Mass General Brigham Incorporated

CCC FOR NHLBI PREVENTION AND EARLY TREATMENT OF ACUTE LUNG INJURY PETAL NETWORK

DISCOVERY: DETERMINANTS OF INCIDENT STROKE COGNITIVE OUTCOMES AND VASCULAR EFFECTS ON RECOVERY

REPRIEVE - CCC - LEAD APPLICATION

POINT OF CARE TECHNOLOGY RESEARCH CENTER IN PRIMARY CARE

MECHANISMS OF IMMUNE FAILURE IN CHRONIC INFECTION: HEPATITIS C AS A KEY PARADIGM

CLINICAL COORDINATING CENTER NETWORK OF EXCELLENCE IN NEUROSCIENCE CLINICAL TRIAL

IMPACT OF AMYLOID ON THE AGING BRAIN

HARVARD-WIDE PROGRAM ON ANTIBIOTIC RESISTANCE

INTERMEDIATE-SIZE EXPANDED ACCESS TRIAL OF AUTOLOGOUS HYBRID TREG/TH2 CELL THERAPY (RAPA-501) OF AMYOTROPHIC LATERAL SCLEROSIS - ALS IS A LETHAL NEURODEGENERATIVE DISEASE ACCELERATED BY NEUROINFLAMMATION. CURRENT FDA-APPROVED THERAPIES HAVE MODEST BENEFITS AND DO NOT ADDRESS INFLAMMATION. TO ADDRESS THIS, RAPA THERAPEUTICS, LLC (RAPA) HAS DEVELOPED AN AUTOLOGOUS T CELL THERAPY (RAPA-501) THAT REDUCES INFLAMMATION, WITH THE GOAL OF REDUCING ALS MORBIDITY AND MORTALITY. RAPA-501 ARE MANUFACTURED EX VIVO TO ATTAIN DUAL TREG/TH2 ANTI- INFLAMMATORY ACTIVITY AND A T-STEM PHENOTYPE THAT PERMITS T CELL THERAPY WITHOUT CONDITIONING CHEMOTHERAPY. IN AN ONGOING CLINICAL TRIAL OF RAPA-501 IN PEOPLE WITH ALS (PWALS) (NCT04220190), RAPA-501 CELLS WERE FOUND TO BE SAFE (NO PRODUCT-RELATED ADVERSE EVENTS), BIOLOGICALLY ACTIVE (DIVERSE ANTI-INFLAMMATORY EFFECTS IN PWALS), AND SHOWED EARLY TRENDS TOWARD STABILIZING PULMONARY FUNCTION DECLINE. A PHASE 2/3 EXPANSION COHORT WAS ADDED TO THE TRIAL TO ASSESS WHETHER RAPA-501 IS EFFICACIOUS IN STANDARD-RISK PWALS. WE WILL EXTEND RAPA-501 THERAPY TO PWALS NOT ELIGIBLE FOR THIS ONGOING PHASE 2/3 TRIAL OR OTHER ALS TRIALS, WHICH NEARLY UNIVERSALLY REQUIRE THAT PARTICIPANTS HAVE A SLOW VITAL CAPACITY (SVC) VALUE OF =50% OF PREDICTED NORMAL. THE PROPOSED EAP WILL ENROLL PWALS WHO HAVE SVC VALUES <50%. THIS POPULATION OF PWALS IS CONSIDERED “HIGH RISK” (~50% CHANCE OF RESPIRATORY FAILURE OR DEATH WITHIN 180 DAYS) AND THUS PARTICULARLY SUITABLE FOR EXPERIMENTAL IMMUNE THERAPIES SUCH AS RAPA-501. IN ADDITION, THE RAPA-501-EAP WILL NOT EXCLUDE PWALS WHO HAVE A PROLONGED TIME FROM ALS-RELATED SYMPTOMS OR LOW ALSFRS-R SCORES. PARTICIPANTS WILL RECEIVE FOUR RAPA-501 IV INFUSIONS (EVERY 42-DAYS AT ESTABLISHED SAFE DOSE, 80 X 106 CELLS/INFUSION). THIS RAPA-501-EAP WILL FURTHER EVALUATE THE SAFETY OF THIS THERAPY, EXPAND AN UNDERSTANDING OF THE RAPA-501 THERAPEUTIC MECHANISM OF ACTION, AND EVALUATE SIGNALS OF EFFICACY IN THIS REAL-WORLD POPULATION OF PWALS USING STANDARD METHODS AND ORIGENT DATA SCIENCES MACHINE LEARNING ALS PREDICTION ALGORITHMS. THE RAPA-501 EAP WILL BE LED BY INVESTIGATORS AT MASS GENERAL HOSPITAL (MGH; DRS. BERRY, BABU, AND PAGANONI) AND SPONSORED BY RAPA, WHICH IS RESPONSIBLE FOR RAPA-501 MANUFACTURING AND FDA REGULATORY FILINGS UNDER EXISTING IND 019480 (DR. FOWLER, SPONSOR). CLINICAL TRIAL SITE INVESTIGATORS HAVE EXPERIENCE WITH RAPA-501 THERAPY (MGH; HACKENSACK UNIVERSITY MEDICAL CENTER; AND MAYO CLINIC ARIZONA) OR OTHER CELLS THERAPIES. SITES ARE GEOGRAPHICALLY DIVERSE AND LIKELY TO ACCRUE A SIGNIFICANT NUMBER OF UNDERSERVED PWALS (U OF IOWA; U OF IDAHO; PROVIDENCE HOSPITAL, PORTLAND, OREGON; UC-IRVINE; COLUMBIA, NYC). IN ADDITION, SEVERAL RESEARCH COLLABORATIONS WILL EMANATE FROM THE INTENSIVE STUDY OF THE CLINICALLY-ANNOTATED, VALUABLE RESEARCH SAMPLES OBTAINED FROM THE RAPA-501 EAP.

MASSACHUSETTS ALZHEIMER'S DISEASE RESEARCH CENTER

HORMONAL CONTROL OF CALCIUM METABOLISM

AN INTERMEDIATE-SIZE EXPANDED ACCESS PROTOCOL FOR AMYOTROPHIC LATERAL SCLEROSIS WITH PRIDOPIDINE - THE SIGMA 1 RECEPTOR (S1R) HAS EMERGED AS AN ATTRACTIVE THERAPEUTIC TARGET IN ALS. MUTATIONS IN THE S1R ARE CAUSATIVE OF ALS AND THE DEGREE OF LOSS OF FUNCTION IN S1R PROTEIN DETERMINES AGE OF ONSET. S1R KNOCK-DOWN EXACERBATES PHENOTYPES IN ALS MOUSE MODELS, AND S1R ACTIVATION IMPACTS PATHWAYS THAT ARE KNOWN TO BE IMPLICATED IN ALS, I.E., NUCLEOCYTOPLASMIC TRANSPORT, PROTEIN QUALITY CONTROL, ENDOPLASMIC RETICULUM (ER) STRESS, MITOCHONDRIAL FUNCTION, AND AUTOPHAGY. RILUZOLE, EDARAVONE, AND PB-TURSO, THE CURRENT STANDARD-OF-CARE MEDICATIONS FOR ALS IN THE US, OFFER ONLY MODEST CLINICAL BENEFIT AND ARE NOT KNOWN TO ACT THROUGH THE S1R. NUEDEXTA, A NON-SELECTIVE S1R AGONIST, IS APPROVED FOR THE TREATMENT OF PSEUDOBULBAR AFFECT AND HAS BEEN SHOWN TO IMPROVE BULBAR FUNCTION IN A SUBSET OF PEOPLE LIVING WITH ALS. PRIDOPIDINE (PRILENIA THERAPEUTICS) IS A POTENT AND HIGHLY SELECTIVE SMALL MOLECULE S1R AGONIST. THE S1R SHOWS HIGH EXPRESSION THROUGHOUT THE BRAIN, PARTICULARLY IN BRAINSTEM MOTOR NUCLEI. IN THE G93A SOD1 ALS MOUSE MODEL, PRIDOPIDINE MODIFIED DISEASE PROGRESSION. THE SAFETY AND EFFICACY OF PRIDOPIDINE ARE CURRENTLY BEING TESTED INTHE HEALEY ALS PLATFORM TRIAL. THE TRIAL DESIGN INCLUDES AN EFFICACY RANDOMIZED CONTROLLED TRIAL (RCT) FOLLOWED BY AN OPEN LABEL EXTENSION (OLE). THE RCT PORTION OF THE PRIDOPIDINE REGIMEN ENROLLED 162 ALS PARTICIPANTS. WHILE IT DID NOT REACH THE PRIMARY ENDPOINT, IT SHOWED TRENDS TOWARD BENEFICIAL EFFECTS OF PRIDOPIDINE ON SEVERAL OUTCOME MEASURES, WITH THE GREATEST IDENTIFIABLE EFFECT ON FUNCTIONAL SCORES, QUANTITATIVE MOTOR SPEECH, AND NEUROFILAMENT LIGHT LEVELS IN EARLY AND FASTER PROGRESSING PARTICIPANTS. THE OLE IS ONGOING. A SECOND EFFICACY TRIAL TARGETING A SELECTED POPULATION OF PEOPLE WITH ALS IS BEING PLANNED. UNFORTUNATELY, A LARGE SEGMENT OF THE REAL-WORLD ALS POPULATION WON’T BE ELIGIBLE TO ENROLL IN THIS SECOND EFFICACY STUDY DUE TO THE RESTRICTIVE ELIGIBILITY CRITERIA. THE CURRENT PROPOSAL IS AN EXPANDED ACCESS PROTOCOL (EAP) OF PRIDOPIDINE IN 200 INDIVIDUALS WITH ALS WHO ARE INELIGIBLE FOR CLINICAL TRIALS. PARTICIPANTS WOULD RECEIVE PRIDOPIDINE FOR UP TO 24 MONTHS, WHILE THE OLE AND THE PLANNED SECOND EFFICACY TRIAL ARE ONGOING. THIS STUDY WILL PROVIDE REAL- WORLD DATA BY EVALUATING THE EFFECTS OF THE DRUG IN A POPULATION THAT IS BROADER THAN THE ONE INCLUDED IN THE EFFICACY TRIALS AND BY COLLECTING SAFETY, CLINICAL, AND BIOLOGICAL OUTCOMES OVER LONGER TERM EXPOSURE.

CENTER FOR INNOVATIVE NEUROTECH ADVANCEMENT - CINTA - PROJECT ABSTRACT - OVERALL WE PROPOSE TO CREATE THE CENTER FOR INNOVATIVE NEUROTECH ADVANCEMENT (CINTA), A NEW CENTER FOR RAPID TRANSFORMATION OF EMERGING TECHNOLOGIES INTO COMMERCIALLY VIABLE, CLINICALLY FOCUSED SOLUTIONS FOR DISORDERS OF THE NERVOUS SYSTEM. THE PD/PIS, DRS. STEVEN SCHACHTER AND PAOLO BONATO, TOGETHER HAVE MANY DECADES OF EXPERIENCE CREATING AND MANAGING COMPLEX MULTI-INSTITUTIONS, MULTI-DISCIPLINARY, NATIONAL TRANSLATIONAL RESEARCH ORGANIZATIONS, AND EXPERTISE IN NEUROTECHNOLOGY-RELATED RESEARCH, AND WILL LEVERAGE THEIR EXPERIENCE TO FURTHER INNOVATE, ADAPT, AND DEPLOY THE WELL-DEVELOPED, PROVEN APPROACH TO NEEDS-DRIVEN HEALTHCARE TECHNOLOGY INNOVATION PIONEERED, DEVELOPED, AND VALIDATED FOR 23 YEARS BY THE CONSORTIA FOR IMPROVING MEDICINE WITH INNOVATION & TECHNOLOGY (CIMIT). LED FOR THE PAST 23 YEARS BY DR. SCHACHTER AND COLLEAGUES, CIMIT HAS A PROVEN TRACK RECORD OF SUCCESS AS A NATIONAL CENTER FOR HEALTHCARE INNOVATION AND A UNIQUE MODEL TO IDENTIFY UNMET MEDICAL NEEDS; FIND, FUND, AND FACILITATE TECHNOLOGY-BASED PROJECTS TO SOLVE THOSE NEEDS; AND RAPIDLY MOVE THESE INNOVATIONS FROM CONCEPT TO MANUFACTURING TO COMMERCIALIZATION TO THE END-USER. COMBINING THEIR DECADES-LONG EXPERTISE AND INTEREST IN NEUROLOGICAL DISORDERS AND REHABILITATION, THE PD/PIS WILL OVERSEE THE ADVANCEMENT OF PROJECTS UNDER CINTA’S FIVE CORES: ADMINISTRATIVE CORE, OUTREACH CORE, EVALUATION CORE, INNOVATOR SUBPROJECTS CORE, AND RESOURCE SUBAWARDS CORE. PAUL TESSIER, PROGRAM DIRECTOR FOR THE ADMINISTRATIVE CORE, WILL HAVE OVERALL RESPONSIBILITY FOR INTEGRATING THE ACTIVITIES OF THE DIFFERENT CORES TO ACCOMPLISH THE OVERALL GOALS OF THE PROPOSED CENTER UNDER THE GUIDANCE OF THE CENTER PD/PIS. THE ADMINISTRATIVE CORE WILL ENSURE ONGOING INPUT FROM NIH PROGRAM DIRECTORS AND SCIENCE OFFICERS, AS WELL AS INPUT FROM THE STEERING COMMITTEE MEMBERS WHO ARE INTEGRAL IN PROVIDING GUIDANCE TO THE PROGRAM TO HELP DIVERSIFY THE TYPES OF PROJECTS AS WELL AS INCREASE REPRESENTATION OF PROPOSERS OF VARYING BACKGROUNDS. KEY CENTER ACTIVITIES TO ACCOMPLISH THE OVERALL GOALS INCLUDE ESTABLISHED NEEDS ASSESSMENT AND PROJECT SOLICITATION PROCESSES, AND CIMIT’S VIRTUAL COLLABORATION PLATFORM, COLAB, TO HELP CINTA INVESTIGATORS AND FACILITATORS TRACK IMPORTANT DELIVERABLES IN FOUR AREAS CRITICAL TO COMMERCIAL SUCCESS. COLAB WILL ALSO BE USED AS A PLATFORM FOR SHARED CINTA RESOURCES, SUCH AS A CINTA WEBSITE WITH ACCESS TO RESOURCES AVAILABLE TO KEY STAKEHOLDERS. FINALLY, CINTA WILL DRAW UPON THE WELL-ESTABLISHED NATIONAL AND INTERNATIONAL COLLABORATION NETWORKS OF CIMIT AND SPAULDING TO ACHIEVE CINTA’S GOALS AND ENHANCE EXTERNALLY FUNDED COLLABORATIONS.

GENETICALLY-ENGINEERED PIG ORGAN TRANSPLANTATION INTO NONHUMAN PRIMATES

CENTER FOR THE STUDY OF INFLAMMATORY BOWEL DISEASE

TOLERANCE-AN APPROACH TO CARDIAC ALLO & XENOTRANSPLANTS

CLINICAL RESEARCH CENTER FOR THE IMPROVED PREVENTION, DIAGNOSIS, AND TREATMENT OF VOCAL HYPERFUNCTION

COCHLEAR SYNAPTOPATHY: PREVALENCE, DIAGNOSIS AND FUNCTIONAL CONSEQUENCES

HARVARD CLINICAL NUTRITION RESEARCH CENTER

FUNCTIONAL CONSEQUENCES OF STEM AND PROGENITOR CELL HETEROGENEITY

GENERAL ANESTHETIC SITES ON LIGAND-GATED ION CHANNELS

2022 MILITARY MEDICAL PHOTONICS PROGRAM AT WELLMAN CENTER FOR PHOTOMEDICINE

R&D, SCIENCE AND ENGINEERING, IN THE AREA OF MEDICAL SCIENCES

CENTER FOR BIOMEDICAL OCT RESEARCH AND TRANSLATION

IDENTIFICATION OF COMMON GENETIC VARIANTS FOR ATRIAL FIBRILLATION AND PR INTERVAL

BOSTON AREA DIABETES ENDOCRINOLOGY RESEARCH CENTER

OVERCOMING RESISTANCE TO BRAF(V600E) TARGETED THERAPIES IN MELANOMA

MOLECULAR RESPONSE AND IMAGING-BASED COMBINATION STRATEGIES FOR OPTIMAL PDT

AN EXPANDED ACCESS PROTOCOL OF INTRAVENOUS TREHALOSE INJECTION 90 MG/ML TREATMENT OF PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS - AMYOTROPHIC LATERAL SCLEROSIS (ALS) IS A RAPIDLY PROGRESSIVE NEURODEGENERATIVE. THERE ARE TWO FDA-APPROVED MEDICATIONS TO SLOW ALS PROGRESSION, RILUZOLE AND EDARAVONE; THEIR EFFECT IS MODEST, BUT ADDITIVE GIVEN THAT THEY TARGET DIFFERENT BIOLOGICAL PATHWAYS. ADDITIONAL PATHOPHYSIOLOGIC PATHWAYS CAN BE TARGETED TO PROVIDE EVEN MORE ADDITIVE EFFECT. AUTOPHAGY IS DYSREGULATED IN ALS AND IS A PROMISING TARGET FOR NOVEL THERAPEUTIC DEVELOPMENT. TREHALOSE (SLS-005, SEELOS THERAPEUTICS) IS A DISACCHARIDE THAT IS WELL KNOWN FOR ITS ABILITY TO ACTIVATE AUTOPHAGY. THREE IN VIVO STUDIES DEMONSTRATED A PROTECTIVE EFFECT IN SOD1 MOUSE MODELS (G93T AND G86R). IN HUMANS, TREHALASE BREAKS DOWN TREHALOSE IN THE GUT, SO IT MUST BE DELIVERED INTRAVENOUSLY (IV) TO PRESERVE ITS EFFECT. THE SAFETY AND EFFICACY OF TREHALOSE ARE CURRENTLY BEING TESTED IN THE HEALEY ALS PLATFORM TRIAL. THE TRIAL DESIGN INCLUDES AN EFFICACY RANDOMIZED CONTROLLED TRIAL (RCT) FOLLOWED BY AN OPEN LABEL EXTENSION (OLE). IN THE TRIAL, PARTICIPANTS UNDERGO WEEKLY IV INFUSIONS OF TREHALOSE, WHICH ARE DONE EITHER AT THE CENTER OR AT HOME BY A TRAINED INFUSION NURSE. UNFORTUNATELY, THE TREHALOSE OLE WILL END FOR MOST PARTICIPANTS BEFORE THE RESULTS OF THE RCT ARE KNOWN DUE TO FINANCIAL CONSTRAINTS AS SEELOS IS A SMALL BUSINESS. FOR THE SAME REASON, EXPANDED ACCESS IS NOT CURRENTLY AVAILABLE TO PEOPLE WHO ARE NOT ELIGIBLE FOR THE RCT. THE CURRENT PROPOSAL IS AN EXPANDED ACCESS PROTOCOL (EAP) OF TREHALOSE THAT WILL INCLUDE BOTH PEOPLE WHO ARE NOT ELIGIBLE FOR CLINICAL TRIALS (COHORT 1) AS WELL AS PEOPLE WHO COMPLETED THEIR PARTICIPATION IN THE TREHALOSE OLE OF THE HEALEY ALS PLATFORM TRIAL AND ARE NO LONGER ELIGIBLE FOR PARTICIPATION IN OTHER TRIALS (COHORT 2). THE LATTER GROUP WILL BE EXPOSED FOR AN ADDITIONAL SIX MONTHS. OUTCOME MEASURES FOR THIS EAP WILL INCLUDE SAFETY, THE BIOFLUID BIOMARKER NEUROFILAMENT LIGHT (NFL), CLINICAL MEASURES OF DISEASE PROGRESSION, AND SURVIVAL. THIS STUDY WILL PROVIDE REAL- WORLD DATA TO SUPPLEMENT THE TREHALOSE CLINICAL DEVELOPMENT PROGRAM BY EVALUATING THE EFFECTS OF THE DRUG IN A POPULATION THAT IS BROADER THAN THE ONE INCLUDED IN THE RCT AND BY COLLECTING OUTCOMES OVER LONGER TERM EXPOSURE. DATA WILL BE COLLECTED IN FORMAT THAT CAN BE SUBMITTED TO FDA AND COULD THEREFORE BE INCLUDED IN A POTENTIAL NDA SUBMISSION.

GENE THERAPY FOR BRAIN TUMORS

VCID BIOMARKER'S COORDINATING CENTER

HEMATOPOIESIS IN CARDIOVASCULAR DISEASE

PROGRAM PROJECT: GENE MUTATION AND RESCUE IN HUMAN DIAPHRAGMATIC HERNIA

PHASE 3 TRIAL OF INOSINE FOR PARKINSON'S DISEASE CCC

NOVEL TREATMENT TARGETS FOR AFFECTIVE DISORDERS THROUGH CROSS-SPECIES INVESTIGATION OF APPROACH/AVOIDANCE DECISION MAKING

TARGETING INFLAMMATION AND ALLOIMMUNITY IN LUNG TRANSPLANT RECIPIENTS WITH CLAZAKIZUMAB - PROJECT SUMMARY/ABSTRACT THE 5-YEAR SURVIVAL AFTER LUNG TRANSPLANTATION IS A DISMAL 53% AND CHRONIC LUNG ALLOGRAFT DYSFUNCTION (CLAD) HAS EMERGED AS THE PRIMARY OBSTACLE TO BETTER LONG-TERM OUTCOMES. CLEARLY, CURRENT STANDARD-OF-CARE IMMUNOSUPPRESSIVE REGIMENS ARE FAILING LUNG TRANSPLANT RECIPIENTS, AND THERE IS A CRITICAL UNMET NEED TO IMPROVE SURVIVAL. PRIMARY GRAFT DYSFUNCTION (PGD), EPISODES OF ACUTE CELLULAR REJECTION (ACR), ANTIBODY-MEDIATED REJECTION (AMR), AND THE DEVELOPMENT OF DONOR-SPECIFIC ANTIBODIES (DSA) ARE WIDELY RECOGNIZED RISK FACTORS FOR THE DEVELOPMENT OF CLAD. FURTHERMORE, MECHANISTIC STUDIES LINK THESE INFLAMMATORY AND ALLOIMMUNE INJURIES TO THE FIBROTIC LESIONS THAT CHARACTERIZE CLAD. IL-6 IS A PLEIOTROPIC CYTOKINE THAT DRIVES THESE DELETERIOUS INFLAMMATORY, IMMUNE, AND FIBROGENIC RESPONSES THUS, AN ESPECIALLY ATTRACTIVE CYTOKINE TO TARGET. INDEED, IN EXPERIMENTAL MODELS, IL-6 SIGNALING BLOCKADE HAS BEEN SHOWN TO SKEW THE TH17/TREG BALANCE IN FAVOR OF REGULATORY CELL COMMITMENT THEREBY EXPANDING TREG NUMBERS, REDUCING ALLOGRAFT REJECTION, AND DIMINISHING MEMORY B CELL NUMBERS AND ANTIBODY FORMATION (PRIMARY AND RECALL). IN HUMAN TRIALS, IL-6R INHIBITION REDUCED ALLOANTIBODY LEVELS IN HIGHLY SENSITIZED KIDNEY ALLOGRAFT RECIPIENTS AND IMPROVED GRAFT AND PATIENT SURVIVAL IN KIDNEY RECIPIENTS WITH THE MOST SEVERE FORM OF CHRONIC ANTIBODY-MEDIATED REJECTION. THESE DATA FORM THE BASIS OF OUR HYPOTHESIS THAT EARLY IL-6 INHIBITION AFTER LUNG TRANSPLANTATION WILL INDUCE A PROTECTIVE/ANTI-INFLAMMATORY MILIEU THAT WILL HAVE LONG- LASTING EFFECTS ON THE HOST'S IMMUNE SYSTEM AND ALLOGRAFT RESULTING IN IMPROVED LONG-TERM GRAFT AND PATIENT SURVIVAL. TO TEST THIS HYPOTHESIS, WE PROPOSE TO CONDUCT A PHASE 2, MULTICENTER, DOUBLE BLIND, RANDOMIZED, PLACEBO-CONTROLLED TRIAL EXAMINING THE IMPACT OF EARLY IL-6 INHIBITION WITH CLAZAKIZUMAB ON CLAD-FREE ALLOGRAFT SURVIVAL AFTER LUNG TRANSPLANTATION. CLAZAKIZUMAB (CSL BEHRING) IS A GENETICALLY ENGINEERED, HIGH AFFINITY, HUMANIZED MONOCLONAL ANTIBODY (IGG1) WHICH BINDS TO IL-6 AND IS A FULL AND COMPETITIVE ANTAGONIST OF IL-6- INDUCED CELL FUNCTION. THE PRIMARY ENDPOINT OF THE CLINICAL TRIAL IS A COMPOSITE OF 1) CLAD, 2) RE-TRANSPLANTATION, OR 3) DEATH. KEY SECONDARY ENDPOINTS INCLUDE PGD, ACR, AMR, DSA. FURTHERMORE, WE PLAN TO LEVERAGE THE RICH CLINICAL DATA AND HUMAN BIOSPECIMENS THAT THIS CLINICAL TRIAL WILL GENERATE TO DEFINE THE UTILITY OF SEVERAL NONINVASIVE BIOMARKERS AS RISK ASSESSMENT, DIAGNOSTIC, AND PREDICTIVE TESTING STRATEGIES. FINALLY, WE WILL CONDUCT MECHANISTIC STUDIES TO EXPLAIN THE EFFECTS OF CLAZAKIZUMAB OBSERVED IN THE CLINICAL TRIAL. THIS TRIAL REPRESENTS THE FIRST APPLICATION OF IL-6 BLOCKADE IN LUNG TRANSPLANTATION AND HAS THE POTENTIAL CHANGE CLINICAL PRACTICE AND IMPROVE OUTCOMES FOR LUNG TRANSPLANT RECIPIENTS. IF CZK THERAPY IS SUCCESSFUL, OUR COMPREHENSIVE AND INTEGRATED MECHANISTIC STUDIES WILL ALLOW US TO ELUCIDATE MECHANISMS OF IMPROVED GRAFT OUTCOMES. IF THERAPY FAILS, WE WILL BE ABLE TO UNDERSTAND WHY. EITHER WAY, INSIGHTS INTO THE MECHANISMS OF ALLOIMUNE INJURY AND CHRONIC LUNG ALLOGRAFT DYSFUNCTION COULD LEAD TO NEW PREVENTATIVE OR TREATMENT REGIMENS.

NOVEL APPROACHES TO INDUCING LUNG ALLOGRAFT TOLERANCE IN NHPS - PROJECT SUMMARY/ABSTRACT OVER 40% OF LUNG ALLOGRAFT RECIPIENTS SUCCUMB WITHIN FIVE YEARS OF BEING TRANSPLANTED, MAKING IT CLEAR THAT THERE IS AN URGENT UNMET NEED TO ADDRESS THE INADEQUACIES OF CHRONIC IMMUNOSUPPRESSION (IS) IN THESE PATIENTS. ACHIEVING A ROBUST STATE OF TOLERANCE IN LUNG RECIPIENTS WOULD REDUCE OR ELIMINATE THE MAJOR LUNG-SPECIFIC AND DRUG-RELATED FACTORS THAT CONTRIBUTE TO THIS DISMAL STATISTIC. TOLERANCE OF KIDNEY ALLOGRAFTS HAS BEEN ACHIEVED IN NONHUMAN PRIMATES (NHPS) AND HUMANS BY USING A COMBINATION OF NONMYELOABLATIVE CONDITIONING AND DONOR BONE MARROW TRANSPLANTATION THAT RESULTS IN TRANSIENT MIXED HEMATOPOIETIC CHIMERISM. HOWEVER, IDENTICAL PROTOCOLS HAVE FAILED TO INDUCE TOLERANCE IN RECIPIENTS OF LUNG ALLOGRAFTS. DESPITE THE RESISTANCE OF LUNG ALLOGRAFTS TO TOLERANCE INDUCTION, WE HAVE NOW SHOWN FOR THE FIRST TIME, THAT ACHIEVING A STATE OF DURABLE (FOR THE LIFE OF THE ORGAN) MIXED CHIMERISM IN NHP RECIPIENTS RESULTS IN LONG-TERM, IS-FREE SURVIVAL OF LUNG ALLOGRAFTS. THIS REMARKABLE RESULT WAS ACHIEVED BY MODIFYING THE MIXED CHIMERISM CONDITIONING TO AUGMENT HOST REGULATORY MECHANISMS. WHILE A SIGNIFICANT ADVANCE, THIS MODIFIED MIXED CHIMERISM PROTOCOL WAS ONLY SUCCESSFUL IN RECIPIENTS OF MHC HAPLO-MATCHED LUNG ALLOGRAFTS AND WAS ASSOCIATED WITH SIGNIFICANT TOXICITY IN THE FORM OF POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE (PTLD), CYTOMEGALOVIRUS (CMV) INFECTION, AND RADIATION-INDUCED MYELOSUPPRESSION. OUR GOAL NOW IS TO RENDER THIS BREAKTHROUGH CLINICALLY APPLICABLE BY GENERATING A SAFER AND MORE EFFECTIVE PROTOCOL THAT IS CAPABLE OF INDUCING LONG-TERM TOLERANCE OF UNRELATED, FULLY MHC MISMATCHED LUNG ALLOGRAFTS USING FDA-APPROVED OR SOON-TO-BE-APPROVED DRUGS. THIS PROGRAM’S UNIFYING HYPOTHESIS IS THAT INDUCING DURABLE CHIMERISM AND LONG-TERM TOLERANCE IN RECIPIENTS OF STRINGENT LUNG ALLOGRAFTS WILL REQUIRE NEXT-GENERATION MIXED CHIMERISM PROTOCOLS THAT AUGMENT SYSTEMIC AND INTRA-GRAFT ADAPTIVE AND INNATE REGULATORY MECHANISMS. IN PROJECT 1, WE WILL TEST THIS HYPOTHESIS USING INTRA-ORGAN DELIVERY OF AIL-6R-SPECIFIC AND MTORI-SPECIFIC NANOTHERAPIES TO REDUCE IS-RELATED COMPLICATIONS, BLOCK TRAINED IMMUNITY, AND PROMOTE INTRA-GRAFT REGULATION. BCL-2 INHIBITION WILL BE USED TO PROMOTE DURABLE MIXED CHIMERISM WHILE DIMINISHING THE TOXICITIES RELATED TO TOTAL BODY IRRADIATION (TBI)-DRIVEN MYELOSUPPRESSION. THESE STUDIES WILL BE COMPLEMENTED BY PROJECT 2, WHICH WILL TEST OUR UNIFYING HYPOTHESIS USING NOVEL STRATEGIES FOR ANTIBODY-BASED CONDITIONING, REGULATORY T CELLS (TREG)-SUPPORTIVE IMMUNOMODULATION, AND GENE- MODIFIED TREGS, ALL POISED FOR IMMEDIATE CLINICAL TRANSLATION. STATE-OF-THE-ART MECHANISTIC ASSAYS COORDINATED BY CORE A (THE MOLECULAR IMMUNOLOGY CORE, ‘MIC’) WILL ENABLE RAPID CROSS-FERTILIZATION OF INSIGHTS GAINED IN EACH PROJECT. WE ANTICIPATE THAT TOGETHER, THESE HIGHLY INTERACTIVE PROJECTS WILL GENERATE ONE OR MORE SAFE AND EFFECTIVE DURABLE MIXED CHIMERISM TOLERANCE PROTOCOLS READY FOR CLINICAL TRIALS BY THE END OF THE FUNDING PERIOD. IF SUCCESSFUL, THESE STUDIES COULD IMPACT THE ENTIRE FIELD OF TRANSPLANTATION AND PROVIDE INSIGHTS THAT COULD ALSO BE FIELD-CHANGING FOR BONE MARROW TRANSPLANTATION AND AUTOIMMUNE DISEASE.

1/2 REPRIEVE EXTENSION FOR TRIAL COMPLETION - PROJECT SUMMARY-ABSTRACT GLOBALLY, CARDIOVASCULAR DISEASE (CVD) BURDEN IS INCREASING AND A MAJOR CAUSE OF MORTALITY AMONG PEOPLE WITH HIV (PWH). HOWEVER, DATA ARE NOT YET AVAILABLE FROM LARGE TRIALS ON AN EFFECTIVE PRIMARY CVD PREVENTION STRATEGY FOR PWH. THE ONGOING REPRIEVE TRIAL WILL ADDRESS THIS CRITICAL KNOWLEDGE GAP, HYPOTHESIZING THAT STATIN THERAPY, WITH PLEIOTROPIC EFFECTS ON LDL, IMMUNE ACTIVATION AND INFLAMMATORY PATHWAYS, WILL MODIFY TRADITIONAL AND NONTRADITIONAL RISKS AND PREVENT MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) IN PWH. REPRIEVE IS WELL-POSITIONED TO PROVIDE HIGH QUALITY, CLINICALLY ACTIONABLE AND GENERALIZABLE INFORMATION TO SHIFT THE CURRENT PARADIGM OF HIV CARE, IN ALIGNMENT WITH THE GOALS OF NHLBI AND OAR TO REDUCE CVD AND IMPROVE THE OVERALL HEALTH OF PWH. REPRIEVE HAS MET MAJOR CHALLENGES, ANTICIPATED FOR A LARGE TRIAL. 7,770 PARTICIPANTS (31% FEMALE, 43% BLACK, 25% LATINO) WERE ENROLLED FROM OVER 100 SITES IN 12 COUNTRIES, A DIVERSE, GENERALIZABLE POPULATION. RETENTION IS HIGH, >90%. ENDPOINT (MACE) ARE ACCUMULATING STEADILY DESPITE A LOW MEDIAN ASCVD RISK SCORE OF 4.5%, CONSISTENT WITH THE HYPOTHESIS THAT NONTRADITIONAL RISKS CONTRIBUTE TO CVD IN HIV. THE MECHANISTIC SUBSTUDY HAS MET ITS GOAL, ENROLLING OVER 800 PARTICIPANTS FOR SERIAL CORONARY CT ANGIOGRAPHY (CTA) AND IMMUNE FUNCTION. PRELIMINARY BASELINE DATA FROM THE SUBSTUDY SUPPORT OUR HYPOTHESIS, LINKING PLAQUE TO CVD RISK BUT ALSO INDEPENDENTLY TO IL-6 AND LP-PLA2, KEY INDICES OF IMMUNE FUNCTION AND ARTERIAL INFLAMMATION THAT ARE BEING TARGETED IN REPRIEVE. MOREOVER, REPRIEVE IS BEING LEVERAGED TO ASSESS STATIN EFFECTS ON COVID SEVERITY, AND LONG-TERM EFFECTS IN PWH, CRITICAL UNANSWERED QUESTIONS FOR THE FIELD. REPRIEVE HAS EXECUTED WELL OVER 6 YEARS AND IS FUNDAMENTALLY STRONG. HOWEVER, WITH A LONG DURATION OF RECRUITMENT AND PROTOCOL REVISIONS TO IDENTIFY THE OPTIMAL AT-RISK GROUP GIVEN NEW GUIDELINES, MEDIAN DURATION OF FOLLOW UP IS STILL SHORT AT 3.5 YEARS. REPRIEVE NEEDS ADDITIONAL TIME, PROJECTED AT 2 YEARS, PLUS A CLOSE OUT YEAR, TO COLLECT NECESSARY MACE TO ENSURE ADEQUATE POWER, ANALYZE, AND DISSEMINATE THIS DATA. THE PRESSING NEED FOR DATA FROM A LARGE GLOBAL PRIMARY PREVENTION TRIAL HAS ONLY GROWN SINCE REPRIEVE WAS INITIATED. COMPLETION OF THE TRIAL WILL PROTECT THE VALUE OF THE INITIAL NIH INVESTMENT AND HONOR THE COMMITMENT TO OUR PARTICIPANTS AND SCIENTIFIC COMMUNITY TO MEET THE AIMS OF THE TRIAL. THIS APPLICATION FOR THE CLINICAL COORDINATING CENTER (CCC) OF THE REPRIEVE EXTENSION FOR TRIAL COMPLETION FOCUSES ON THE CLINICAL RATIONALE AND COORDINATION OF THE TRIAL. THE DATA COORDINATING CENTER (DCC) APPLICATION FOCUSES ON DATA MANAGEMENT, INCLUDING THE CORONARY CTA DATA OF THE MECHANISTIC SUBSTUDY, AND THE STATISTICAL RATIONALE FOR THE TRIAL DESIGN.

CONNECTOME 2.0: DEVELOPING THE NEXT GENERATION HUMAN MRI SCANNER FOR BRIDGING STUDIES OF THE MICRO-, MESO- AND MACRO-CONNECTOME

TRAINING PROGRAM IN ENDOCRINOLOGY AND DIABETES

INTEGRATING PATIENT-SPECIFIC CLINICAL AND BIOLOGICAL FACTORS TOWARDS INDIVIDUALIZING UTILIZATION OF PROTON AND PHOTON RADIATION THERAPY. - OVERALL - SUMMARY THIS IS A JOINT APPLICATION FOR A PROGRAM PROJECT GRANT BY MASSACHUSETTS GENERAL HOSPITAL AND MD ANDERSON CANCER CENTER. THE PROGRESS WE MADE IN OUR MOST RECENT PROGRAM PROJECTS (A P01 AND A U19) HAS BEEN CRITI- CAL TO THE CLINICAL, PHYSICAL, AND BIOLOGICAL ASPECTS OF PROTON THERAPY AND ITS SIGNIFICANCE AS AN IMPORTANT CANCER TREATMENT MODALITY. THE MAIN ACHIEVEMENTS OF THE RECENTLY COMPLETED U19 (END DATE 8/31/20) WERE (1) THE DE- VELOPMENT AND ACTIVATION OF DEFINITIVE ESOPHAGUS, LIVER AND GLIOMA RANDOMIZED PROTON VS. PHOTON THERAPY TRIALS IN COOPERATION WITH NRG, NCI AND NCTN; (2) UNDERSTANDING AND MODELING THE DIFFERENCES IN RESPONSE OF NOR- MAL TISSUES TO HIGHLY DISPARATE PROTON AND PHOTON DOSE DISTRIBUTION PATTERNS; (3) UNDERSTANDING THE COMPLEXITIES OF THE BIOLOGICAL EFFECTS OF PROTONS RELATIVE TO PHOTONS; AND (4) THE DEVELOPMENT OF ADVANCED INTENSITY MODU- LATED PROTON THERAPY INCORPORATING PHYSICAL UNCERTAINTIES AND THE VARIABLE BIOLOGICAL EFFECTIVENESS OF PROTONS. OUR RESEARCH ALSO REVEALED MAJOR GAPS IN THE KNOWLEDGE OF THE BIOLOGICAL EFFECTS OF PROTONS, SIGNIFICANT LIMITA- TIONS OF THE CURRENT POPULATION-BASED MODELS OF NORMAL TISSUE AND TUMOR RESPONSE TO PROTONS VS. PHOTONS, AND UNCERTAINTY IN THE APPROPRIATENESS OF PROTON THERAPY IN THE FACE OF HETEROGENEITIES IN PATIENT CHARACTERISTICS AND TREATMENT TECHNIQUES IN UNSELECTED GROUPS OF PATIENTS. ON THE BRIGHT SIDE, OUR RESEARCH ALSO DISCOVERED THE STRONG POTENTIAL OF PROTON THERAPY TO REDUCE SUPPRESSION OF THE IMMUNE SYSTEM, WHICH IS COMMONLY ASSOCIATED WITH PHOTON THERAPY AND HAS BEEN SHOWN TO LEAD TO ADVERSE OUTCOMES. THE OVERALL GOALS OF THE PROPOSED P01 ARE (A) UNDERSTANDING RELATIVE CLINICAL, BIOLOGICAL AND IMMUNOSUPPRESSIVE EFFECTS OF PROTON THERAPY VS. PHOTON THERAPY; (B) ENHANCING OUTCOMES BASED ON THE PHYSICAL, BIOLOGICAL AND IMMUNOLOGICAL PROPERTIES OF PROTONS AND PHOTONS; AND (C) APPLYING INDIVIDUALIZED (AS OPPOSED TO POPULATION-BASED) APPROACHES FOR THE SE- LECTION OF THE OPTIMUM RADIATION MODALITY FOR EACH PATIENT AND TO ENHANCE THE POTENTIAL FOR OUTCOMES WITH THE USE OF RADIATION DOSE DISTRIBUTIONS TAILORED TO THE INDIVIDUAL PATIENT’S BASELINE AND TUMOR CHARACTERISTICS. THE ACHIEVEMENT OF THESE GOALS WILL BE CARRIED OUT IN THREE PROJECTS. PROJECT 1: UNDERSTANDING NORMAL TISSUE TOX- ICITY TO IDENTIFY PATIENTS MOST LIKELY TO BENEFIT FROM PROTON VS. PHOTON THERAPY; PROJECT 2: RADIATION-INDUCED LYMPHOPENIA (RIL): UNDERSTANDING, PREDICTIVE MODELING AND DEVELOPING PHOTON AND PROTON-BASED MITIGATION STRATEGIES; AND PROJECT 3: INVESTIGATING ENHANCED SENSITIVITY OF TUMORS TO PROTON BEAM THERAPY: MECHANISMS AND BIOMARKERS. THE PROJECTS ARE HIGHLY INTEGRATED IN THAT DECISIONS REGARDING TREATMENT MODALITY SELECTION, TREATMENT TECHNIQUE AND OPTIMIZATION TO MAXIMALLY ENHANCE THE THERAPEUTIC RATIO CANNOT BE ACCOMPLISHED BY ANY ONE PROJECT ALONE. SUCH DECISIONS MUST CONSIDER AND BALANCE NORMAL TISSUE COMPLICATIONS, TUMOR RE- SPONSE BASED ON GENOTYPIC FACTORS, AND RADIATION-INDUCED IMMUNOSUPPRESSION. THE THREE PROJECTS WILL BE SUP- PORTED BY AN ADMINISTRATIVE CORE AND THREE RESOURCE CORES: CORE 1: DATA MANAGEMENT AND COMPUTATIONAL SUPPORT; CORE 2: TRANSLATIONAL BIOSPECIMENS AND IMAGING BIOMARKERS; AND CORE 3: BIOSTATISTICS.

CLINICAL RESEARCH CAREER DEVELOPMENT PROGRAM

BIO-MICROELECTROMECHANICAL SYSTEMS RESOURCE CENTER

SILVIO O. CONTE CENTER FOR STRESS PEPTIDE ADVANCED RESEARCH, EDUCATION, & DISSEMINATION (SPARED) AT MCLEAN HOSPITAL

CENTER FOR SUICIDE RESEARCH AND PREVENTION - SUICIDE IS ONE OF THE LEADING CAUSES OF DEATH WORLDWIDE AND THE 10TH LEADING CAUSE OF DEATH IN THE US. A MAJOR BARRIER TO SUICIDE PREVENTION HAS BEEN THAT THE CUTTING-EDGE SCIENTIFIC ADVANCES THAT HAVE OCCURRED IN THE PAST FEW DECADES HAVE NOT YET BEEN TRANSLATED AND IMPLEMENTED INTO CLINICAL PRACTICE SETTINGS. WE PROPOSE THE DEVELOPMENT OF A PRACTICE-BASED CENTER FOR SUICIDE RESEARCH AND PREVENTION (CSRP) THAT WILL SUPPORT THE DEVELOPMENT, DEPLOYMENT, AND EVALUATION OF PRACTICE-READY AND DEPLOYMENT-FOCUSED INTERVENTIONS AIMED AT IMPROVING THE IDENTIFICATION AND EFFECTIVE TREATMENT OF THOSE AT RISK OF SUICIDE. THIS CENTER WILL BE A COLLABORATIVE EFFORT BETWEEN RESEARCHERS, CLINICIANS, AND STAKEHOLDERS AT MASS GENERAL BRIGHAM (MGB) AND HARVARD UNIVERSITY. OUR FOCUS IS ON IMPROVING THE IDENTIFICATION AND PREVENTION OF SUICIDE-RELATED BEHAVIORS (SRBS) AMONG PATIENTS PRESENTING FOR TREATMENT AT EMERGENCY DEPARTMENTS (EDS) AND PSYCHIATRIC INPATIENT UNITS. DECADES OF RESEARCH HAVE SHOWN THAT 50% OF PEOPLE WHO DIE BY SUICIDE ARE SEEN IN A HEALTHCARE SETTING WITHIN ONE MONTH BEFORE THEIR DEATH, 40% VISIT AN ED THE YEAR BEFORE THEIR DEATH, AND THE SUICIDE RATE IS HIGHEST IN THE WEEKS IMMEDIATELY FOLLOWING DISCHARGE FROM A PSYCHIATRIC INPATIENT HOSPITALIZATION. OUR FIRST AIM IS TO BUILD AND MAINTAIN A COHESIVE AND INNOVATIVE TRANSDISCIPLINARY CENTER DEDICATED TO ADVANCING SUICIDE PREVENTION. THIS WILL BE ACCOMPLISHED VIA THE WORK OF OUR PROPOSED ADMINISTRATIVE CORE AND METHODS CORE. OUR SECOND AIM IS TO CONDUCT FOUR PRACTICE-FOCUSED RESEARCH PROJECTS THAT TARGET PREDICTION AND PREVENTION OF SUICIDAL BEHAVIORS IN ED AND INPATIENT SETTINGS. OUR SIGNATURE PROJECT (SIG) WILL IMPLEMENT A PREVIOUSLY-DEVELOP MACHINE LEARNING PREDICTION ALGORITHM BASED ON ELECTRONIC HEALTH RECORD (EHR) AND SELF-REPORT DATA COLLECTED IN THE ED AND RANDOMLY ASSIGN THE CLINICIANS OF 4,000 PATIENTS TO RECEIVE (EXPERIMENTAL CONDITION) OR NOT RECEIVE (CONTROL CONDITION) THE PREDICTED PROBABILITY THAT THEIR PATIENT WILL MAKE A SUICIDE ATTEMPT AFTER ED DISCHARGE. WE WILL TEST THE IMPACT OF THIS INTERVENTION ON THE SUICIDE ATTEMPT RATE AND CLINICIAN DECISION-MAKING. THE SIG ALSO WILL EXAMINE CLINICIAN ACCEPTABILITY AND ADHERENCE, PREDICTION MODEL IMPROVEMENT, AND THE DEVELOPMENT OF TREATMENT OPTIMIZATION RULES REGARDING PATIENTS' LIKELIHOOD OF BENEFITING FROM HOSPITALIZATION VERSUS ALTERNATIVE TREATMENTS. OUR THREE EXPLORATORY PROJECTS (EXP): (EXP1) WILL USE THE SIG PREDICTION MODEL TO IDENTIFY ED PATIENTS AT RISK OF SUICIDAL BEHAVIOR AND EXPERIMENTALLY TEST THE EFFECTIVENESS OF AN ENHANCED OUTREACH INTERVENTION ADMINISTERED IN COLLABORATION WITH A COMMUNITY PARTNER – SAMARITANS OF BOSTON; (EXP2) WILL IMPLEMENT AND TEST EHR-BASED RISK ALGORITHMS IN TWO INPATIENT UNITS WITH A SPECIAL FOCUS ON THE USE OF SOCIAL DETERMINANTS OF HEALTH TO IMPROVE PREDICTION AMONG UNDER-REPRESENTED ADOLESCENTS; AND (EXP3) WILL TEST A JUST-IN-TIME ADAPTIVE INTERVENTION USING AN INNOVATIVE MICRO-RANDOMIZED TRIAL DESIGN TO CONNECT AT-RISK PATIENTS WITH CARE WHEN NEEDED MOST. THE THIRD AIM OF THE CENTER IS TO SUPPORT EDUCATION, DISSEMINATION, AND IMPLEMENTATION EFFORTS THAT WILL HAVE A SIGNIFICANT AND SUSTAINED EFFECT ON SUICIDE PREVENTION.

AIRWAY MICROBIOME AND AGE 6Y ASTHMA PHENOTYPES IN 2 DIVERSE MULTICENTER COHORTS

BRAIN CONNECTS: THE CENTER FOR LARGE-SCALE IMAGING OF NEURAL CIRCUITS (LINC) - PROJECT SUMMARY: THIS PROJECT WILL DEVELOP AND VALIDATE A COMPREHENSIVE TOOLSET OF NOVEL TECHNOLOGIES FOR IMAGING AXONAL PROJECTIONS ACROSS SCALES, AND WILL DEPLOY THIS TOOLSET TO MAP A COMPLEX SYSTEM OF CORTICO- SUBCORTICAL PROJECTIONS IN THE MACAQUE AND HUMAN BRAIN. WE WILL COMBINE THE COMPLEMENTARY STRENGTHS OF THREE INNOVATIVE MICROSCOPY TECHNIQUES. FIRST, POLARIZATION-SENSITIVE OPTICAL COHERENCE TOMOGRAPHY (PS-OCT) WILL PROVIDE LABEL-FREE, UNDISTORTED IMAGING OF AXONAL ORIENTATIONS AT THE SCALE OF MICROSCOPIC FASCICLES, ALLOWING US TO FOLLOW FASCICLES ACROSS THE BRAIN WITHOUT THE NEED FOR AXON SEGMENTATION. SECOND, WHOLE-MOUNT LIGHT- SHEET MICROSCOPY (LSM) OF CLEARED AND IMMUNOLABELED SECTIONS WILL ALLOW US TO IMAGE FASCICLES AT THE SUB- MICRON SCALE, RESOLVING INDIVIDUAL AXONS. THIRD, HIERARCHICAL PHASE-CONTRAST TOMOGRAPHY (HIP-CT) WILL ALLOW US TO IMAGE BOTH THE AXONS AND THEIR MICRO-ENVIRONMENT, AT A RANGE OF SCALES FROM A FEW MICRONS DOWN TO SUB- MICRON. WE WILL SCALE THESE THREE MICROSCOPY TECHNIQUES UP TO IMAGE A LARGE SUB-VOLUME OF THE BRAIN (UP TO TWO THIRDS OF A HEMISPHERE) THAT CONTAINS SUBCORTICAL PROJECTIONS OF THE MOTOR, PREMOTOR, AND PREFRONTAL CORTEX. IN THE MACAQUE BRAINS, FLUORESCENT TRACER INJECTIONS WILL ALLOW DIRECT VALIDATION OF OUR NOVEL MICROSCOPY TECHNIQUES. IN COMBINATION WITH AN EXTENSIVE COLLECTION OF PRIOR TRACER INJECTIONS, THE MACAQUE DATA WILL ALSO PROVIDE THE TOPOGRAPHIC ORGANIZATIONAL RULES OF FIBERS IN CORTICO-SUBCORTICAL BUNDLES, WHICH WE WILL THEN USE TO VALIDATE OUR NOVEL MICROSCOPY TECHNIQUES IN HUMAN BRAINS. IN BOTH MACAQUE AND HUMAN SPECIMENS, WE WILL ALSO COLLECT EXTENSIVE, CUTTING-EDGE, WHOLE-BRAIN DIFFUSION MRI DATA, WHICH WILL PROVIDE THE LINK TO NON-INVASIVE NEUROIMAGING. THE UNPRECEDENTED DATASETS GENERATED BY OUR PROJECT WILL ENABLE RESEARCH DISCOVERY IN TWO USE CASES. IN THE FIRST USE CASE, WE WILL ANNOTATE PROJECTIONS OF THE MOTOR, PREMOTOR, AND PREFRONTAL CORTEX TO THE SUBTHALAMIC NUCLEUS (STN). WE WILL USE THEM TO ADVANCE OUR UNDERSTANDING OF CIRCUITS ASSOCIATED WITH CLINICAL IMPROVEMENTS IN FOUR DISEASES THAT ARE TREATED WITH DEEP-BRAIN STIMULATION IN NEIGHBORING SUBZONES OF THE STN: DYSTONIA, TOURETTE’S SYNDROME, PARKINSON’S DISEASE, AND OBSESSIVE-COMPULSIVE DISORDER. IN THE SECOND USE CASE, WE WILL INVESTIGATE THE MAPPING FROM THE AXONAL ORIENTATIONS AND MICROSTRUCTURAL FEATURES OBTAINED FROM THE MICROSCOPY DATA TO DMRI SIGNALS ACQUIRED IN THE SAME BRAINS. IN ADDITION TO THE UNPRECEDENTED DATASETS AND THE TWO USE CASES DESCRIBED ABOVE, THIS PROJECT WILL GENERATE STATE-OF-THE-ART PIPELINES FOR PRE- PROCESSING, CO-REGISTRATION, AXON SEGMENTATION, TRACTOGRAPHY, AND QUANTIFICATION, ACROSS THE SCALES SPANNED BY THE ACQUIRED DATA. WE WILL DEVELOP A NOVEL PLATFORM FOR SHARING THE MICROSCOPY, TRACER, AND MRI DATA WITH THE RESEARCH COMMUNITY. THIS WILL GO WELL BEYOND A STATIC DATA REPOSITORY, ALLOWING THE USER TO INTERACT WITH THE DATA REMOTELY AND PROVIDING A “VALIDATION ENGINE” FOR TESTING NEUROIMAGING SOFTWARE TOOLS AGAINST THE GOLD STANDARD POST MORTEM DATA COLLECTED BY THIS PROJECT. IF SUCCESSFUL, THIS PROJECT WILL GENERATE A SCALABLE AND VALIDATED TOOLSET FOR IMAGING CONNECTIONAL ANATOMY, WITH A DIRECT LINK IT TO ITS APPLICATIONS IN THE STUDY OF HUMAN DISEASE.

TRAINING PROGRAM IN NERVOUS SYSTEM TUMORS

MA/REGION 1 PARTNERSHIP FOR REGIONAL HEALTH DISASTER RESPONSE

OPTIMIZING HIV CARE IN LESS DEVELOPED COUNTRIES

LABORATORY FOR EARLY PSYCHOSIS RESEARCH (LEAP)

HARVARD REPRODUCTIVE ENDOCRINE SCIENCES CENTER

TARGETING INFLAMMATION AND ALLOIMMUNITY IN HEART TRANSPLANT RECIPIENTS WITH TOCILIZUMAB

LOOK AHEAD: ACTION FOR HEALTH IN DIABETES

NEW APPROACHES TO INDUCING CARDIAC ALLOGRAFT TOLERANCE - PROJECT SUMMARY / ABSTRACT ACHIEVING TOLERANCE, DEFINED AS LONG-TERM ALLOGRAFT SURVIVAL IN THE ABSENCE OF ONGOING IMMUNOSUPPRESSION, IS THE ULTIMATE GOAL IN TRANSPLANTATION. TOLERANCE OF KIDNEY ALLOGRAFTS HAS BEEN ACHIEVED IN NON-HUMAN PRIMATES (NHPS) AND IN HUMANS USING A COMBINATION OF NON-MYELOABLATIVE CONDITIONING AND DONOR BONE MARROW TRANSPLANTATION (DMBT) THAT RESULTS IN TRANSIENT DONOR CHIMERISM. HOWEVER, UNTIL NOW, TRANSIENT MIXED-CHIMERISM PROTOCOLS THAT ACHIEVE LONG-TERM TOLERANCE OF KIDNEY ALLOGRAFTS IN NHPS HAVE CONSISTENTLY FAILED TO INDUCE TOLERANCE IN RECIPIENTS OF HEART ALLOGRAFTS. IT IS WELL KNOWN THAT SOME ORGANS, SUCH AS KIDNEY AND LIVER, ARE “TOLERANCE-PRONE” WHILE OTHERS, SUCH AS HEART AND LUNG, ARE “TOLERANCE-RESISTANT.” DESPITE THE IMMUNE BARRIERS POSED BY THE HEART, OUR LABORATORY HAS RECENTLY DEVELOPED NOVEL PROTOCOLS THAT HAVE, FOR THE FIRST TIME, ACHIEVED LONG-TERM, STABLE TOLERANCE OF HEART TRANSPLANTS IN CYNOMOLGUS MONKEY RECIPIENTS. THIS REMARKABLE RESULT WAS ATTAINED IN HEART RECIPIENTS EXHIBITING ONLY TRANSIENT MIXED CHIMERISM BY INCLUDING DONOR KIDNEY COTRANSPLANTATION, WHICH ENHANCED THE CONTRIBUTIONS OF HOST REGULATORY T CELLS FOLLOWING MIXED CHIMERISM CONDITIONING. WHILE THE COMBINATION OF KIDNEY AND HEART TRANSPLANTATION PRODUCED REMARKABLE RESULTS, THIS STRATEGY DOES NOT HAVE WIDE CLINICAL FEASIBILITY DUE TO THE USE OF EXPERIMENTAL AGENTS AND THE ETHICAL BARRIER OF SACRIFICING A KIDNEY SIMPLY TO INDUCE HEART TOLERANCE. ALTHOUGH LUNG ALLOGRAFTS WILL NOT BE STUDIED IN THIS PROGRAM, OUR RECENT FINDINGS IN LUNG RECIPIENTS PROVIDE PROOF OF PRINCIPLE THAT DURABLE MIXED CHIMERISM CAN BE ACHIEVED IN NHPS AND THAT THIS STATE RESULTS IN LONG TERM TOLERANCE OF RESISTANT THORACIC ORGANS; THESE WERE THE FIRST NHPS TO BECOME TOLERANT OF LUNG ALLOGRAFTS. THUS, THE UNIFYING GOAL OF THIS OVERALL PROGRAM IS TO DESIGN INNOVATIVE MIXED CHIMERISM STRATEGIES FOR HEART ALONE RECIPIENTS THAT EITHER AMPLIFY THE CONTRIBUTIONS OF REGULATORY T CELLS AND MACROPHAGES IN TRANSIENT MIXED CHIMERISM PROTOCOLS (PROJECT 1) OR ACHIEVE DURABLE MIXED CHIMERISM (PROJECT 2) WHILE USING CLINICALLY-RELEVANT AGENTS FOR HOST CONDITIONING (PROJECT 3). PROJECT 1 WILL FOCUS ON ENHANCING THE CONTRIBUTION OF REGULATORY T CELLS AND MACROPHAGES IN PROTOCOLS WHICH INDUCE TRANSIENT MIXED CHIMERISM. PROJECT 2 WILL FOCUS ON ACHIEVING DURABLE MIXED CHIMERISM USING NEXT-GENERATION CONDITIONING REGIMENS, INNOVATIVE IMMUNOSUPPRESSION PLATFORMS. PROJECT 3 WILL INVESTIGATE NOVEL, CLINICALLY-APPLICABLE, AGENTS WHICH ENHANCE COSTIMULATION BLOCKADE AND DIMINISH TOXICITY. CORE A WILL INVESTIGATE THE MECHANISMS BY WHICH TREATMENTS DESCRIBED IN PROJECTS 1-3 INFLUENCE THE HOST IMMUNE RESPONSE. THE PROGRAM WILL BE ORGANIZED IN SUCH A WAY THAT EARLY MECHANISTIC DISCOVERIES/ADVANCES IN CORE A WILL INFORM AND REFINE THE AIMS OF PROJECTS 1-3. THE COMPLEMENTARY MODELS AND APPROACHES DESCRIBED IN THIS APPLICATION ARE UNIQUE STRENGTHS OF THIS PROGRAM PROJECT. WE ANTICIPATE THAT TOGETHER, THESE HIGHLY INTERACTIVE PROJECTS WILL GENERATE ONE OR MORE SAFE AND EFFECTIVE TOLERANCE PROTOCOLS THAT WILL BE READY FOR CLINICAL TRIAL(S) IN HEART ALLOGRAFT RECIPIENTS BY THE END OF THE FUNDING PERIOD.

PHYSIOLOGIC AND PATHOLOGIC COUPLING IN THE NEUROVASCULAR UNIT

CELL AND MOLECULAR TRAINING FOR CARDIOVASCULAR BIOLOGY

SINGLE-NEURON MARKING IN THE STUDY OF ABNORMAL COCHLEAS

FROM NERVE TO BRAIN: TOWARD A MECHANISTIC UNDERSTANDING OF SPINAL CORD STIMULATION IN HUMAN SUBJECTS - PROJECT SUMMARY SPINAL CORD STIMULATORS (SCS) AND RELATED DEVICES ARE COMMONLY USED TO TREAT REFRACTORY PAIN CONDITIONS, ALTHOUGH MECHANISMS UNDERLYING PAIN REDUCTION REMAIN UNCLEAR. IMPROVED UNDERSTANDING OF SCS AND THE DEVELOPMENT OF BIOMARKERS ARE CRITICAL FOR IMPROVING DEVICE DESIGN AND STIMULATION PATTERNS AND OPTIMIZING PATIENT SELECTION FOR DEVICE TREATMENT. THE MAIN HYPOTHESIS OF THIS PROPOSAL IS THAT SCS DEVICES REDUCE PAIN BY MODULATING THE EXCITABILITY OF PERIPHERAL SENSORY NERVE FIBERS THAT PROJECT WITHIN THE SPINAL DORSAL COLUMNS, AND THIS EFFECT CAN BE LEVERAGED FOR BIOMARKER DEVELOPMENT. THE RATIONALE FOR THIS HYPOTHESIS IS THAT FIRST ORDER LOW-THRESHOLD MECHANORECEPTORS PROJECT FROM THE PERIPHERY THROUGH THE DORSAL COLUMN/MEDIAL LEMNISCUS SYSTEM TO THE BRAINSTEM. THESE ARE THE NEURONS THAT (1) HAVE CLOSEST PROXIMITY TO THE EPIDURAL SPACE, THE LOCATION OF STIMULATION, AND (2) HAVE PROCESSES IN BOTH THE PERIPHERY AND SPINAL CORD TRACTS. WE WILL APPLY SPECIALIZED TESTS OF PERIPHERAL NERVE EXCITABILITY, THRESHOLD TRACKING NERVE CONDUCTION STUDIES, TO DETECT CHANGES IN THE EXCITABILITY EXERTED ON THESE NEURONS BY SCS. WE WILL ALSO PERFORM SECONDARY MEASUREMENTS TO DETERMINE OTHER POTENTIAL MECHANISMS OF SCS IN THE PERIPHERAL AND CENTRAL NERVOUS SYSTEMS: MICRONEUROGRAPHY, TO DETECT MODULATION OF PRIMARY NOCICEPTOR NEURON EXCITABILITY; PET-MRI, TO MEASURE CHANGES IN BRAIN NEUROINFLAMMATION; PLASMA CYTOKINES AND CHEMOKINES, TO DETECT SYSTEMIC NEUROINFLAMMATORY EFFECTS DUE TO SCS. WE WILL PERFORM SENSORY PHENOTYPING TO IDENTIFY MECHANISMS IN SPECIFIC SUBGROUPS AND PAIN AND PSYCHOMETRIC INSTRUMENTS TO QUANTIFY RESPONSES. AIM 1 WILL USE A MULTIPLE CROSSOVER DESIGN IN SUBJECTS WHO HAVE STABLY IMPLANTED SCS DEVICES, AND SCS SETTINGS WILL BE TOGGLED BETWEEN THERAPEUTIC AND MINIMAL SETTINGS. CROSSOVER INTERVALS WILL INCLUDE BOTH TWO-WEEK PERIODS AND RAPID TWO-HOUR PERIODS BETWEEN SETTING CHANGES. AIM 2 WILL CONSIST OF A PROSPECTIVE ASSESSMENT OF SUBJECTS PRIOR AND AFTER IMPLANTATION OF NEW SCS DEVICES, WITH A GOAL OF IDENTIFYING PREDICTORS OF PAIN REDUCTION RESPONSE. THE SUCCESSFUL COMPLETION OF THIS STUDY WILL YIELD NEW MECHANISMS BY WHICH SCS REDUCES PAIN, RELEVANT BIOMARKERS, AND FURTHER DEVELOPMENT OF PROMISING OUTCOMES FOR BROAD PAIN RESEARCH.

NEUROSCIENCE RESIDENT RESEARCH PROGRAM

PROSPECTIVE STUDY OF THE GUT MICROBIOME IN AGING

A NOVEL PHOTORECEPTOR PROTEIN AND RETINAL DEGENERATIONS

RESEARCH TRAINING IN DIGESTIVE DISEASES

IMPROVING THE CLINICAL EFFECTIVENESS AND UNDERSTANDING OF THE BIOPHYSICAL BASIS

CONTROL OF C. ELEGANS LINEAGE BY HETEROCHRONIC GENES

P-30 CORE GRANT FOR VISION RESEARCH

BOOSTING MIND-BODY MECHANISMS AND OUTCOMES FOR CHRONIC PAIN

RECURRENT HEMORRHAGIC STROKE IN MINORITY POPULATIONS

MECHANISMS OF KIDNEY-INDUCED CARDIAC ALLOGRAFT TOLERANCE

COMPREHENSIVE CHARACTERIZATION OF VARIANTS UNDERLYING HEART AND BLOOD DISEASES WITH CRISPR BASE EDITING - PROJECT SUMMARY HOW GENOMIC VARIATION INFLUENCES CELLULAR FUNCTION IS A FUNDAMENTAL PROBLEM WITH TREMENDOUS IMPORTANCE FOR HUMAN DISEASE. WHILE IT HAS TRADITIONALLY BEEN DIFFICULT TO STUDY THE EFFECTS OF SPECIFIC SEQUENCE VARIANTS IN AN EXPERIMENTALLY CONTROLLED MANNER, PRECISE GENOME EDITING TECHNOLOGIES SUCH AS CRISPR BASE EDITING ENABLE “WRITING” OF TRAIT-ASSOCIATED VARIANTS TO CELLS TO UNRAVEL THEIR FUNCTION. IN THIS PROPOSAL, WE WILL PERFORM MULTI-MODAL GENOME EDITING-BASED FUNCTIONAL CHARACTERIZATION OF A TOTAL OF 72,000 GENOMIC VARIANTS ASSOCIATED WITH CARDIOVASCULAR DISEASES (CVDS) AND HEMATOLOGICAL TRAITS. CVD AND BLOOD TRAITS ARE UNIQUELY SUITED TO FUNCTIONAL DISSECTION BECAUSE CARDIOVASCULAR (CORONARY ARTERY DISEASE, HIGH BLOOD PRESSURE, DYSLIPIDEMIA) AND BLOOD TRAITS HAVE AMONG THE BEST-POWERED MULTI-ETHNIC GWAS OF ANY TRAITS, AND A SUBSTANTIAL COMPONENT OF TRAIT VARIABILITY CAN BE CAPTURED IN CELLULAR ASSAYS THAT CAN BE SCALED TO PERFORM HIGH-THROUGHPUT SCREENING. WE HAVE ASSEMBLED AN INTERDISCIPLINARY TEAM OF WORLD-CLASS EXPERTS TO PROVIDE A GENERALIZABLE PIPELINE TO UNRAVEL THE FUNCTIONAL IMPACT OF CVD AND BLOOD TRAIT VARIANTS BY INTEGRATING: (1) RICH AND ANCESTRY-DIVERSE HUMAN GENETIC DISCOVERIES, (2) BROADLY TARGETABLE CRISPR BASE EDITORS AND EFFICIENT DELIVERY TO PRIMARY HUMAN CELLS, (3) HIGH-CONTENT ASSAYS TO PROFILE PHENOTYPES AT THE LEVELS OF CHROMATIN, GENE EXPRESSION AND CELLULAR FUNCTION, AND (4) COMPUTATIONAL METHODS TO DESIGN, INTERPRET, VISUALIZE, AND SHARE EXPERIMENTAL RESULTS. IN AIM 1, WE WILL EMPLOY A ROBUST, THREE-TIERED VARIANT PRIORITIZATION SCHEME THAT INCORPORATES EVIDENCE FOR DISEASE ASSOCIATION FROM LARGE, MULTI-ETHNIC GWAS AS WELL AS PROBABILITY OF CAUSALITY TO NOMINATE VARIANTS FOR FUNCTIONAL ASSESSMENT. THROUGH THIS SCHEME, WE WILL SELECT VARIANTS ASSOCIATED WITH RED BLOOD CELL AND NEUTROPHIL TRAITS, CORONARY ARTERY DISEASE, BLOOD PRESSURE, AND HDL AND LDL CHOLESTEROL THAT SPAN A RANGE OF ALLELIC FREQUENCIES AND LIKELY CAUSALITY TO TEST IN HIGH-THROUGHPUT CELLULAR ASSAYS. IN AIM 2, WE WILL PERFORM SYSTEMATIC CELLULAR PHENOTYPE-BASED SCREENS USING BASE EDITORS TO INSTALL CANDIDATE VARIANTS AS WELL AS CRISPR EPIGENETIC INHIBITION AND ACTIVATION TO EXPLORE VARIANT-CONTAINING REGULATORY ELEMENTS. WE WILL USE EIGHT ESTABLISHED, SCALABLE CELLULAR PHENOTYPIC READOUTS, EACH OF WHICH WILL ENABLE US TO ASSESS WHICH OF 12,000 VARIANTS AND VARIANT-CENTERED ELEMENTS ALTER CVD AND BLOOD TRAIT-ASSOCIATED CELLULAR PHENOTYPES. WE WILL ADDITIONALLY EMPLOY A HIGH-THROUGHPUT, GENOME-INTEGRATED CHROMATIN ACCESSIBILITY ASSAY TO ASSESS WHICH VARIANTS ALTER CHROMATIN ACCESSIBILITY IN TRAIT-RELEVANT CELL LINES. WE WILL FOLLOW UP WITH TARGETED SINGLE CELL RNA-SEQ OF 5,600 VARIANTS IN PRIMARY CELLS FROM DONORS OF DIFFERENT SEX AND ETHNICITY. IN AIM 3, WE WILL PRODUCE A CATALOG OF VALIDATED VARIANTS AND THEIR ASSOCIATION WITH PHENOTYPES FOR EACH OF THE PROPOSED SCREENS. WE WILL COLLABORATE WITH OTHER IGVF GROUPS TO UTILIZE THESE DATA TO OPTIMIZE MODELS THAT PREDICT FUNCTIONAL VARIANTS, REGULATORY ELEMENTS AND DISEASE-CAUSING BIOLOGICAL MECHANISMS, ULTIMATELY LEADING TO MORE COMPLETE UNDERSTANDING OF THE GENETIC UNDERPINNINGS OF CARDIOVASCULAR AND BLOOD DISEASE RISK.

NEXT-GENERATION CLINICAL PHENOTYPING AND PATHOPHYSIOLOGY OF LARYNGEAL DYSTONIA AND VOICE TREMOR - PROJECT SUMMARY / ABSTRACT LARYNGEAL DYSTONIA (LD) AND VOICE TREMOR (VT) ARE HYPERKINETIC NEUROLOGICAL DISORDERS THAT SIGNIFICANTLY IMPAIR VOICE AND SPEECH PRODUCTION AND NEGATIVELY IMPACT THE PATIENT’S QUALITY OF LIFE, EXTENDING BEYOND SPEECH MOTOR ALTERATIONS AND OFTEN CAUSING OCCUPATIONAL DISABILITY AND LIFE-LONG SOCIAL ISOLATION. THE STANDARDS OF CLINICAL CARE OF LD AND VT ARE NOT ESTABLISHED; THAT IS, THE DIFFERENTIAL DIAGNOSTIC CRITERIA REMAIN VAGUE, LEADING TO A HIGH RATE OF MISDIAGNOSIS, WHEREAS TREATMENT IS LARGELY LIMITED TO TEMPORARY SYMPTOM MANAGEMENT WITH BOTULINUM TOXIN INJECTIONS INTO THE AFFECTED LARYNGEAL MUSCLES. ONE OF THE MAJOR CAUSES OF SUBOPTIMAL CLINICAL CARE OF THESE PATIENTS IS THE LIMITED UNDERSTANDING OF THEIR DISTINCT CLINICAL CHARACTERISTICS AND NEURAL PATHOPHYSIOLOGY. WE PROPOSE A MULTI-INSTITUTIONAL, CROSS-DISCIPLINARY CENTER RESEARCH PROGRAM THAT WILL FOCUS ON THE DELINEATION OF UNIQUE CLINICAL AND PATHOPHYSIOLOGICAL FEATURES OF LD AND VT IN ORDER TO ESTABLISH THE FUNDAMENTAL FRAMEWORK FOR THE ENHANCED CLINICAL MANAGEMENT OF THESE DISORDERS, INCLUDING THEIR ACCURATE DIAGNOSIS AND DISORDER-SPECIFIC THERAPIES. THE CENTER RESEARCH GOALS WILL BE ACCOMPLISHED THROUGH COLLABORATIVE CLINICAL RESEARCH STUDIES AT MASSACHUSETTS EYE AND EAR INFIRMARY, MASSACHUSETTS GENERAL HOSPITAL, UNIVERSITY OF CALIFORNIA SAN FRANCISCO, AND UNIVERSITY OF UTAH, WHICH WILL INCLUDE THREE CENTER PROJECTS, A SCIENTIFIC CORE THAT INCORPORATES THE CLINICAL RESEARCH AND DATA SCIENCE COMPONENTS, AND AN ADMINISTRATIVE CORE THAT PROVIDES AN OVERALL ORGANIZATIONAL INFRASTRUCTURE TO THE CENTER ACTIVITIES. THE OVERALL SPECIFIC AIMS OF THIS CENTER WILL BE (1) CHARACTERIZATION OF CLINICAL PHENOTYPES OF LD AND VT; (2) UNDERSTANDING DISORDER-SPECIFIC NEURAL PATHOPHYSIOLOGY IN LD AND VT; (3) DEEP BRAIN STIMULATION IN LD AND VT, AND (4) MACHINE-LEARNING PLATFORMS FOR DIFFERENTIAL DIAGNOSIS OF LD AND VT. WE EXPECT THAT OUR CROSS-DISCIPLINARY AND COLLABORATIVE CENTER, ENCOMPASSING THE EXPERTISE IN OTOLARYNGOLOGY, SPEECH-LANGUAGE PATHOLOGY, NEUROLOGY, NEUROSURGERY, BRAIN AND LARYNX IMAGING, INVASIVE NEUROPHYSIOLOGY, AND CLINICAL NEUROSCIENCE AND APPLYING COMPLEMENTARY MULTIMODAL METHODOLOGIES ACROSS THESE FIELDS, WILL HAVE A SIGNIFICANT POSITIVE IMPACT ON DEVELOPING NEW KNOWLEDGE ABOUT THE LINKS BETWEEN SYMPTOMATOLOGY AND PATHOPHYSIOLOGY OF LD AND VT, WHICH WILL HELP DEFINE THE NEW STANDARDS OF ENHANCED CLINICAL CARE OF THESE DISORDERS.

COST-EFFECTIVENESS OF PREVENTING HIV COMPLICATIONS

NEUROIMAGING ACUPUNCTURE EFFECTS BRAIN ACTIVITY IN CHRONIC LOW BACK PAIN

HARVARD-VISION CLINICAL SCIENTIST DEVELOPMENT PROGRAM

CENTER FOR FUNCTIONAL IMAGING TECHNOLOGIES

CENTER FOR MESOSCALE MAPPING

SEX DIFFERENCES IN MAJOR DEPRESSION: IMPACT OF PRENATAL STRESS-IMMUNE AND AUTONOMIC DYSREGULATION

PET IMAGING OF THROMBUS

BUILDING COMMUNITY CAPACITY FOR DISABILITY PREVENTION FOR MINORITY ELDERS

PROGRAM FOR AIDS CLINICAL RESEARCH TRAINING (PACRT)

A RANDOMIZED CONTROLLED TRIAL OF ELECTROCONVULSIVE THERAPY PLUS USUAL CARE VERSUS SIMULATED-ECT PLUS USUAL CARE FOR THE ACUTE MANAGEMENT OF SEVERE AGITATION IN ALZHEIMER'S DEMENTIA (ECT-AD)

CLINICAL COORDINATING CENTER FOR THE HEALTH INITIATIVE IN EARLY PHASE PAIN INVESTIGATION CLINICAL NETWORK

PARKINSONS DISEASE SCALABLE IPSC AUTOLOGOUS CELL THERAPY

INTEGRATED SYSTEMS NEUROSCIENCE STUDIES OF ANAESTHESIA

HUNTINGTON'S DISEASE REPEAT INSTABILITY AND PATHOGENESIS

INFECTIOUS DISEASE AND BASIC MICROBIOLOGICAL MECHANISMS

TRAINING GRANT IN MOLECULAR IMAGING RESEARCH

LATE-ONSET UNEXPLAINED EPILEPSY AS A RISK FACTOR FOR DEMENTIA - PROJECT SUMMARY / ABSTRACT LATE-ONSET UNEXPLAINED EPILEPSY (LOUE), DEFINED AS EPILEPSY STARTING AFTER AGE 55 WITH NO CLEARLY IDENTIFIED CAUSE, HAS EMERGED AS A SIGNIFICANT RISK FACTOR FOR ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (AD/ADRD). LOUE AFFLICTS 50,000 NEW PATIENTS IN THE U.S. EACH YEAR AND WILL SOON AFFECT MANY MORE AS OUR ELDERLY POPULATION GROWS. INDIVIDUALS PRESENTING WITH LOUE HAVE NO PRIOR HISTORY OF DEMENTIA. YET, LOUE IS ASSOCIATED WITH A 2-3X INCREASED RISK OF DEVELOPING DEMENTIA, AND UP TO 25% OF LOUE DEVELOP DEMENTIA WITHIN 4 YEARS AFTER THEIR FIRST SEIZURE. WE HAVE LITTLE UNDERSTANDING OF THE MECHANISMS UNDERLYING DEMENTIA IN LOUE; NO TOOLS TO PREDICT WHICH INDIVIDUALS WITH LOUE ARE AT HIGHEST RISK; AND NO TREATMENTS TO PREVENT DEMENTIA IN LOUE. 30-40% OF LOUE MAY HARBOR AD PATHOLOGY AND/OR OCCULT CEREBROVASCULAR DISEASE, AND WE HYPOTHESIZE THAT THESE PATHOLOGIES DRIVE MUCH OF THE INCREASED DEMENTIA RISK IN LOUE. YET, OTHER PATHOLOGIES AND MECHANISMS ARE ALSO POSSIBLE AND NEED TO BE IDENTIFIED. OUR LONG-TERM GOAL IS TO DEVELOP A PRECISION MEDICINE APPROACH TO PREVENTING DEMENTIA IN LOUE, IN WHICH INDIVIDUALIZED RISK ASSESSMENT AND DISEASE SUBTYPING CAN SPECIFICALLY INFORM A PATIENT’S DEMENTIA PROGNOSIS AND GUIDE TARGETED THERAPIES TO REDUCE DEMENTIA RISK. WE HYPOTHESIZE THAT RIGOROUS, DATA-DRIVEN PHENOTYPING OF LOUE BASED ON CLINICAL FEATURES, BIOMARKERS, AND COGNITIVE OUTCOMES, WILL ADVANCE MECHANISTIC UNDERSTANDING OF DEMENTIA IN LOUE AND ACCELERATE THERAPEUTIC DEVELOPMENT TO REDUCE DEMENTIA RISK. THE GOALS OF THIS PROPOSAL ARE TO ELUCIDATE THE RISK FACTORS AND MECHANISMS THAT LEAD TO DEMENTIA IN LOUE AND TO DEVELOP TOOLS FOR DEMENTIA RISK-STRATIFICATION IN LOUE. TO ACCOMPLISH THESE GOALS, WE WILL CARRY OUT A PROSPECTIVE, MULTI- CENTER, LONGITUDINAL OBSERVATIONAL STUDY OF LOUE FOCUSED ON UNDERSTANDING MECHANISMS AND PREDICTING OUTCOMES OF AD/ADRD IN LOUE. WE WILL ENROLL 600 PARTICIPANTS WITH LOUE ACROSS 7 SITES OVER 3 YEARS. PARTICIPANTS WILL UNDERGO A BASELINE EVALUATION WITH CLINICAL HISTORY, COGNITIVE TESTING, BRAIN MRI, OVERNIGHT EEG, AND PLASMA AD BIOMARKERS, AND WILL BE FOLLOWED LONGITUDINALLY WITH INTERVAL HISTORY EVERY 6 MONTHS AND ANNUAL COGNITIVE TESTING. OUR SPECIFIC AIMS ARE: 1) TO ESTABLISH AN UNBIASED FRAMEWORK FOR IDENTIFYING MECHANISMS LEADING TO DEMENTIA IN LOUE, WE WILL ORGANIZE LOUE INTO DISEASE SUBTYPES BASED ON: (A) ASSOCIATED NEUROPATHOLOGY; (B) CLINICAL PHENOTYPE; AND (C) COGNITIVE TRAJECTORY; 2) TO ADVANCE MECHANISTIC UNDERSTANDING OF DEMENTIA IN LOUE, WE WILL IDENTIFY EPILEPSY-RELATED, NEUROPATHOLOGIC, NEUROPHYSIOLOGIC, AND STRUCTURAL FEATURES ASSOCIATED WITH DEVELOPMENT OF DEMENTIA IN LOUE; AND 3) TO ENABLE PROGNOSTICATION OF DEMENTIA IN LOUE, WE WILL DEVELOP PRACTICAL CLINICAL TOOLS TO FORECAST AN INDIVIDUAL’S RISK OF DEVELOPING DEMENTIA AFTER PRESENTATION WITH LOUE. THIS STUDY WILL BE THE FIRST LARGE-SCALE STUDY OF LOUE THAT WILL DEFINE ITS RELATIONSHIP TO AD/ADRD AND HAVE SUFFICIENT POWER TO DRAW CONCLUSIONS THAT WILL DIRECTLY IMPACT CLINICAL CARE. THIS STUDY WILL ALSO ESTABLISH FOUNDATIONAL KNOWLEDGE AND RISK-STRATIFICATION TOOLS THAT WILL FACILITATE THE DESIGN OF EFFICIENT AND INFORMATIVE CLINICAL TRIALS FOR DEMENTIA PREVENTION IN LOUE.

BASIC SCIENCE RESEARCH TRAINING FOR ANESTHETISTS

METABOLIC SYNDROME, LIFESTYLE MODIFICATION AND RESISTANCE TRAINING IN HIV DISEASE

PROTEOMIC GENETIC & LONGITUDINAL PATHWAYS TO OVARIAN CANCER BIOMARKER DISCOVERY

AGING OF EMOTION CIRCUITRY: IMPACT OF SEX, DEPRESSION, AND FETAL IMMUNE ORIGINS

THREE-DIMENSIONAL AND MULTISCALE ORGAN OF CORTI BIOMECHANICS

OPTIMIZING HIV CARE IN LESS DEVELOPED COUNTRIES

GENETIC AND MOLECULAR BASIS OF LONGEVITY

COMPARATIVE EFFECTIVENESS OF POST-DISCHARGE STRATEGIES FOR HOSPITALIZED SMOKERS

MOLECULAR IMMUNOLOGY AND TUMOR BIOLOGY

IMAGING GENETICS OF SPASMODIC DYSPHONIA

REGIONAL EMERGING SPECIAL PATHOGEN TREATMENT CENTER COOPERATIVE AGREEMENT - THE RECIPIENT, MASSACHUSETTS GENERAL HOSPITAL, SUPPORTS THIS FIVE-YEAR REGIONAL EMERGING SPECIAL PATHOGEN TREATMENT CENTER COOPERATIVE AGREEMENT PROJECT. THE GOAL OF THIS PROJECT IS TO WORK WITH OUR HEALTHCARE, PUBLIC HEALTH, AND EMS PARTNERS TO ASSURE THAT PATIENTS WITH SUSPECTED OR CONFIRMED HIGH CONSEQUENCE INFECTIOUS DISEASES (HCIDS) RECEIVE THE SAFEST AND BEST CARE POSSIBLE IN THE MOST APPROPRIATE CLINICAL LOCATION AT EVERY STAGE OF THEIR CARE. WE SUPPORT THIS MISSION THROUGH THREE OBJECTIVES: 1) ENSURING OUR SPECIALIZED HCID CARE UNITS AT MGH ARE ALWAYS PREPARED, EQUIPPED, AND TRAINED TO THE HIGHEST STANDARDS, 2) PROMOTING REGIONWIDE HCID READINESS SUPPORTED BY EXPERT EDUCATION, TRAINING, EXERCISING, AND COLLABORATIVE CONSULTATIONS FROM OUR RESPTC, AND 3) WORKING WITH IDENTIFIED HEALTHCARE FACILITIES AND OUR PUBLIC HEALTH AND EMS PARTNERS IN PLANNING AND RESPONSE TO ENSURE PATIENTS WITH SUSPECTED OR CONFIRMED HCID INFECTIONS CAN MOVE EFFICIENTLY AND SAFELY TO APPROPRIATE EXPERT RECEIVING HEALTHCARE FACILITIES EQUIPPED TO CARE FOR THE PATIENT FOR THE DURATION OF THEIR ILLNESS. THE EXPECTED OUTCOMES OF THIS PROJECT ARE 1) ONGOING READINESS TO SAFELY CARE FOR PATIENTS WITH HCIDS WITHIN THE MGH BCU WHEN NEEDED, 2) INCREASED CAPABILITIES AMONG THE ENTIRE REGION’S HEALTHCARE FACILITIES FOR SAFE IDENTIFICATION AND ISOLATION OF, AND INITIATION OF CARE FOR PATIENTS WITH HCIDS, AND 3) AN UPDATED REGIONAL PLAN FOR THE CARE OF PATIENTS WITH HCIDS SUPPORTED BY ENHANCED COMMUNICATIONS AND PATIENT TRANSPORTATION PROTOCOLS. THE PRODUCTS FROM THIS PROJECT ARE A FUNCTIONING BCU AT MGH, A ROBUST REGIONAL TRAINING PROGRAM, AND AN UPDATED REGIONAL HCID PLAN.

NASAL MICRORNA DURING BRONCHIOLITIS AND AGE 6Y ASTHMA PHENOTYPES: MARC-35 COHORT

IMPROVING OUTCOMES FOR HIV-INFECTED CHILDREN IN SOUTH AFRICA AND COTE D'IVOIRE

THE NEIGHBORHOOD: POAG HERITABLE OVERALL OPERATIONAL DATABASE

NEURONAL ION AND VOLUME SHIFTS AFTER ACUTE BRAIN INJURY

RESEARCH TRAINING IN PULMONARY IMMUNOLOGY AND ALLERGY AT MGH

IMMUNE RESPONSES TO VIBRIO CHOLERAE INFECTION AND VACCINATION IN HAITI

EARLY STRESS, PTSD, AND THE NEUROBIOLOGY OF ADDICTION

THE PURPOSE OF THIS AGREEMENT IS TO FUND RESEARCH SUPPORTING THE DEFENSE ADVANCED RESEARCH PROJECTS AGENCY DARPA DEFENSE SCIENCES OFFICES DSO STRENGTHENING RESILIENT EMOTIONS AND NIMBLE COGNITION THROUGH ENGINEERING NEUROPLASTICITY STRENGTHEN PROGRAM. THIS EFFORT SHALL BE CARRIED OUT GENERALLY AS SET FORTH IN EXHIBIT B, RESEARCH DESCRIPTION DOCUMENT, DATED JUNE 27, 2023, AND IN THE RECIPIENTS REVISED PROPOSAL TITLED, NOVEL AND CONVENTIONAL INTERVENTIONS FOR COGNITIVE AND EMOTIONAL FLEXIBILITY IN PATIENT TRAUMA NOCICEPT, DATED JANUARY 23, 2023, COPIES OF WHICH ARE IN THE POSSESSION OF BOTH PARTIES.

THE MASSACHUSETTS GENERAL HOSPITAL HARVARD CENTER FOR REPRODUCTIVE MEDICINE - PROJECT ABSTRACT INFERTILITY AFFECTS UP TO 13% OF REPRODUCTIVE AGE COUPLES ACROSS THE GLOBE BUT THE UNDERLYING MECHANISTIC BASIS OF INFERTILITY AND THE ROLE OF INFERTILITY AS AN OVERALL MARKER OF GENERAL HEALTH IS UNCLEAR. THESE KNOWLEDGE GAPS HINDER THE DIAGNOSIS, TREATMENT AND PREVENTION OF INFERTILITY LEADING TO PHYSICAL, PSYCHOLOGICAL AND FINANCIAL BURDEN TO COUPLES WITH INFERTILITY. TO ADDRESS THESE CHALLENGES, THE MASSACHUSETTS GENERAL HOSPITAL HARVARD CENTER FOR REPRODUCTIVE MEDICINE HAS ASSEMBLED AN INTEGRATIVE TEAM OF INVESTIGATORS WITH EXPERTISE IN REPRODUCTIVE MEDICINE, GENOMICS, POPULATION GENETICS AND GENETIC LITERACY WHO WILL CONDUCT CLINICAL TRANSLATIONAL INVESTIGATION IN HUMANS WITH INFERTILITY: AIM 1: TO ELUCIDATE THE GENETIC AND PHENOMIC ARCHITECTURE OF INFERTILITY THROUGH THE LENS OF SPECIFIC RARE DISEASES AND COMMON TRAITS; AIM 2: TO CATALYZE A COLLABORATIVE THINK-TANK FOCUSED ON REDUCING THE SUFFERING AND COSTS OF INFERTILITY, IN A MANNER THAT IS OUTWARD LOOKING, FORWARD THINKING AND INTEGRATES GLOBAL PERSPECTIVES; AIM 3: TO NUCLEATE A VIBRANT HUB FOR OUTREACH, TRAINING AND COMMUNITY ENGAGEMENT THAT BRINGS THE SCIENTIFIC TEAM CLOSER TO THE PATIENTS THEY SERVE, THE TRAINEES THEY WANT TO MENTOR, AND THE LARGER COMMUNITY OF SCIENTISTS AND CLINICIANS WHO ARE INVESTED IN REDUCING THE BURDENS CAUSED BY INFERTILITY. THESE AIMS WILL BE ACHIEVED USING TWO CLINICAL RESEARCH PROJECTS WHICH WILL BE SUPPORTED BY A GENOMICS AND FUNCTIONAL CORE, OUTREACH CORE AND ADMINISTRATIVE CORE. PROJECT 1 WILL PERFORM NEXT-GENERATION SEQUENCING AND TARGETED GENOTYPE-DRIVEN PHENOTYPING STUDIES IN CLINICAL COHORTS ENRICHED FOR GENETICALLY DRIVEN INFERTILITY FROM ADMIXED AND CONSANGUINEOUS POPULATIONS CHARACTERIZED BY BOTH HYPOGONADOTROPIC AND HYPERGONADOTROPIC HYPOGONADISM IN BOTH SEXES. PROJECT 2 WILL BRING TOGETHER >1,800,000 MULTI-ETHNIC POPULATION BIOBANK SAMPLES TO PERFORM GENOME-WIDE ASSOCIATION STUDIES, PHENOME-WIDE ASSOCIATION STUDIES, AND MENDELIAN RANDOMIZATION STUDIES TO IMPLICATE KEY BIOLOGIC PATHWAYS DETERMINING FERTILITY AND SYNTHESIZE THE GENETIC RESULTS ACROSS INFERTILITY AND RELATED TRAITS TO CHARACTERIZE THE EFFECTS OF THE IDENTIFIED GENES AND PATHWAYS ON REPRODUCTIVE HEALTH AND OVERALL MORBIDITY. THE GENOMICS AND FUNCTIONAL CORE WILL PROVIDE GENOMIC TECHNOLOGIES, DATA ANALYTICS, COMPUTATIONAL AND STATISTICAL SUPPORT, AND WILL GENERATE GENETICALLY ENGINEERED HUMAN INDUCED PLURIPOTENT CELLS FOR VALIDATION OF PROJECT 1 & 2 GENETIC DISCOVERIES. THE OUTREACH CORE WILL BUOY PROJECT 1 & 2 ACTIVITIES BY ENGAGING KEY STAKEHOLDERS THROUGH PATIENT GROUP MEETINGS, CREATING CLINICIAN-FACING MATERIALS TO ENABLE COMMUNICATION OF GENETIC RESULTS AND LAUNCH A WEBSITE INSPIRED BY DESIGN-THINKING FOR BROAD DISSEMINATION TO PATIENTS, FAMILIES AND CLINICIANS. THE ADMINISTRATIVE CORE WILL ADVANCE THE CENTER’S SCIENTIFIC GOALS BY PROVIDING TIMELY SUPPORT TO FOSTER ENGAGEMENT AND COMMUNICATION BETWEEN INVESTIGATORS, PATIENTS, RESEARCH TRAINEES AND THE BROADER ACADEMIC COMMUNITY. THROUGH THESE INTERDIGITATING ACTIVITIES, THE CENTER WILL TRAIN THE NEXT GENERATION OF REPRODUCTIVE BIOLOGISTS AND THE RESULTS EMANATING FROM ITS ACTIVITIES WILL HELP INFORM CLINICAL CARE AND ALLEVIATE THE SUFFERING OF PATIENTS WITH INFERTILITY.

STRENGTHENING HEALTHCARE INFECTION PREVENTION AND CONTROL AND IMPROVING PATIENT SAFETY IN THE UNITED STATES

HUNTINGTON'S DISEASE: LEARNING FROM EXTREMES

IMAGING AND ANALYSIS TECHNIQUES TO CONSTRUCT A CELL CENSUS ATLAS OF THE HUMAN BRAIN

HARNESSING DIVERSE BIOINFORMATIC APPROACHES TO REPURPOSE DRUGS FOR ALZHEIMERS DISEASE

ROLES OF NUCLEUS ACCUMBENS CREB AND KAPPA FUNCTION IN DEPRESSION

VASCULAR PATHOLOGY IN EARLY AND ASYMPTOMATIC CEREBRAL AMYLOID ANGIOPATHY

TRAINING PROGRAM IN CANCER BIOLOGY

CELL TYPE SPECIFIC GENOMIC AND FUNCTIONAL DISSECTION OF FEAR OFF AMYGDALA PATHWAYS

CIRCUMVENTING ACQUIRED RESISTANCE TO GROWTH FACTOR RECEPTOR KINASE INHIBITORS

INTEGRATING COMMON AND RARE VARIATION TO DISCOVER GENES ASSOCIATED WITH TOURETTE SYNDROME

SLEEP-DEPENDENT MEMORY PROCESSING IN SCHIZOPHRENIA

NEUROIMAGING STUDIES OF REWARD PROCESSING IN DEPRESSION

CELL BIOLOGY OF VASOPRESSIN-INDUCED WATER CHANNELS

MINIMIZING ICU NEUROLOGICAL DYSFUNCTION WITH DEXMEDETOMIDINE-INDUCED SLEEP (MINDDS II) - PROJECT SUMMARY / ABSTRACT UP TO A THIRD OF ELDERLY PATIENTS RECOVERING FROM CARDIAC SURGERY EXPERIENCE POSTOPERATIVE DELIRIUM (POD), AN ACUTE STATE OF CONFUSION MARKED BY INATTENTION AND GLOBAL COGNITIVE DYSFUNCTION. POD IS A BURDENSOME CLINICAL AND PATIENT-CENTERED OUTCOME ASSOCIATED WITH LONG-TERM COGNITIVE DEFICITS LIKE ALZHEIMER'S DISEASE (AD) AND RELATED DEMENTIAS (AD/RD), PROLONGED HOSPITALIZATION AND INSTITUTIONALIZATION, HIGHER READMISSION RATES, AND INCREASED MORTALITY. WE RECENTLY FOUND ELEVATED TAU IN THE SERUM OF PATIENTS THAT DEVELOPED POD AFTER CARDIAC SURGERY AND AN ASSOCIATION BETWEEN TAU AND POD SEVERITY, SUGGESTING THAT PERIOPERATIVE STRESSORS EXACERBATE LATENT ADRD PATHOLOGY, AND EVIDENCE TO SUGGEST THAT DEXMEDETOMIDINE MODIFIES THE ASSOCIATION WITH PREOPERATIVE TAU. RECENT STUDIES HAVE SUGGESTED THAT APPROXIMATELY 30% TO 40% OF POD MAY BE PREVENTABLE. HOWEVER, MULTICOMPONENT NONPHARMACOLOGICAL POD PREVENTION STRATEGIES ARE RESOURCE INTENSIVE AND INCREASINGLY CHALLENGING TO IMPLEMENT GIVEN THE CURRENT LABOR SHORTAGE IN HEALTHCARE. A RECENT ENHANCED RECOVERY AND PERIOPERATIVE QUALITY INITIATIVE JOINT CONSENSUS STATEMENT ON POD PREVENTION HIGHLIGHTED THE NEED FOR A SAFE AND EASY-TO-IMPLEMENT PROPHYLACTIC PHARMACOLOGICAL STRATEGY. AT PRESENT, DEFINITIVE GUIDELINES OR LARGE CLINICAL TRIALS DO NOT SUPPORT THE ADMINISTRATION OF ANY MEDICATION FOR POD PREVENTION. IN THE PILOT MINIMIZING ICU NEUROLOGICAL DYSFUNCTION WITH DEXMEDETOMIDINE-INDUCED SLEEP (MINDDS) RANDOMIZED CONTROLLED TRIAL, WE FOUND THAT NIGHTTIME INTRAVENOUS DEXMEDETOMIDINE SIGNIFICANTLY REDUCED THE INCIDENCE OF POD IN PATIENTS OLDER THAN 60. HOWEVER, REPLICATION IN A LARGE, MORE PRAGMATIC TRIAL IS WARRANTED TO SUPPORT THE WIDESPREAD IMPLEMENTATION OF NIGHTTIME DEXMEDETOMIDINE FOR POD PREVENTION. THIS PROPOSAL WILL STUDY NIGHTTIME INTRAVENOUS AND SUBLINGUAL DEXMEDETOMIDINE TO PROVIDE DEFINITIVE EVIDENCE FOR POD PREVENTION EFFICACY. ADDITIONALLY, IT WILL CREATE A BIOREPOSITORY TO AID BIOMARKER DISCOVERY AND INSIGHTS INTO POD AND COGNITIVE RECOVERY AFTER CARDIAC SURGERY. IN AIM 1, WE WILL PERFORM A LARGE (N = 1800), PRAGMATIC, PHASE III, RANDOMIZED, BLINDED, DOUBLE PLACEBO-CONTROLLED, THREE-ARM STUDY OF NIGHTTIME DEXMEDETOMIDINE FOR POD PREVENTION AND COGNITIVE IMPROVEMENT IN ELDERLY PATIENTS FOLLOWING CARDIAC SURGERY. IN AIM 2, WE WILL EXAMINE THE EFFECT OF NIGHTTIME DEXMEDETOMIDINE ON PATIENT-REPORTED OUTCOMES, MORBIDITY, AND MORTALITY. IN AIM 3, WE WILL ESTABLISH A BIOREPOSITORY OF PLASMA, RIBONUCLEIC, AND DEOXYRIBONUCLEIC SAMPLES. THE PROPOSAL HAS

GENETIC AND ENVIRONMENTAL RISK FACTORS FOR EXFOLIATION SYNDROME AND GLAUCOMA

THE PATHOGENESIS OF RNA SPLICING FACTOR RP

AN AUTOIMMUNE CENTER OF EXCELLENCE FOR THE STUDY OF IGG4-RELATED DISEASE

MITF: A MASTER GENE FOR MELANOCYTE DEVELOPMENT

IMPACT OF DEPRESSION ON ALZHEIMER'S DISEASE: PRENATAL IMMUNE ORIGINS AND SHARED IMPACT OF SEX

DISEASE-MODIFYING GENES IN HUNTINGTON'S DISEAE

EVALUATION OF SMALL-FIBER POLYNEUROPATHY AS A CAUSE OF CHRONIC WIDESPREAD PAIN IN YOUTH

CLINICAL DIAGNOSTIC SEQUENCING OF STRUCTURAL VARIATION

POST-DPP FOLLOWUP STUDY

MOLECULAR SIGNALING IN SHIGELLA DISSEMINATION

DEVELOPMENT OF THE HUMAN DYNAMIC NEUROCHEMICAL CONNECTOME SCANNER

RESTORING COMMUNICATION WITH AN INTRACORTICAL NEURAL INTERFACE SYSTEM

SCALABLE PHENOTYPING TO ASSAY RISK IN CHILDHOOD AFTER EXPOSURES IN PREGNANCY: SPARC-XP - PROJECT SUMMARY INFECTION IN PREGNANCY IS A SIGNIFICANT RISK FOR NEURODEVELOPMENTAL DISORDERS IN OFFSPRING, DEMONSTRATED IN NATIONAL REGISTRIES, LARGE EPIDEMIOLOGIC STUDIES, AND ELECTRONIC HEALTH RECORDS COHORTS. MECHANISTIC STUDIES IN ANIMALS HAVE SIMILARLY ESTABLISHED ADVERSE EFFECTS OF MATERNAL INFECTION ON OFFSPRING NEURODEVELOPMENT AND BEHAVIOR. DESPITE THIS COMPELLING EVIDENCE OF RISK, AT PRESENT THERE ARE NO VALIDATED METHODS TO PREDICT WHICH EXPOSED CHILDREN WILL DEVELOP AUTISM, ADHD, OR OTHER ADVERSE OUTCOMES. BETTER RISK STRATIFICATION METHODS ARE URGENTLY NEEDED TO GUIDE EARLY INTERVENTION. DEVELOPING RELIABLE, GENERALIZABLE RISK PREDICTION REQUIRES LARGE, REPRESENTATIVE POPULATIONS AND THE ABILITY TO CONDUCT LOW-COST PHENOTYPING, VALUABLE IN EXTENDING THE PREDICTION AFFORDED BY ELECTRONIC HEALTH RECORDS ALONE. THIS CONCEPT REPRESENTS THE CRUX OF THE IMPACT-MH INITIATIVE AND THE ORGANIZING PRINCIPLE OF THIS PROPOSAL, WHICH SEEKS TO FILL A KEY KNOWLEDGE GAP IN PREDICTING NEURODEVELOPMENTAL OUTCOMES. THIS STUDY WILL GENERATE RISK MODELS TO PREDICT NEURODEVELOPMENTAL OUTCOMES BY AGE 8 AMONG OFFSPRING OF MOTHERS WITH INFECTIONS DURING PREGNANCY, FOCUSING ON TWO ACTIONABLE TIME POINTS: AT BIRTH, AND BETWEEN AGES 3 AND 5. IT WILL FIRST USE STANDARD AND EMERGING MACHINE LEARNING METHODS TO ANALYZE ELECTRONIC HEALTH RECORDS (EHR) DATA FROM AT LEAST 150,000 MATERNAL-OFFSPRING DYADS ACROSS 2 HEALTH SYSTEMS, CHARACTERIZING MATERNAL INFECTIONS, PREGNANCY COMPLICATIONS, AND OFFSPRING PHENOTYPES. THESE EHR DATA WILL BE AUGMENTED BY PROSPECTIVE PHENOTYPING OF 750 INFECTION- EXPOSED CHILDREN ENROLLED ACROSS 2 SITES: MASSGENERAL BRIGHAM HEALTH SYSTEM IN MASSACHUSETTS, AND VANDERBILT UNIVERSITY MEDICAL CENTER IN TENNESSEE. THE INVESTIGATORS WILL COLLECT PARENTAL REPORT OF DEVELOPMENTAL DATA, ACCELEROMETRY DATA TO ASSESS MOTOR FUNCTION AND SLEEP, AND WILL PERFORM VIRTUAL NEUROCOGNITIVE TESTING AT AGE 3- 5 YEARS. THEY WILL COMPARE RISK STRATIFICATION MODELS USING ELECTRONIC HEALTH RECORDS AUGMENTED WITH NATURAL LANGUAGE PROCESSING, PARENTAL REPORTS, NEUROCOGNITIVE TESTING, AND ACCELEROMETRY. CHILDREN WILL AGAIN BE ASSESSED AT AGE 6-8 YEARS TO ASCERTAIN DIAGNOSES. OPTIMAL PREDICTION MODELS FROM THE MASSACHUSETTS COHORT WILL BE EXTERNALLY VALIDATED IN THE TENNESSEE COHORT. TOGETHER, THESE AIMS WILL YIELD TOOLS FOR RISK STRATIFICATION IN CHILDREN EXPOSED TO MATERNAL INFECTION DURING PREGNANCY, APPLYING INNOVATIVE METHODS TO ELECTRONIC HEALTH RECORDS INTEGRATED WITH REMOTE BEHAVIORAL PHENOTYPING. THE PROJECT WILL BE LED BY PRINCIPAL INVESTIGATORS WITH EXPERTISE IN PREGNANCY EXPOSURES, LARGE-SCALE ELECTRONIC HEALTH RECORDS, MACHINE LEARNING, AND NEURODEVELOPMENTAL PHENOTYPING.

FUNCTIONAL ANALYSIS OF EPIGENETIC COMPLEXES

IMAGING ORGAN SYSTEM INTERFACES IN ISCHEMIC HEART DISEASE

THE POWER OF EXTRACELLULAR VESICLES IN GLIOBLASTOMA

VASCULAR DYSFUNCTION IN CEREBRAL AMYLOID ANGIOPATHY

GLOBAL TRAVEPINET (GTEN): U.S. TRAVELERS? HEALTH RESEARCH, SURVEILLANCE, COMMUNICATION AND OUTREACH NETWORK

ACTIVITY-DEPENDENT INFLUENCES ON AUDITORY CIRCUITS

PATHOGENESIS OF CLADE C HIV INFECTION

NIDCD NATIONAL TEMPORAL BONE, HEARING AND BALANCE PATHOLOGY RESOURCE REGISTRY

AAV-MEDIATED EDITING TO TREAT HUMAN AUTOSOMAL DOMINANT HEARING LOSS DFNA41 AND DFNA2 - PROJECT SUMMARY/ABSTRACT 1 IN 500 NEWBORNS SUFFERS FROM GENETIC HEARING LOSS (HL), AND THERE ARE NO FDA-APPROVED DRUGS OR BIOLOGICAL TREATMENTS FOR ANY TYPE OF HL. GENOME EDITING THAT DISRUPTS OR REPAIRS DNA MUTATIONS OR MODULATES RNA LEVELS IS BEING DEVELOPED INTO NEW THERAPIES FOR MANY DISEASES. DESPITE THE UNPRECEDENTED PROGRESS, THE TRANSLATION OF GENOME EDITING INTO THERAPY IN HUMANS HAS BEEN CHALLENGING DUE TO THE OBSTACLES IN DELIVERY, SAFETY, AND EFFICACY. THIS IS PARTICULARLY RELEVANT FOR IN VIVO EDITING THERAPY DUE TO THE ADDED COMPLEXITY, INCLUDING DAMPED EDITING EFFICIENCY, INEFFICIENCY IN REACHING THE TARGET CELLS, AND THE LACK OF EVIDENCE OF TRANSLATABILITY FROM ANIMAL (MOUSE) INTO HUMANS. IN THIS PROPOSAL, WE WILL DEVELOP FIRST- IN-CLASS CRISPR-CAS-BASED THERAPEUTICS FOR GENETIC HEARING LOSS BY CONDUCTING IND-ENABLING STUDIES OF AAV2-MEDIATED DELIVERY OF SACAS9-KKH/GRNA TO TARGET TWO DOMINANT GENETIC HEARING LOSS, DFNA41 DUE TO A P2RX2 MUTATION AND DFNA2 DUE TO A KCNQ4 MUTATION. THIS PROJECT WILL BE CONDUCTED BY A CONSORTIUM OF FIVE CORE TEAMS WITH UNIQUE AND COMPLEMENTARY EXPERTISE AND EXPERIENCE IN GENE AND EDITING TREATMENTS FOR GENETIC HEARING LOSS, FROM ANIMAL MODELS TO HUMAN TRIALS, EDITING TECHNOLOGY, AND REGULATORY PROCESSES. WE HAVE RECENTLY CONDUCTED THE FIRST SUCCESSFUL GENE THERAPY OF OTOF CLINICAL TRIAL BY DUAL ADENO-ASSOCIATED VIRUS (AAV) THAT LEADS TO HEARING RESTORATION IN CHILDREN WITH CONGENITAL GENETIC HEARING LOSS DFNB9, WHICH INCLUDED A SAFETY STUDY OF AAV IN NON-HUMAN PRIMATES (NHPS) AND THE DEVELOPMENT OF A MINIMALLY INVASIVE SURGICAL PROCEDURE FOR AAV INNER EAR DELIVERY IN HUMANS. WE HAVE FURTHER DEVELOPED A LARGE ANIMAL PIG MODEL OF DOMINANT GENETIC HEARING LOSS DFNA36 BY INSERTING A MUTATION INTO THE TMC1 GENE AND SUCCESSFULLY RESCUED HEARING IN THE PIG MODEL BY LOCAL AAV DELIVERY OF EDITING COMPLEX, DEMONSTRATING THE CROSS-SPECIES TRANSLATABILITY OF EDITING THERAPY FOR GENETIC HEARING LOSS. FOR THE CURRENT PROPOSAL, WE HAVE OBTAINED THE THERAPEUTIC BENEFIT OF HEARING RESCUE RESULTS BY AAV2 DELIVERY OF SACAS9-KKH/GRNA TO TREAT DFNA41 AND DFNA2 MOUSE MODELS, WHICH LAYS THE FOUNDATION OF AN IND-ENABLING STUDY. LEVERAGING OUR UNPARALLELED EXPERTISE AND EXPERIENCE IN HUMAN GENETIC HEARING LOSS, INCLUDING EFFICACIOUS EDITING TREATMENT IN MOUSE AND PIG MODELS, AAV SAFETY STUDY IN NHP, AND THE FIRST SUCCESSFUL HUMAN GENE THERAPY CLINICAL TRIAL, WE WILL CONDUCT THE FOLLOWING STUDIES: 1). ESTABLISH OFF-TARGET EDITING PROFILES IN HUMAN CELLS AND HUMAN INNER EAR TISSUES; 2). EFFICACY STUDY BY ESCALATING DOSES OF AAV2 IN DFNA41 AND DFNA2 MOUSE MODELS; 3). BIODISTRIBUTION AND TOXICITY STUDY IN WT MICE BY AN ESCALATING DOSE OF AAV2; 4). BIODISTRIBUTION AND TOXICITY STUDY OF GLP GRADE AAV2 IN NHP; 5). PATIENT NATURAL HISTORY STUDY, AND 6). REGULATORY INTERACTIONS & IND COMPLETION. WE HAVE ASSEMBLED A TEAM OF EXPERTS IN EACH AREA WITH A PROJECT MANAGER TO EXECUTE THE PLAN, DEVELOP A STREAMLINED REGULATORY PATH FOR TWO TYPES OF DFNA DEAFNESS, AND DISSEMINATE THIS REGULATORY INFORMATION TO THE SCIENTIFIC COMMUNITY. SUCCESSFUL COMPLETION OF THE IND-ENABLING STUDIES MAKES OUR APPROACH APPLICABLE TO OVER 20 DOMINANT GENETIC HEARING LOSS DUE TO HAIR CELL MUTATIONS.

INFLAMMATION AND COLORECTAL NEOPLASIA

PERCEPTUAL IMPLICATIONS OF COCHLEAR IMPLANT ELECTRODE-NEURON INTERFACES

NOVEL METHODS TO INFORM HIV/TB CLINICAL TRIAL DEVELOPMENT

IMPACT OF MATERNAL SUBSTANCE USE ON OFFSPRING NEUROBEHAVIORAL DEVELOPMENT - SUBSTANCE USE IN PREGNANCY IS A SIGNIFICANT PUBLIC HEALTH PROBLEM AND IS ASSOCIATED WITH ADVERSE OFFSPRING NEURODEVELOPMENTAL AND BEHAVIORAL OUTCOMES, INCLUDING COGNITIVE DYSFUNCTION, AUTISM SPECTRUM DISORDER, ATTENTION DEFICIT HYPERACTIVITY DISORDER, AND MOOD DISORDERS. HOWEVER, THE MECHANISMS BY WHICH MATERNAL SUBSTANCE USE RESULTS IN OFFSPRING NEURODEVELOPMENTAL MORBIDITY REMAIN LARGELY UNKNOWN. EMERGING EVIDENCE HIGHLIGHTS MATERNAL IMMUNE DYSREGULATION AS A PLAUSIBLE MECHANISM BECAUSE THE USE OF OPIOIDS, CANNABIS, AND ALCOHOL HAS BEEN ASSOCIATED WITH IMMUNE ACTIVATION, WITH SUBSEQUENT EFFECTS ON THE DYNAMIC INTERACTION BETWEEN THE PLACENTAL IMMUNE AND SEROTONIN SYSTEM. OUR STUDY’S OBJECTIVES ARE TO DETERMINE THE IMPACT OF MATERNAL SUBSTANCE USE ON MATERNAL IMMUNE ACTIVATION AND OFFSPRING NEUROBEHAVIORAL DEVELOPMENTAL TRAJECTORIES, AND TO DEFINE THE PLACENTA’S ROLE IN MEDIATING THESE ASSOCIATIONS. THIS STUDY CAPITALIZES ON THE 25-SITE NIH/NIDA HEALTHY BRAIN AND CHILD DEVELOPMENT STUDY (HBCD), THE LARGEST (~7500 MOTHER/CHILD DYADS) LONG-TERM UNITED STATES STUDY OF EARLY BRAIN AND CHILD DEVELOPMENT OUTCOMES AFTER MATERNAL HIGH-RISK EXPOSURES, INCLUDING SUBSTANCE USE. IT IS PART OF THE NIH’S HELPING TO END ADDICTION LONG-TERM (HEAL) INITIATIVE TO SPEED SCIENTIFIC SOLUTIONS TO THE NATIONAL OPIOID PUBLIC HEALTH CRISIS. THE NIH HEAL INITIATIVE BOLSTERS RESEARCH ACROSS NIH TO IMPROVE TREATMENT FOR OPIOID MISUSE AND ADDICTION. WE PROPOSE TO BRIDGE THE MECHANISTIC GAP BETWEEN MATERNAL SUBSTANCE USE AND KNOWN ADVERSE CHILD OUTCOMES, BY PERFORMING MATERNAL IMMUNE PROFILING, AND PLACENTAL AND CORD BLOOD IMMUNE AND SEROTONIN PROFILING IN 400 PREGNANCIES ACROSS 4 GEOGRAPHICALLY DIVERSE HBCD SITES. THESE BIOLOGICAL MEASURES WILL BE LINKED TO MATERNAL PHENOTYPING, CHILD BRAIN IMAGING, AND BEHAVIORAL MEASURES COLLECTED BY THE CORE HBCD STUDY FROM 0-15 MONTHS OF AGE. THE COMPLEMENTARY STUDIES PROPOSED HERE WILL CREATE A BIOLOGICAL LINK BETWEEN THE PRENATAL ENVIRONMENT AND POSTNATAL OUTCOMES THAT IS ABSENT FROM THE HBCD CORE PROTOCOL. OUR MULTIDISCIPLINARY TEAM WILL QUANTIFY MATERNAL INFLAMMATION AND IMMUNE ACTIVATION INDUCED BY EXPOSURE TO MATERNAL SUBSTANCE USE THROUGH STUDIES OF MATERNAL CYTOKINES, T CELLS AND MONOCYTES (AIM 1). WE WILL DEFINE THE IMPACT OF MATERNAL SUBSTANCE USE ON PLACENTAL AND FETAL IMMUNE ACTIVATION AND FETOPLACENTAL SEROTONIN SIGNALING (AIM 2). LASTLY, WE WILL LINK MATERNAL SUBSTANCE USE TO NEONATAL NEUROINFLAMMATION, AS ASSESSED BY A NOVEL ANALYTIC METHOD APPLIED TO EXISTING HBCD MRI DATA. (AIM 3). USING STATISTICAL MODELING, WE WILL ESTIMATE THE EXTENT TO WHICH MATERNAL-FETAL IMMUNE ACTIVATION, DYSREGULATED SEROTONIN SIGNALING, AND NEONATAL BRAIN INFLAMMATION MEDIATE OBSERVED ASSOCIATIONS BETWEEN SUBSTANCE USE AND EARLY CHILD BEHAVIORAL OUTCOMES. COMPLETION OF THESE AIMS WILL PROVIDE NEW MECHANISTIC INSIGHTS INTO THE IMPACT OF MATERNAL SUBSTANCE USE ON MATERNAL, PLACENTAL, AND FETAL IMMUNE ACTIVATION, AND HELP ELUCIDATE THE INFLUENCE OF PLACENTAL IMMUNE DYSREGULATION AND ALTERED SEROTONIN SIGNALING ON CHILD NEURODEVELOPMENTAL MORBIDITY. RESULTS WILL GUIDE SCREENING AND THERAPEUTIC STRATEGIES TO MITIGATE ADVERSE TRANSGENERATIONAL IMPACTS OF MATERNAL SUBSTANCE USE.

DEMYSTIFYING THE ANTIVIRAL ACTIVITY OF THE IGG3+ ANTIBODY RESPONSE

EARLY LIFE STRESS AND DEPRESSION: MOLECULAR AND FUNCTIONAL IMAGING APPROACHES

MOLECULAR ETIOLOGY OF EARLY ONSET DYSTONIA

TIME-GATED DIFFUSE CORRELATION SPECTROSCOPY FOR FUNCTIONAL IMAGING OF THE HUMAN BRAIN

COMPLICATIONS OF IMMUNOSUPRESSION FOR EYE DISEASES

JASPER-MH: JOINTLY ASSESSED SCALABLE PHENOTYPES FOR MENTAL HEALTH - MENTAL HEALTH AMONG YOUNG ADULTS REPRESENTS A PUBLIC HEALTH CRISIS, REQUIRING MORE EFFICIENT AND PRECISE MEANS OF UNDERSTANDING ILLNESS TRAJECTORIES IN THE GENERAL POPULATION. SUCH MODELS COULD PROVIDE OPPORTUNITIES FOR EARLY IDENTIFICATION AND INTERVENTION FOR MENTAL ILLNESS DURING THE PERIOD OF ADOLESCENCE TO YOUNG ADULTHOOD, AS YOUTH NAVIGATE KEY PSYCHOSOCIAL MILESTONES AND NEUROPSYCHIATRIC ILLNESS BECOMES ENTRENCHED. WORK BY THE INVESTIGATORS AND OTHERS HAS DEMONSTRATED THE UTILITY OF ELECTRONIC HEALTH RECORDS (EHR) FOR DEVELOPING RISK STRATIFICATION MODELS FOR PSYCHIATRIC OUTCOMES. YET, THE INVESTIGATORS AND OTHERS HAVE ALSO SHOWN THAT THE DIAGNOSTIC CODES AVAILABLE IN EHR ARE INSUFFICIENT TO RELIABLY PREDICT THE EVOLUTION OF PSYCHOPATHOLOGY OVER TIME. AS SUCH, RFA MH-23-105 SEEKS STRATEGIES TO AUGMENT EHR-BASED MODELS TO EFFICIENTLY CAPTURE SIGNATURES THAT MAY IMPROVE CLINICAL PREDICTION. AMONG THE BROAD RANGE OF POTENTIAL MEASURES, BRIEF BATTERIES THAT CAPTURE DIMENSIONAL TRAITS, INCLUDING QUANTITATIVE SYMPTOMS AND COGNITION, ARE AT THE CORE OF EVIDENCE- BASED, DEVELOPMENTALLY RELEVANT PSYCHOPATHOLOGY FRAMEWORKS AND ARE CONSISTENT WITH THE CONSENSUS THAT CLINICAL STAGING MUST BE APPROACHED THROUGH A TRANSDIAGNOSTIC LENS. VARIATION IN SUCH TRAITS IS NOT WELL-CAPTURED BY STANDARD EHR DATA BUT REPRESENTS AN IMPORTANT ASPECT OF NEURODEVELOPMENT AND ITS RELATIONSHIP TO CLINICAL AND FUNCTIONAL OUTCOMES. THIS STUDY PROPOSES TO INTEGRATE REMOTELY-DELIVERED COGNITIVE TASKS AND BRIEF SYMPTOM INVENTORIES TO ENHANCE PREDICTION OF PROSPECTIVE OUTCOMES AMONG TRANSITION AGE YOUTH. SPECIFICALLY, IT WILL APPLY METHODS DEVELOPED BY THE INVESTIGATORS TO A COHORT OF N= 10,000 INDIVIDUALS AGE 18-20 IDENTIFIED FROM EHR IN THE MASS GENERAL BRIGHAM HEALTH CARE SYSTEM AND ASSESSED PROSPECTIVELY EVERY 6 MONTHS FOR 2 YEARS. AIM 1 WILL IDENTIFY, ENROLL, AND RETROSPECTIVELY CHARACTERIZE THIS COHORT, EXTENDING EHR CODES WITH VALIDATED NLP METHODS TO CHARACTERIZE DIMENSIONAL PSYCHIATRIC SYMPTOMS AND COGNITIVE FUNCTIONING RETROSPECTIVELY FOR UP TO 10 YEARS, USING DATA CENSORED 6 OR 24 MONTHS PRIOR TO BASELINE TO PREDICT CURRENT STATUS. AIM 2 WILL COLLECT ENHANCED PHENOTYPING (NEUROCOGNITIVE AND SELF-REPORT PSYCHIATRIC AND PSYCHOSOCIAL FUNCTIONING DATA) ON THIS COHORT EVERY 6 MONTHS AND APPLY BOTH STANDARD AND NOVEL INTERPRETABLE MACHINE LEARNING METHODS TO DERIVE PREDICTORS OF 180-DAY PSYCHIATRIC OUTCOMES. AIM 3 WILL APPLY INTERPRETABLE MACHINE LEARNING METHODS TO DETERMINE THE VALUE OF ENHANCED PHENOTYPING OVER EHR DATA ALONE FOR 24-MONTH OUTCOMES . WE HYPOTHESIZE THAT ADDING THESE LOW COST, LOW BURDEN PHENOTYPES WILL IMPROVE THE PERFORMANCE OF MODELS PREDICTING LONGITUDINAL NEUROPSYCHIATRIC OUTCOMES IN A MANNER THAT CAN BE TRANSLATED ACROSS HEALTH CARE SYSTEMS WITH DIVERSE POPULATIONS.

AN INTEGRATED TRANSLATIONAL APPROACH TO OVERCOME DRUG RESISTANCE

A DOSE SELECTION TRIAL OF LIGHT THERAPY FOR IMPAIRED SLEEP IN PARKINSON'S DISEASE

MECHANOTRANSDUCTION IN C. ELEGANS

INVESTIGATING A CANDIDATE THERAPEUTIC FOR RETT SYNDROME

GROWTH DIFFERENTIATION CONTROL IN PRIMARY KERATINOCYTES

CELL BIOLOGY OF ASTROCYTES IN THE OPTIC NERVE HEAD

GENETICALLY ENGINEERED VIRUSES FOR BRAIN TUMOR THERAPY

A MAGNETIC PARTICLE IMAGER (MPI) FOR FUNCTIONAL BRAIN IMAGING IN HUMANS

IKAROS REGULATION: STUDY ON HEMO-LYMPHOPOIESIS

CENTER OF RESEARCH TRANSLATION ON OSTEOPOROSIS BONE ANABOLIC THERAPIES - PROJECT SUMMARY – OVERALL OSTEOPOROSIS IS A MAJOR PROBLEM IN OUR AGING POPULATION. WHILE THE PHARMACOLOGICAL TREATMENT OF OSTEOPOROSIS HAS ADVANCED SUBSTANTIALLY OVER THE PAST 2 DECADES, TREATMENT THAT CAN TRULY REDUCE THE RISKS OF FRACTURE TO YOUTHFUL LEVELS REMAINS ELUSIVE. BONE ANABOLIC THERAPIES (PARATHYROID HORMONE RECEPTOR AGONISTS TERIPARATIDE/ABALOPARATIDE AND THE ANTI-SCLEROSTIN ANTIBODY ROMOSOZUMAB) REPRESENT AN IMPORTANT COMPONENT OF OUR THERAPEUTIC ARMAMENTARIUM FOR THIS COMMON, COSTLY, SERIOUS, AND DEBILITATING DISEASE. WITHOUT AN OPTIMIZED ABILITY TO STIMULATE BONE FORMATION, CURE OF OSTEOPOROSIS FOR MANY PATIENTS WITH SEVERE DISEASE WILL NOT BE ACHIEVED. NOTABLY, THE ANABOLIC EFFICACY OF OUR CURRENTLY-USED AGENTS WANES OVER TIME FOR UNKNOWN REASONS. THE GOAL OF THE CORT IS TO ELUCIDATE MECHANISMS OF ACTION OF OSTEOPOROSIS ANABOLIC THERAPIES, AND TO UNDERSTAND WHY THEY STOP WORKING. IN DOING SO, THE CORT WILL ACCELERATE TRANSLATION OF KNOWLEDGE TO IMPROVE OUR UNDERSTANDING OF OSTEOPOROSIS PATHOBIOLOGY. TO ACHIEVE THIS GOAL, THE OVERALL FOCUS OF THE CORT IS TO DEFINE THE CELLULAR AND MOLECULAR MECHANISMS OF ACTION OF CURRENTLY-USED OSTEOPOROSIS ANABOLIC AGENTS IN HUMANS. A HIGHLY-COLLABORATIVE, MULTI-DISCIPLINARY, INTERNATIONAL NETWORK OF INVESTIGATORS BASED AT SEVERAL HARVARD MEDICAL SCHOOL-BASED INSTITUTIONS AND IMPERIAL COLLEGE LONDON HAVE COME TOGETHER TO TACKLE THIS CHALLENGE. IN PROJECT 1, INVESTIGATORS WILL DEFINE THE EFFECTS OF ROMOSOZUMAB AND TERIPARATIDE ON SKELETAL STEM CELLS INCLUDING OSTEOBLAST PROGENITORS USING FLOW CYTOMETRY, SINGLE CELL RNA SEQUENCING, AND HISTOPATHOLOGY. STUDIES WILL BE PERFORMED USING SAMPLES FROM PATIENTS RECEIVING ANABOLIC THERAPY AND IN COMPLEMENTARY GENETICALLY-MODIFIED MOUSE MODELS WHERE LINEAGE TRACING AND SINGLE CELL RNA SEQUENCING CAN BE COMBINED. IN PROJECT 2, INVESTIGATORS WILL DEFINE THE EFFECTS OF ROMOSOZUMAB AND TERIPARATIDE ON OSTEOCYTES. BASED ON PRELIMINARY DATA, OSTEOCYTES CAN DIRECTLY REGULATE BONE MATRIX FORMATION AND REMODELING, LEADING TO THE EXCITING HYPOTHESIS, TESTED HERE IN HUMAN AND MOUSE SAMPLES THAT ANABOLIC AGENTS IMPACT CORTICAL BONE VIA DIRECT EFFECTS ON OSTEOCYTIC PERILACUNAR REMODELING. PROJECTS 1 AND 2 WILL BE SUPPORTED BY A HIGHLY INNOVATIVE BIOINFORMATICS CORE THAT WILL INCORPORATE CROSS-SPECIES TRANSCRIPTOMICS DATASETS WITH AVAILABLE HUMAN AND MOUSE GENETICS IN ORDER TO DEVELOP NOVEL HYPOTHESES, ALSO TESTED HERE, REGARDING GENES AND GENE NETWORK THAT MEDIATE BONE ANABOLIC RESPONSES. CORT EFFORTS WILL BE FURTHER ENHANCED BY THE COMPLEMENTARY EXPERIENCE OF INVESTIGATORS IN OSTEOPOROSIS CLINICAL RESEARCH, BONE BIOMECHANICS, BONE STEM CELL BIOLOGY, OSTEOCYTE BIOLOGY, BONE MARROW MICROENVIRONMENT INVESTIGATION, STATISTICAL GENETICS, OSTEOPOROSIS EPIDEMIOLOGY, AND GENETIC ORIGINS OF BONE DISEASE.

REPRIEVE - DCC

REGULATION OF IRON HOMEOSTASIS BY BMP SIGNALING

LEAD APPLICANT ORGANIZATION NAME: MGH INSTITUTE OF HEALTH PROFESSIONS (MGH IHP) LEAD APPLICANT ENTITY ORGANIZATION TYPE: EDUCATION TRAINING PROVIDER LEAD APPLICANT LOCATION (CITY AND STATE): BOSTON, MA NAMES OF REQUIRED PARTNERS:WORKFORCE DEVELOPMENT: MASSHIRE WORKFORCE BOARDS (BOSTON, METRO NORTH, METRO SOUTH WEST). TRAINING PARTNER: MGH INSTITUTE OF HEALTH PROFESSIONS (MGH IHP) EMPLOYER PARTNERS: BUNKER HILL COMMUNITY COLLEGE (BHCC) BRIGHAM WOMENS HOSPITAL (BWH 4 CLINICAL UNITS) MASSACHUSETTS GENERAL HOSPITAL (MGH WITH 4 CLINICAL UNITS).PLEASE NOTE: MEETING FOA REQUIREMENTS, BWH AND MGH ARE PART OF THE MASS GENERALBRIGHAM (MGB) SYSTEM AND EACH HAVE AT LEAST FOUR (4) HIRING DEPARTMENTS OR SPECIALTIES INCLUDED TO MEET AND SURPASS THE REQUIRED EMPLOYER PARTNER THRESHOLD. MGH IHP, THE LEAD ENTITY, WILL LEVERAGE ADDITIONAL RESOURCES TO SUPPLEMENT GRANT ACTIVITIES BY EMPLOYING PARTICIPANTS. LABOR UNION: MASSACHUSETTS NURSING ASSOCIATION (MNA) NAMES OF OPTIONAL PARTNERS:RECRUITMENT PARTNERS AND WORKFORCE INDUSTRY INTERMEDIARIES: BHCC BWH MGH MGH IHP NANTUCKET COTTAGE HOSPITAL NATIONAL ASSOCIATION OF HISPANIC NURSES, MASSACHUSETTS CHAPTER (NAHN) NEW ENGLAND REGIONAL BLACK NURSES ASSOCIATION (NERBNA) SALEM HOSPITAL.WORKFORCE INDUSTRY INTERMEDIARIES: COMMONWEALTH CORPORATION (COMMCORP) MASSACHUSETTS ASSOCIATION OF CERTIFIED NURSES (MACN) NURSING COUNCIL OF WORKFORCE SUSTAINABILITY (NCWS) GEOGRAPHIC SCOPEO IDENTIFY SCOPE: LOCAL REGIONAL, STATEWIDE, OR NATIONAL: LOCAL REGIONALO A DESCRIPTION OF THE AREA TO BE SERVED, AND IDENTIFICATION OF THE SPECIFICLOCATION(S) WHERE GRANT SERVICES WILL BE PROVIDED: (E.G., CITIES, COUNTIES, OR STATE(S)): GREATER BOSTON REGION (BOSTON, WALTHAM, LYNN, MEDFORD, CAMBRIDGE) SALEM, GLOUCESTER, PEABODY, LYNN, EVERETT, CHELSEA, REVERE, NANTUCKET COUNTY TOTAL FEDERAL FUNDING REQUESTED: 5,885,354.00 TOTAL MATCH PROPOSED: 1,189,305.00 PROJECT TITLE NAME: NURSING EXPANSION EDUCATION (TRACK 1) IN THE GREATER BOSTONREGION: MGH INSTITUTE OF HEALTH PROFESSIONS PROPOSED NUMBER OF PARTICIPANTS WHO START TRAINING (OUTCOME PROJECTION 2 FROMTHE SUBMITTED PERFORMANCE TABLE): 224 SUMMARY OF GRANT PURPOSE AND EMPLOYMENT AND TRAINING ACTIVITIES OFFERED: RECRUIT,TRAIN, AND EMPLOY CURRENT NURSES TO BECOME NURSE EDUCATORS IN BOTH THE CLINICAL AND ACADEMIC SETTINGS. ALL ASPECTS OF THE GRANT ACTIVITIES EMPLOY DIVERSITY, EQUITY, AND INCLUSION STRESS CAREER PATHWAYS TO HIGHER PAYING JOBS AND INCLUDE EDUCATION ABOUT AND EMPLOYMENT IN HIGH QUALITY JOBS. TARGET POPULATION(S) TO BE SERVED: THE TARGET POPULATION IS THE NURSES WHO WILL BERECRUITED (ESPECIALLY THOSE FROM HISTORICALLY UNDERREPRESENTED POPULATIONS) TO BECOME NURSE EDUCATORS. THE SELECTED TRAINING TRACK (NURSE EDUCATION PROFESSIONAL OR NURSING CAREER PATHWAYS):NURSE EDUCATION PROFESSIONAL TARGETED OCCUPATIONS: SOC 25-1072 NURSING INSTRUCTORS AND TEACHERS, POST-SECONDARY RECOGNIZED POSTSECONDARY CREDENTIALS OFFERED: MS, NURSING EDUCATION CERTIFICATE OFCOMPLETIONNEW OR EXISTING PROGRAM(S)1) MS IN LEADERSHIP IN NURSING EDUCATION (MS-LNE) 2) A POST-MASTERS CERTIFICATE IN NURSINGEDUCATION (PMC-NE WHICH PREPARES STUDENTS FOR CERTIFICATION EXAM AS A CNE) AND 3) ACONTINUING PROFESSIONAL DEVELOPMENT (CPD) PREPARATION COURSE (WHICH PREPARES STUDENTS TOCERTIFICATION EXAM AS A CERTIFIED NURSE EDUCATION-CLINICAL LEADER). PUBLIC CONTACT INFORMATION: MGH INSTITUTE OF HEALTH PROFESSIONS,36 FIRST AVENUEBOSTON, MA 02129

DEFINING THE IMPACT OF DRUG USE ON IMMUNE FUNCTION AND FITNESS AGAINST HIV-1 - PAR-20-221: NIDA AVANT-GARDE - ABSTRACT ALEX K. SHALEK ABSTRACT HIV-1 PREVENTION AND CURE STRATEGIES ARE URGENTLY NEEDED FOR PEOPLE WHO INJECT DRUGS (PWID) WITH OPIOID USE DISORDER (OUD) OR POLYSUBSTANCE USED DISORDER (PSUD) GIVEN SUBSTANTIAL RISK FOR, AND INCIDENCE OF, HIV-1 AND OTHERS INFECTION. MOST PROPHYLACTIC AND THERAPEUTIC STRATEGIES UNDER DEVELOPMENT FOR HIV-1 AND OTHER INFECTIONS RELY ON MODULATING HOST IMMUNITY. NEVERTHELESS, WE DO NOT HAVE A WORKING KNOWLEDGE OF HOW OPIOIDS—WHICH, THEMSELVES, ARE IMMUNOMODULATORY—AND THE LIVED EXPERIENCES OF THOSE WITH OUD OR PSUD (INCLUSIVE OF EXPOSURE TO CONTAMINATED EQUIPMENT, COMMUNITY INFECTIONS, AND PHYSICAL AND SOCIAL ENVIRONMENTAL FACTORS) ALTER IMMUNE FUNCTION IN THE ABSENCE OR PRESENCE OF HIV-1 INFECTION AND, THUS, THE EFFICACY OF INTERVENTIONS AGAINST HIV-1 AND OTHER PATHOGENS. WE HYPOTHESIZE THAT OPIOIDS AND OUD/PSUD MODULATE BASELINE IMMUNE RESPONSES IN THE HOST (“FUNCTION”), AS WELL AS IMMUNITY AGAINST OTHER PATHOGENS (“FITNESS”), IMPACTING PREVENTION AND CURE STRATEGIES. HERE, WE PROPOSE A PIONEERING PROGRAM TO DEFINE, AT UNPRECEDENTED RESOLUTION, THE CELLULAR AND MOLECULAR IMPACT OF OUD AND PSUD ON IMMUNE FUNCTION AND RESPONSE TO PATHOGENS, SUCH AS HIV-1. WE WILL ALSO DEVELOP AND UTILIZE AN INNOVATIVE “COMPRESSED’ SCREENING PLATFORM TO FUNCTIONALLY TEST, IN HIGH-THROUGHPUT, INFORMED CHEMICAL AND BIOLOGICAL PERTURBATIONS FOR PREVENTION AND CURE STRATEGIES. MORE SPECIFICALLY, WE WILL DEPLOY—AND, WHERE NECESSARY, DEVELOP—CUTTING-EDGE SINGLE-CELL AND BULK GENOMIC PROFILING METHODS TO GENERATE FUNCTIONAL HYPOTHESES ON HOW OUD AND PSUD ALTER CRITICAL PHYSIOLOGY ASSOCIATED WITH DRUG METABOLISM (LIVER), INNATE MUCOSAL DEFENSE (GASTROINTESTINAL TRACT (GI)), AND ADAPTIVE IMMUNE FUNCTION IN TISSUES OF RELEVANCE TO HIV-1 (LIVER, GI, AND PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS)). WE WILL EXPLICITLY CHARACTERIZE AND CONTRAST CHANGES IN THE PRESENCE AND ABSENCE OF HIV-1 INFECTION. TO SYSTEMATICALLY TEST RESULTING HYPOTHESES, WE WILL CREATE AND IMPLEMENT “COMPRESSED” PERTURBATION SCREENS TO EXAMINE SIMULTANEOUSLY THE INDIVIDUAL IMPACT OF MULTIPLE CHEMICAL AND BIOLOGICAL PERTURBATIONS ON LIMITED PRIMARY SAMPLES (E.G., PBMCS, TISSUE BIOPSIES). THIS WILL ENABLE US TO DELINEATE HOW FACTORS ASSOCIATED WITH SEVERAL ASPECTS OF OUD AND PSUD INTERSECT WITH HIV-1 INFECTION. GIVEN MY LAB’S BROAD AND YET DEEP INTERDISCIPLINARY EXPERTISE IN DEVELOPING AND APPLYING INNOVATIVE EXPERIMENTAL AND COMPUTATIONAL TECHNOLOGIES TO OBTAIN MECHANISTIC INSIGHTS INTO THE CELLULAR AND MOLECULAR DRIVERS OF HUMAN HEALTH AND DISEASE, AND OUR TEAM OF COMMITTED CLINICAL COLLABORATORS IN BOSTON AND BEYOND, WE ARE UNIQUELY POSITIONED TO SUCCESSFULLY EXECUTE THIS PIONEERING, TRANSFORMATIVE INVESTIGATION OF THE IMPACT OF OUD AND PSUD ON IMMUNE FUNCTION. OVERALL, OUR WORK WILL DEFINE THE IMMUNOLOGICAL LANDSCAPE OF OUD AND PSUD, AND INFORM STRATEGIES TO IMPROVE BASELINE IMMUNITY AND THE EFFICACY OF PREVENTIONS AND CURES AGAINST HIV-1 AND OTHER PATHOGENS FOR THOSE WITH OUD AND OSUD, AND THE GENERAL POPULATION.

VAXCELERATE 3.0: A SCALABLE AND EFFICIENT SELF-ASSEMBLING VACCINE PLATFORM TO ENABLE RAPID DEVELOPMENT OF US MILITARY VACCINES

PRECISION PREVENTION RESEARCH PROGRAM

THE NEURAL BASIS OF LANGUAGE COMPREHENSION: INSIGHTS FROM SPATIOTEMPORAL IMAGING

CORTICAL-BASAL GANGLIA SPEECH NETWORKS

CENTER FOR SKELETAL RESEARCH (OVERALL APPLICATION)

DEVICE-INDEPENDENT ACQUISITION AND REAL TIME SPATIOTEMPORAL ANALYSIS OF CLINICAL ELECTROPHYSIOLOGY DATA

MASSIVE WAVELENGTH-DIVISION MULTIPLEXING AND IMAGING WITH LASER PARTICLES

TREAT-TO-TARGET SERUM URATE VERSUS TREAT-TO-AVOID SYMPTOMS IN GOUT: A RANDOMIZED CONTROLLED TRIAL (TRUST) - ABSTRACT GOUT IS THE MOST COMMON INFLAMMATORY ARTHRITIS, AFFECTING MORE THAN 9 MILLION AMERICAN ADULTS, WITH A DISEASE BURDEN RISING WORLDWIDE. DESPITE SUBSTANTIAL CLINICAL CONSEQUENCES, GOUT CARE IS INCONSISTENT, WITH CONSIDERABLE GAPS IN THE EVIDENCE BASE. THE PRIMARY CONTRIBUTOR TO HETEROGENEOUS GOUT CARE IS A LACK OF AGREEMENT ABOUT THE VALUE OF ACHIEVING A TARGET SERUM URATE (SU), DUE TO A LACK OF HIGH-LEVEL EVIDENCE. RHEUMATOLOGY GUIDELINES EMPHASIZE A TREAT TO TARGET SERUM URATE (TTT-SU) APPROACH (E.G., SU <6 MG/DL, A URATE SUB- SATURATION POINT); HOWEVER, CITING THE ABSENCE OF EVIDENCE, SU IS NOT EVEN MEASURED DURING URATE-LOWERING THERAPY IN THE VAST MAJORITY OF GOUT PATIENTS IN PRIMARY CARE PRACTICE, WHERE >90% OF GOUT CARE OCCURS. WE AIM TO GENERATE HIGH-LEVEL EVIDENCE TO RESOLVE THE GUIDELINE CONFLICT BY MOBILIZING RHEUMATOLOGISTS AND PRIMARY CARE PROVIDERS (PCPS). FURTHERMORE, GOUT IS A METABOLIC CONDITION COMPLICATED BY A HIGH RISK OF MYOCARDIAL INFARCTION, DIABETES, CHRONIC KIDNEY DISEASE, AND PREMATURE DEATH, ALTHOUGH IT REMAINS UNKNOWN WHETHER GOUT CAUSALLY LEADS TO THESE OUTCOMES. REMOVING MONOSODIUM URATE CRYSTAL DEPOSITION BY LOWERING SU CAN REDUCE GOUTY INFLAMMATION, LIKELY BY BLUNTING THE INFLAMMASOME PATHWAY. HOWEVER, IT IS UNKNOWN WHETHER LOWERING SU RESULTS IN LESS KIDNEY DAMAGE, BETTER GLYCEMIC CONTROL, OR REDUCED CARDIOVASCULAR RISK. NIH FUNDING ALLOWED US TO CONVENE A CONFERENCE IN 2018 (R13AR073116) WITH PCPS AND RHEUMATOLOGISTS TO EXAMINE THE EXISTING DATA, DEFINE THE CONTROVERSIES, AND ELICIT INPUT ON THE NECESSARY INFORMATION TO FILL THE CRITICAL EVIDENCE GAP. INFORMED BY THIS CONFERENCE, WE RECEIVED FUNDING IN 2020 (AR076077) TO PLAN A RANDOMIZED CONTROLLED TRIAL (RCT). DURING THE PAST 1.5 YEARS, WE CARRIED OUT KEY ACTIVITIES TO GAIN INSIGHTS FROM ALL RELEVANT STAKEHOLDERS. A MODIFIED DELPHI PANEL, INCLUDING GOUT PATIENTS, NURSES AND PHYSICIAN ASSISTANTS, PCPS, AND RHEUMATOLOGISTS, CAME TO CONSENSUS REGARDING KEY PROTOCOL DECISIONS. MOCK RECRUITMENT ACTIVITIES ALLOWED US TO TEST AND REFINE FEASIBLE PROCEDURES WHICH WILL LEAD TO SUCCESSFUL PRE-SCREENING, SCREENING, AND PATIENT RECRUITMENT DURING THE PROPOSED MULTI-SITE RCT WITH THE FOLLOWING TWO AIMS. AIM 1) TO CONDUCT A RCT COMPARING TTASX WITH TTT-SU AMONG PATIENTS WITH GOUT AND HYPERURICEMIA (HU). WE HAVE DEVELOPED A TRIAL PROTOCOL ACCEPTABLE FOR ALL RELEVANT STAKEHOLDERS THAT WILL EFFECTIVELY ANSWER THE PRIMARY HYPOTHESIS THAT A TTT-SU STRATEGY RESULTS IN SIGNIFICANTLY FEWER GOUT FLARES (PRIMARY OUTCOME) OVER A TWO-YEAR FOLLOW-UP THAN TTASX. TO ENSURE EQUIPOISE AND GENERALIZABILITY, WE WILL RECRUIT PATIENTS FROM PCP PRACTICES. AIM 2) TO TEST THE EFFECTS OF LOWERING SU ON KIDNEY FUNCTION, GLYCEMIC STATUS, AND BLOOD PRESSURE AMONG PATIENTS WITH GOUT ENROLLED IN THE RCT. THE CORRESPONDING HYPOTHESES ARE THAT LOWERING SU TO A GREATER EXTENT IN THE TTT-SU ARM COMPARED WITH TTASX WILL RESULT IN: A) SLOWER DECLINE IN ESTIMATED GLOMERULAR FILTRATION RATE; B) LOWER HBA1C; AND C) IMPROVED BLOOD PRESSURE IN GOUT PATIENTS.

FUNCTIONAL ROLE AND THERAPEUTIC TARGETING OF EXOSOMES AND EXTRACELLULAR RNA BIOMARKERS IN HEART FAILURE

STUDY OF WOMEN'S HEALTH ACROSS THE NATION - III

TOWARDS CURATIVE THERAPIES FOR HYPOGONADOTROPIC DISEASES

DISSECTING PEDIATRIC BRAIN TUMOR MICROENVIRONMENT TO IMPROVE TREATMENT

NEURAL, COGNITIVE AND ABUSE-RELATED CONSEQUENCES OF CHRONIC THC EXPOSURE DURING ADOLESCENCE IN NONHUMAN PRIMATES

THE ACTIVATION OF ERBB3 SIGNALING AS A RESISTANCE MECHANISM TO TARGETED THERAPIES

LYOPHILIZED INJECTABLE FOR POINT-OF-CARE THERAPEUTIC FOR POST-TRAUMATIC OSTEOARTHRITIS

FREE SURFER DEVELOPMENT, MAINTENANCE, AND HARDENING

AUDITORY NEURAL CODING OF SPEECH

MIXED CHIMERISM INDUCED TOLERANCE IN HEART RECIPIENTS REQUIRES DONOR KIDNEY COTRANSPLANTATION

IMPROVING MITRAL COMPENSATION IN ISCHEMIC REGURGITATION

AIRWAY MICROBIOME AND AGE 6Y ASTHMA PHENOTYPES IN 2 DIVERSE MULTICENTER COHORTS

CEREBRAL AMYLOID ANGIOPATHY AND MECHANISMS OF BRAIN AMYLOID ACCUMULATION

ENABLING IMPROVED APPLICABILITY AND TRANSFERABILITY OF POLYGENIC SCORES ACROSS DIVERSE POPULATIONS- A FOCUS ON SOUTH ASIANS - POLYGENIC SCORES – WHICH QUANTIFY INHERITED RISK BY INTEGRATING INFORMATION FROM MANY COMMON SITES OF DNA VARIATION – HOLD CONSIDERABLE PROMISE FOR ENABLING A TAILORED APPROACH TO CLINICAL MEDICINE. HOWEVER, ALONGSIDE CONSIDERABLE (AND WARRANTED) ENTHUSIASM, WE AND OTHERS HAVE HIGHLIGHTED A CRUCIAL EQUITY ISSUE – CURRENT POLYGENIC SCORES HAVE DIMINISHED PREDICTIVE POWER IN NON-EUROPEAN ANCESTRIES. BY ASSEMBLING A TEAM WITH DEEP EXPERTISE IN STATISTICAL GENETICS, CLINICAL INFORMATICS, DATA SHARING, AND GENOMIC MEDICINE, WE OUTLINE THE FUNCTIONAL AND FINE-MAPPING APPROACH TO IMPROVE RESPONSIBLE RISK-MODELING OF POLYGENIC RISK SCORES (‘FFAIRR-PRS’) APPROACH TO SYSTEMATICALLY ADDRESS THE KEY FACTORS DRIVING DIMINISHED PERFORMANCE. TO ENABLE ANALYSIS BY THE NHGRI CONSORTIUM WITHIN THE ANVIL ECOSYTEM, WE WILL CONTRIBUTE GENETIC AND RICH PHENOTYPE DATA FROM >57,136 INDIVIDUALS OF SOUTH ASIAN ANCESTRY FROM THE GENES & HEALTH AND UK BIOBANK STUDIES AND WHOLE GENOME SEQUENCING DATA FROM 5,734 SOUTH ASIANS FROM THE GENOMEASIA PHASE 2 TO SERVE AS AN ANCESTRY-MATCHED REFERENCE PANEL. SOUTH ASIAN INDIVIDUALS ARE PRIORITIZED BASED ON MARKED UNDER-REPRESENTATION IN GENOME-WIDE ASSOCIATION STUDIES – ACCOUNTING FOR 23% OF THE GLOBAL POPULATION BUT ONLY 1.2% OF INDIVIDUALS STUDIED – AND POLYGENIC PREDICTION EFFORTS TO DATE, AS WELL AS A KEY PUBLIC HEALTH NEED FOR ENHANCED RISK STRATIFICATION. INDIVIDUAL LEVEL DATA IN ANVIL WILL BE PAIRED WITH SUMMARY ASSOCIATION STATISTICS OF >100,000 SOUTH ASIANS AND INDIVIDUAL >1 MILLION INDIVIDUALS OF OTHER ANCESTRIES, WHICH WILL ENABLE ENHANCED FINE-MAPPING, SORE WEIGHTING, AND TRANSETHNIC BENCHMARKING ACTIVITIES. OUR STUDY SITE AIMS TO (1) AGGREGATE AND HARMONIZE GENOTYPING AND PHENOTYPE DATA AND DELIVER A SHARABLE AND SCALABLE END-TO-END ANALYTIC PIPELINE THAT STARTS WITH GENOTYPING ARRAY DATA AND A PHENOTYPE FILE AND ENABLES AUTOMATED OUTPUT OF POLYGENIC SCORE BENCHMARKING PARAMETERS.; (2) DEVELOP AND SHARE THE NEW ‘FFAIRR-PRS’ STATISTICAL GENETICS FRAMEWORK, LEVERAGING: (I) FINE-MAPPING TO ASSIGN CAUSAL PROBABILITIES BASED ON >180 FUNCTIONAL GENOMIC ANNOTATIONS; (II) INCORPORATING CORRELATIONS BETWEEN EFFECT SIZES ACROSS TRAITS; AND (III) INTEGRATION OF SOUTH ASIAN AND NON-SOUTH ASIAN GWAS DATA; AND (3) BENCHMARK FFAIRR-PRS SCORES FOR 27 IMPORTANT PHENOTYPES IN THE SOUTH ASIAN DATASETS, AND DEVELOP RISK MODELS THAT INTEGRATE GENETIC AND NONGENETIC FACTORS. PERFORMANCE WILL BE BENCHMARKED IN ACCORDANCE WITH CLINGEN COMPLEX DISEASE WORKING GROUP RECOMMENDATIONS AND COMPARED AGAINST INDIVIDUALS OF EUROPEAN AND OTHER MAJOR ANCESTRY GROUPS. BEYOND ENHANCED POLYGENIC SCORES – AWARE OF AN ULTIMATE AIM OF CLINICAL IMPLEMENTATION – WE WILL DEVELOP A FRAMEWORK FOR INTEGRATED ABSOLUTE RISK MODELS CALIBRATED TO THE U.S. POPULATION THAT ACCOUNT FOR RARE MONOGENIC VARIANTS OF LARGE EFFECT, FAMILY HISTORY, LIFESTYLE, AND CLINICAL RISK FACTORS BY ADAPTING THE INDIVIDUALIZED COHERENT ABSOLUTE RISK ESTIMATOR (ICARE) TOOL DEVELOPED BY CO-I CHATTERJEE.

IDENTIFICATION OF RESISTANCE MECHANISMS TO ANAPLASTIC LYMPHOMA KINASE INHIBITORS

FAST MRI AT THE LIMIT OF BIOLOGICAL TEMPORAL RESOLUTION

ASSEMBLING THE GENETIC ARCHITECTURE OF X-LINKED DYSTONIA PARKINSONISM

DEVELOPMENT OF WHOLE-BRAIN IN VIVO 2HG IMAGING FOR PRECISION MEDICINE IN MUTANT IDH GLIOMA

2/7 PSYCHIATRIC GENOMICS CONSORTIUM: ADVANCING DISCOVERY AND IMPACT - PROJECT SUMMARY NOW IN ITS 13TH YEAR, THE PSYCHIATRIC GENOMICS CONSORTIUM IS PERHAPS THE MOST INNOVATIVE AND PRODUCTIVE EXPERIMENT IN THE HISTORY OF PSYCHIATRY. THE PGC UNIFIED THE FIELD AND ATTRACTED A CADRE OF OUTSTANDING SCIENTISTS (802 INVESTIGATORS FROM 157 INSTITUTIONS IN 41 COUNTRIES). PGC WORK HAS LED TO IDENTIFICATION OF ~500 GENETIC LOCI IN THE 11 PSYCHIATRIC DISORDERS WE STUDY. OUR WORK HAS LED TO 320 PAPERS, MANY IN HIGH-PROFILE JOURNALS (NATURE 3, CELL 5, SCIENCE 2, NAT GENET 27, NAT NEUROSCI 9, MOL PSYCH 37, BIOL PSYCH 25). AS SUMMARY STATISTICS ARE FREELY AVAILABLE, PSYCHIATRIC DISORDERS OFTEN FEATURE PROMINENTLY IN PAPERS BY NON-PGC INVESTIGATORS. TO ADVANCE DISCOVERY AND IMPACT, WE PROPOSE TO CONTINUE THE WORK OF THE PGC ACROSS 11 DISORDER GROUPS. CONSIDERABLE NEW DATA ARE COMING IN THE NEXT FIVE YEARS. WE THUS CAN RAPIDLY AND EFFICIENTLY INCREASE OUR KNOWLEDGE OF THE FUNDAMENTAL BASIS OF MAJOR PSYCHIATRIC DISORDERS. AIM 1: WE WILL CONTINUE TO ADVANCE GENETIC DISCOVERY FOR SEVERE PSYCHIATRIC DISORDERS IN ALL WORKING GROUPS, SYSTEMATICALLY INTERFACE WITH LARGE BIOBANK STUDIES TO ENSURE MAXIMAL COMPARABILITY, AND AGGRESSIVELY PROMOTE NEW STUDIES OF INDIVIDUALS WITH PSYCHIATRIC DISORDERS FROM DIVERSE ANCESTRIES TO INCREASE DISCOVERY AND IMPROVE FINE-MAPPING. AIM 2: MOST STUDIES ANALYZE COMMON VARIATION (AIM 1), RARE CNV (AIM 2), AND RARE EXOME/GENOME RESEQUENCING RESULTS (VIA COLLABORATION) IN ISOLATION: WE WILL APPLY AN INTEGRATIVE FRAMEWORK TO RIGOROUSLY EVALUATE THE CONTRIBUTIONS OF ALL MEASURED TYPES OF GENETIC VARIATION ON RISK FOR PSYCHIATRIC DISORDERS. AIM 3: WE WILL MOVE BEYOND CLASSICAL CASE-CONTROL DEFINITIONS TO A MORE BIOLOGICALLY-BASED AND NUANCED UNDERSTANDING BY ENABLING LARGE TRANS-DIAGNOSTIC STUDIES, CONVENE TRANS-DISCIPLINARY TEAMS TO USE GENETICS TO ADDRESS UNRESOLVED QUESTIONS ABOUT THE NATURE OF PSYCHIATRIC DISORDERS, AND TO PROMOTE LARGE STUDIES OF THE SEVEREST CASES SEEN IN PSYCHIATRIC PRACTICE (LEVERAGING THE GLOBAL REACH OF PGC INVESTIGATORS). AIM 4: WE WILL WORK TO MAXIMIZE THE IMPACT OF OUR WORK VIA TRANSLATIONAL EFFORTS: CLOSE COLLABORATIONS WITH NEUROSCIENCE CONSORTIA TO UNDERSTAND THE BIOLOGICAL IMPLICATIONS OF OUR FINDINGS; WORK TO IDENTIFY MODIFIABLE CAUSAL RISK FACTORS; AND WORK TO ROBUSTLY PREDICT CLINICAL OUTCOMES AND IDENTIFY PATIENT SUBSETS. AIM 5: WE WILL INCREASE IMPACT OF OUR WORK BY EXTENDING AND FORMALIZING OUTREACH TO DIFFERENT COMMUNITIES (INCLUDING PHARMA AND BIOTECH), VIA DIGITAL MEDIA (TWITTER, FACEBOOK, WIKIPEDIA), AND BY DEVELOPING, DISTRIBUTING, AND UPDATING RESOURCES/EDUCATIONAL MATERIAL FOR PATIENTS, FAMILIES, AND MEDICAL PROFESSIONALS. WE WILL CONVENE A SCIENTIFIC ADVISORY BOARD TO ENSURE WE RESPOND POSITIVELY TO THOSE INVESTED IN OUR RESULTS SUCCESSFUL COMPLETION OF THIS BODY OF WORK WILL GREATLY ADVANCE KNOWLEDGE OF THE GENETIC BASIS OF PSYCHIATRIC DISORDERS WITH POTENTIALLY MAJOR NOSOLOGICAL AND TREATMENT IMPLICATIONS. THESE GOALS ARE CONSISTENT WITH A CORE MISSION OF THE NIMH, AND THE CENTRAL IDEA OF THE PGC: TO CONVERT THE FAMILY HISTORY RISK FACTOR INTO BIOLOGICALLY, CLINICALLY, AND THERAPEUTICALLY MEANINGFUL INSIGHTS.

MOLECULAR DEFINITION OF PSEUDOHYPOPARATHYROIDISM

DETERMINANTS OF INCEPTION OF INFLAMMATION IN INFLAMMATORY BOWEL DISEASES - PROJECT SUMMARY CROHN’S DISEASE (CD) AND ULCERATIVE COLITIS (UC) AFFECT OVER 2 MILLION INDIVIDUALS IN THE UNITED STATES AND ARE ASSOCIATED WITH CONSIDERABLE MORBIDITY. EXISTING TREATMENTS ACHIEVE REMISSION IN FEWER THAN 50% OF PATIENTS. FURTHER, DESPITE ACHIEVING ENDOSCOPIC REMISSION, UP TO 30% OF PATIENTS WITH CD OR UC WILL RELAPSE OVER THE SUBSEQUENT THREE YEARS. PATHOPHYSIOLOGIC MECHANISMS LEADING TO RELAPSE HAVE NOT BEEN WELL ESTABLISHED. THE CENTRAL PREMISE OF OUR PROPOSAL IS THAT DESPITE ENDOSCOPIC, THERE EXISTS A LOCAL PRO-INFLAMMATORY MICROBIAL MILIEU AND TRANSCRIPTIONAL PROFILE THAT FAVORS DISEASE RELAPSE. WE HYPOTHESIZE THAT CURRENT CLINICAL TOOLS DO NOT HAVE SUFFICIENT RESOLUTION TO CAPTURE THIS STATE. EXISTING COHORTS, BY RECRUITING PATIENTS IN A HETEROGENEOUS STATE OF ACTIVE INFLAMMATION, CANNOT BE USED TO INFER MECHANISMS OF LOSS OF REMISSION AND INCEPTION OF INFLAMMATION. A TARGETED EFFORT THAT COMPREHENSIVELY AND LONGITUDINALLY PROFILES A HOMOGENEOUS COHORT OF PATIENTS IN DEEP REMISSION IS ESSENTIAL TO DEFINE THE DYNAMIC RELATIONSHIP BETWEEN MICROBIAL ALTERATIONS, METABOLOMIC, TRANSCRIPTIONAL, AND PROTEOMIC PERTURBATIONS, AND ONSET OF INFLAMMATION. IDENTIFYING DEFICIENT COMPONENTS FAVORING RELAPSE ALSO ALLOWS THE DEVELOPMENT OF INTERVENTION TO REPLACE THESE DEFICIENCIES, THEREBY EXTENDING REMISSION. THEY WILL ALSO PROVIDE CLUES AND SERVE AS STARTING POINTS FOR DEVELOPMENT OF NOVEL THERAPIES. IN THE FIRST AIM, WE WILL RECRUIT 300 PATIENTS WITH IBD IN CLINICAL AND ENDOSCOPIC REMISSION AND PROSPECTIVELY, SYSTEMATICALLY FOLLOW THEM FOR 3 YEARS. WE WILL COMPREHENSIVELY CHARACTERIZE SUCH PATIENTS THROUGH SERIAL SAMPLING OF MUCOSAL AND FECAL MICROBIOME, SERUM AND FECAL METABOLOME, AND PROTEOME IN ADDITION TO DETAILED ENVIRONMENTAL EXPOSURE ASSESSMENT AND MEASUREMENT OF DRUG PHARMACOKINETICS. WE WILL DETERMINE THE DYNAMIC PREDICTIVE UTILITY OF EACH OF THESE PARAMETERS IN DEFINING FUTURE RELAPSE FROM A STATE OF QUIESCENCE. IN THE SECOND AIM, WE WILL DEFINE THE ROLE OF PRO-INFLAMMATORY CHANGES AT THE CELLULAR LEVEL BY PERFORMING SINGLE CELL TRANSCRIPTOMIC ANALYSIS FROM COLONIC AND ILEAL BIOPSIES IN PATIENTS WITH QUIESCENT CD AND UC RECRUITED AS ABOVE. THIS WILL PROVIDE IMPORTANT INSIGHTS INTO LOSS OF CONTROL OF INFLAMMATION AT THE TISSUE LEVEL THAT DETERMINES FUTURE CLINICAL ACTIVITY. THE FINAL STUDY AIM WILL TRAIN AND VALIDATE A MACHINE-LEARNING PREDICTIVE MODEL TO DEFINE THE CONTRIBUTION OF EACH ADDITIONAL BIOLOGIC LAYER TO INCEPTION OF INFLAMMATION AND TO IDENTIFY MORE ROBUST BIOMARKERS OF A STATE OF SUSTAINED REMISSION. DEFINING THE MOLECULAR BASIS OF FUTURE RELAPSE IN PATIENTS IN DEEP REMISSION WILL PROVIDE INSIGHTS INTO THE ‘PRE-DISEASE’ STATE, ALLOWING FOR IDENTIFICATION OF IMMUNE PATHWAYS OF RELEVANCE IN PREVENTING DISEASE. DEFINING THE FUNDAMENTAL MECHANISMS THROUGH WHICH DISEASE INCEPTION OCCURS FROM QUIESCENCE IS CRITICALLY IMPORTANT TO INFORM KEY STEPS IN THE PATHOGENESIS OF THESE COMPLEX DISEASES, WHICH IN TURN, WILL OFFER OPPORTUNITIES FOR TARGETED MECHANISM-DRIVEN INTERVENTIONS TO AID DURABLE MAINTENANCE OF REMISSION AND HEALTH. THE APPROACHES AND ANALYSES OUTLINED ALSO HAVE BROAD APPLICABILITY TO OTHER AUTOIMMUNE DISEASES.

P63 MEDIATORS AS THERAPEUTIC TARGETS IN HNSCC

THE ROLE OF HEPOXILIN A3 IN NEUTROPHIL BREACH OF THE INFECTED AIRWAY MUCOSA

STRUCTURE AND FUNCTION OF INTEGRINS IN THE KIDNEY