL INDEPENDENTLY VALIDATE THE RISK MODEL DEVELOPED IN AIM 1 (AIM 3A) AND EXPLORE SIMILARITIES AND DIFFERENCES IN DELIRIUM MECHANISMS BETWEEN CARDIAC AND NON-CARDIAC SURGERIES (AIM 3B). THIS COMPREHENSIVE APPROACH AIMS TO PROVIDE NEW INSIGHTS INTO THE MOLECULAR MECHANISMS UNDERLYING DELIRIUM RISK, PATHOGENESIS, AND ITS ASSOCIATION WITH 12-MONTH COGNITIVE DECLINE. ULTIMATELY, THE PROJECT SEEKS TO DEVELOP ACCURATE BLOOD-BASED BIOMARKERS FOR PREOPERATIVE DELIRIUM RISK PREDICTION, PROGNOSTICATION OF COGNITIVE DECLINE FOLLOWING DELIRIUM, AND LAY THE GROUNDWORK FOR TARGETED INTERVENTIONS TO IMPROVE OUTCOMES IN OLDER ADULTS AT RISK OF DELIRIUM FOLLOWING CARDIAC SURGERY.

ISOLATION AND ASSESSMENT OF BLOOD-CIRCULATING CANCER EXOSOMES WITH LSS AND SERS LAB ON A CHIP OPTICAL SPECTROSCOPIC INSTRUMENT

EPIGENOMICS OF HUMAN INSULIN RESISTANCE

IMPACT OF CIRCADIAN RHYTHM IN OBTAINING REFERENCE PROFILES OF EXRNAS IN HEALTHY I

MYOCARDIAL TISSUE CHARACTERIZATION WITH MR RELAXOMETRY IN HEART FAILURE

HEMOPEXIN AS AN EARLY BIOMARKER OF ANTHRACYCLINE CARDIAC TOXICITY - PROJECT SUMMARY THIS PROJECT SEEKS TO CONTRIBUTE NEW INSIGHTS INTO THE ROLE OF HEME METABOLISM IN THE PATHOGENESIS OF ANTHRACYCLINE CARDIAC TOXICITY BY LEVERAGING STUDIES IN HUMAN PATIENTS AND MOUSE MODELS. THE PROJECT WILL BE LED BY AARTI ASNANI, MD, CARDIOLOGIST AND DIRECTOR OF CARDIO-ONCOLOGY AT BETH ISRAEL DEACONESS MEDICAL CENTER (BIDMC) AND ASSISTANT PROFESSOR AT HARVARD MEDICAL SCHOOL (HMS). DR. ASNANI WILL COLLABORATE WITH A MULTIDISCIPLINARY TEAM THAT WILL PROVIDE EXPERTISE IN HEME AND CANCER BIOLOGY. ANTHRACYCLINES SUCH AS DOXORUBICIN (DOX) ARE VERY EFFECTIVE CHEMOTHERAPIES, BUT THEIR USE IS LIMITED BY CARDIAC TOXICITY. CURRENT RISK STRATIFICATION AND CARDIOPROTECTIVE STRATEGIES ARE INADEQUATE IN PATIENTS TREATED WITH ANTHRACYCLINES, LARGELY BECAUSE THEY DO NOT REFLECT THE UNDERLYING MOLECULAR MECHANISMS OF TOXICITY. TO ADDRESS THIS UNMET NEED, WE USED APTAMER-BASED PROTEOMICS TO MEASURE OVER 1,300 PLASMA PROTEINS IN A DISCOVERY COHORT OF WOMEN TREATED WITH ANTHRACYCLINES FOR BREAST CANCER. IN ADDITION TO CHANGES IN PROTEINS PREVIOUSLY ASSOCIATED WITH ANTHRACYCLINE CARDIOMYOPATHY, WE IDENTIFIED HEMOPEXIN (HPX) AS A NEW BIOMARKER OF CARDIAC TOXICITY, FINDINGS THAT WERE VALIDATED IN A SECOND PATIENT COHORT USING AN ELISA-BASED ASSAY. HPX IS A 57-KDA CIRCULATING GLYCOPROTEIN SYNTHESIZED IN THE LIVER THAT HAS A HIGH BINDING AFFINITY FOR THE IRON-CONTAINING MOLECULE HEME, WHICH IS PRO-OXIDANT AND INFLAMMATORY. UPON BINDING TO HEME, HPX UNDERGOES RECEPTOR-MEDIATED ENDOCYTOSIS VIA LRP-1, WHICH IS EXPRESSED BY CIRCULATING MACROPHAGES AND ENABLES HEME RECYCLING IN THE SPLENIC RETICULOENDOTHELIAL SYSTEM. THIS HEME DETOXIFICATION PATHWAY IS LARGELY MEDIATED BY INTRACELLULAR HEME OXYGENASE-1. INTRACELLULAR IRON OVERLOAD AND MACROPHAGE-MEDIATED INFLAMMATION HAVE BEEN DESCRIBED AS KEY MOLECULAR MECHANISMS OF DOX CARDIAC TOXICITY, UNDERSCORING THE BIOLOGICAL PLAUSIBILITY OF HPX AS A BIOMARKER IN THIS SETTING. MOTIVATED BY THESE HUMAN FINDINGS, WE USED A MOUSE MODEL OF CHRONIC DOXORUBICIN CARDIOMYOPATHY TO ASSESS THE MECHANISTIC IMPLICATIONS OF HPX INDUCTION IN ANTHRACYCLINE CARDIAC TOXICITY. BASED ON OUR PRELIMINARY FINDINGS, WE HYPOTHESIZE THAT HPX IS NOT ONLY A BIOMARKER OF CARDIAC TOXICITY, BUT ALSO A CARDIOPROTECTIVE PATHWAY THAT IS ACTIVATED IN RESPONSE TO ANTHRACYCLINES. WE WILL ADDRESS THIS HYPOTHESIS IN THE FOLLOWING AIMS: (1) TO CHARACTERIZE THE EFFECTS OF HPX GAIN AND LOSS-OF-FUNCTION ON CARDIAC PHENOTYPES IN A MOUSE MODEL OF CHRONIC DOX CARDIOMYOPATHY; (2) TO DEFINE THE ROLE OF HPX IN DOX CARDIAC TOXICITY THROUGH INTEGRATIVE ANALYSES OF HPX KINETICS AND BIODISTRIBUTION, HEME/IRON METABOLISM, AND CHEMICAL AND GENETIC HO- 1 MODULATION; AND (3) TO ASSESS THE GENERALIZABILITY OF BLOOD HEME, HPX, AND OTHER MECHANISTIC BIOMARKERS OF CARDIAC TOXICITY IN DIVERSE PATIENT POPULATIONS TREATED WITH ANTHRACYCLINES. IN ADDITION TO ESTABLISHING HPX AS A BIOMARKER OF ANTHRACYCLINE CARDIAC TOXICITY, THIS LINE OF INVESTIGATION WILL CLARIFY THE ROLE OF HEME METABOLISM IN CARDIOVASCULAR DISEASE MORE BROADLY. MODULATION OF HPX AND ASSOCIATED PATHWAYS COULD ULTIMATELY REPRESENT A NEW THERAPEUTIC STRATEGY TO PROTECT THE HEART DURING CHEMOTHERAPY.

A CONVERSATION AID ON MAMMOGRAPHY SCREENING TO SUPPORT SHARED DECISION MAKING BETWEEN CLINICIANS AND WOMEN AGED 75 AND OLDER

LEVERAGING OMICS DATA TO UNDERSTAND SLEEP HEALTH AND ITS CONSEQUENCES AMONG DIVERSE HISPANICS/LATINOS - PROJECT SUMMARY HISPANICS/LATINOS ARE THE FASTEST GROWING DEMOGRAPHIC GROUP IN THE U.S., EXPECTED TO COMPRISE 24% OF THE US POPULATION BY 2060. LATINOS EXPERIENCE HIGH RATES OF HEALTH DISPARITIES, INCLUDING A HIGH BURDEN OF DIABETES MELLITUS (DM), UNCONTROLLED HYPERTENSION (HTN), OBESITY, AND ALZHEIMER'S DISEASE AND VASCULAR DEMENTIAS. THE HISPANIC COMMUNITY HEALTH STUDY/STUDY OF LATINOS (HCHS/SOL) IS A LONGITUDINAL COHORT STUDY ESTABLISHED IN 2004, FOLLOWING ~16,500 US LATINOS FROM FOUR GEOGRAPHIC AREAS AND MULTIPLE LATINO BACKGROUNDS (MEXICAN, SOUTH AMERICAN, CENTRAL AMERICAN, CUBAN, DOMINICAN, AND PUERTO RICAN). WE OVERSAW THE COLLECTION AND ANALYSIS OF SLEEP MEASURES DURING THE HCHS/SOL BASELINE EXAM. ALONG WITH OUR COLLEAGUES, WE IDENTIFIED A HIGH PREVALENCE OF SLEEP DISORDERS WHICH VARIED BY SOCIAL AND BEHAVIORAL FACTORS AND LATINO BACKGROUND, AND WERE ASSOCIATED WITH INCIDENT DM, HTN, AND COGNITIVE DECLINE AND IMPAIRMENT. THIS PROJECT WILL APPLY INTEGRATIVE AND MULTI-DISCIPLINARY RESEARCH METHODS TO STUDY BIOLOGICAL MECHANISMS THAT RESULT IN THE SLEEP-RELATED RISK OF DM, HTN, AND COGNITIVE DECLINE ACROSS DIVERSE LATINOS. FIRST, WE WILL IDENTIFY METHYLATION AND METABOLOMICS MEASURES ASSOCIATED WITH SLEEP PHENOTYPES AND CHARACTERIZE THEM BIOLOGICALLY. WE FURTHER IDENTIFY A SUBSET OF THESE OMICS MEASURES THAT ARE LINKED TO MODIFIABLE LIFESTYLE AND SOCIOCULTURAL MEASURES. SECOND, WE WILL DEVELOP METABOLOMICS AND METHYLATION BIOMARKERS OF SLEEP BY COMBINING INFORMATION ACROSS MULTIPLE MARKERS. WE WILL STUDY THE ASSOCIATION OF SUCH BIOMARKERS WITH INCIDENT OUTCOMES (DM, HTN, COGNITIVE DECLINE AND IMPAIRMENT). THIRD, WE WILL ESTIMATE THE EFFECT OF SLEEP PHENOTYPES ON MODIFYING GENETIC RISKS FOR DM, HTN, AND COGNITIVE OUTCOMES USING A GENE-BY-SLEEP INTERACTION ANALYSIS WITH POLYGENIC RISK SCORES FOR EACH OUTCOME. WE WILL ALSO PERFORM MULTI-OMICS ANALYSES SYNTHESIZING MULTIPLE OMICS MEASURES TO UNDERSTAND BIOLOGICAL PATHWAYS. FINALLY, WE WILL APPLY CAUSAL ANALYSIS TO QUANTIFY THE POTENTIAL REDUCTION IN RISKS OF INCIDENT DM, HTN, AND COGNITIVE DECLINE AND IMPAIRMENT FOLLOWING POTENTIAL INTERVENTION ON SLEEP PHENOTYPES, UNDER THE ASSUMPTION THAT METABOLOMICS AND GENETIC PATHWAYS CAN BE BLOCKED. WE WILL ESTIMATE THESE EFFECTS IN AGGREGATE AND ACROSS LATINO BACKGROUNDS. OUR WORK WILL LEAD TO THE DEVELOPMENT OF PUBLIC HEALTH INTERVENTIONS AT THE COMMUNITY-(E.G., IN LATINOS OF MEXICAN ORIGIN) AND PATIENT-LEVEL BY IDENTIFYING INDIVIDUALS (E.G., BASED ON SPECIFIC GENETIC OR METABOLOMIC PROFILES) WHO WOULD BENEFIT MOST FROM IMPROVING THEIR SLEEP.

SKIN INFLAMMATORY PHENOTYPES AS BIOMARKERS OF MYOCARDIAL AND VASCULAR REMODELING

A NATIONAL CURRICULUM IN CANCER GENOMICS FOR PATHOLOGY RESIDENTS

REPETITIVE TMS-INDUCED MODULATION OF CORTICAL EXCITABILITY IN AD

MULTI-TISSUE HIGH-THROUGHPUT PROTEOMIC AND GENOMIC STUDY IN PARKINSON'S DISEASE

PHOTOPHOBIA DURING MIGRAINE: SENSORY, AUTONOMIC AND EMOTIONAL RESPONSES TO LIGHT

DEVELOPING A TRANSLATION PIPELINE FOR VHL MUTANT MALIGNANCIES

MECHANISMS OF CSD-EVOKED PERSISTENT ACTIVATION OF MENINGEAL NOCICEPTORS

DEVELOPMENT OF COMPLETEMENT INHIBITORS TO LIMIT TISSUE AS ADJUVANTS TO RESUSCITATION

DE NOVO SYNTHESIS, AND FUNCTIONAL AND STRUCTURAL CHARACTERIZATION OF NOVEL AMINOGLYCOSIDE ANALOGUES TO BYPASS RESISTANCE MECHANISMS AND OPTIMIZE SELECTIVITY

THE CO-CLINICAL TRIAL PROJECT

THE EFFECTS OF PD-1 ON TUMOR-MEDIATED ?EMERGENCY? MYELOPOIESIS AND FATE COMMITMENT OF MYELOID CELLS: IMPLICATIONS FOR ANTI-TUMOR IMMUNITY

EICOSANOID PROFILES AS DETERMINANTS OF HFPEF

REPEATED CHALLENGE OF INSUFFICIENT SLEEP: EFFECTS ON ENDOTHELIAL FUNCTION

A MULTI-DIMENSIONAL LINKED REGISTRY TO IDENTIFY BIOLOGICAL, CLINICAL, HEALTH SYSTEM, AND SOCIOECONOMIC RISK FACTORS FOR COVID-19-RELATED CARDIOVASCULAR EVENTS - PROJECT SUMMARY/ABSTRACT THERE IS MOUNTING CONCERN THAT PATIENTS HOSPITALIZED WITH COVID-19 EXPERIENCE UNEXPECTEDLY HIGH RATES OF CARDIAC AND VASCULAR EVENTS. IDENTIFYING WHICH PATIENTS ARE AT HIGHEST RISK FOR COVID-19-RELATED CARDIOVASCULAR EVENTS AND DELINEATING HOW THESE EVENTS AFFECT SHORT- AND LONG-TERM OUTCOMES MAY HELP SUPPORT INDIVIDUALIZED PATIENT CARE, ILLUMINATE UNDERLYING PATHOPHYSIOLOGIC MECHANISMS, AND ACCELERATE THE DEVELOPMENT OF EFFECTIVE THERAPIES. HOWEVER, LITTLE IS KNOWN ABOUT HOW MULTI-DIMENSIONAL RISK FACTORS, INCLUDING PRIOR MEDICAL CONDITIONS, SOCIOECONOMIC INDICATORS, AND CIRCULATING LEVELS OF BIOMARKERS AFFECT PATIENT OUTCOMES. BUILDING ON OUR TEAM'S EXPERTISE IN DATA LINKAGE, PREDICTION MODELING, AND BIOMARKER DISCOVERY, WE WILL CREATE A UNIQUE AND POWERFUL LINKED DATA RESOURCE TO CHARACTERIZE THE BIOLOGICAL, CLINICAL, HEALTH SYSTEM, AND SOCIOECONOMIC RISK FACTORS FOR THE DEVELOPMENT OF CARDIOVASCULAR SEQUELAE OF COVID-19 AND EXAMINE THEIR IMPACT ON HEALTH OUTCOMES. TO CREATE THIS DATA RESOURCE, WE HAVE PARTNERED WITH THE AMERICAN HEART ASSOCIATION, WHOSE COVID-19 CARDIOVASCULAR DISEASE REGISTRY IS ACTIVELY CAPTURING HIGH-QUALITY, STANDARDIZED INFORMATION ON ALL ADULTS HOSPITALIZED WITH CONFIRMED SARS-COV-2 INFECTION AT >100 U.S. SITES SPANNING 30 STATES. WE WILL LINK THIS REGISTRY TO COMPREHENSIVE HEALTH CARE CLAIMS, A NATIONAL SOCIOECONOMIC DEPRIVATION INDEX, AND DETAILED HEALTH CARE SYSTEM INFORMATION. IN AIM 1, WE WILL APPLY TRADITIONAL AND MACHINE LEARNING APPROACHES TO THE LINKED MULTICENTER REGISTRY IN ORDER TO IDENTIFY THE CLINICAL, HEALTH SYSTEM, AND SOCIOECONOMIC FACTORS THAT PREDICT IN-HOSPITAL MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) AMONG COVID-19 PATIENTS. IN AIM 2, WE WILL CHARACTERIZE LONG-TERM MACE (I.E., AT 1 AND 2 YEARS AFTER DISCHARGE FROM THE INDEX COVID-19 HOSPITALIZATION) AMONG OLDER ADULTS IN A LARGE MULTICENTER REGISTRY LINKED WITH LONGITUDINAL MEDICARE CLAIMS, AND IDENTIFY THE CLINICAL, HEALTH SYSTEM, AND SOCIOECONOMIC FACTORS THAT PREDICT THEIR OCCURRENCE. BASED ON THIS WORK, WE WILL CREATE CLINICALLY IMPLEMENTABLE RISK SCORES WHICH WILL ESTIMATE, AT THE TIME OF ADMISSION FOR AND DISCHARGE FROM AN INDEX COVID-19 HOSPITALIZATION, A PATIENT'S RISK OF DEVELOPING A MAJOR CARDIOVASCULAR EVENT. IN AIM 3, WE EVALUATE THE PROTEOMIC PROFILES OF A SUBSET OF PATIENTS IN THE LINKED REGISTRY WITH BIOBANKED SERIAL BLOOD SAMPLES, AND IDENTIFY BIOCHEMICAL MARKERS THAT PREDICT THE OCCURRENCE OF MACE, BOTH DURING INDEX HOSPITALIZATION FOR COVID-19 AND AFTER DISCHARGE. THIS RESEARCH WILL ADVANCE OUR COLLECTIVE UNDERSTANDING OF THE BIOLOGICAL, CLINICAL, AND SOCIOECONOMIC PREDICTORS OF COVID-19-RELATED CARDIOVASCULAR MORBIDITY AND MORTALITY. BY IDENTIFYING PATIENTS AT GREATEST AT RISK OF CARDIOVASCULAR EVENTS, OUR WORK WILL HELP FRONTLINE CLINICIANS BETTER INDIVIDUALIZE CLINICAL MANAGEMENT STRATEGIES AND HEALTH SYSTEMS IMPROVE CARE DELIVERY DURING FUTURE WAVES OF THE PANDEMIC.