Fello Inc

RAPID EXPANSION OF ANTIRETROVIRAL THERAPY PROGRAMS

STATISTICAL AND DATA MANAGEMENT CENTER FOR THE AIDS CLINICAL TRIALS GROUP

PHACS - DATA AND OPERATIONS CENTER

STATISTICAL AND DATA MANAGEMENT CENTER-PEDIATRIC,ADOLESCENT, AND MATERNAL CTG

HARVARD CLINICAL AND TRANSLATIONAL SCIENCE CENTER

THE HARVARD CLINICAL AND TRANSLATIONAL SCIENCE CENTER

HARVARD CLINICAL AND TRANSLATIONAL SCIENCE CENTER (UL1)

PEDIATRIC HIV/AIDS COHORT STUDY (PHACS) 2020

NEW ENGLAND REGIONAL CENTER OF EXCELLENCE FOR BIODEFENS*

HARVARD UNIVERSITY CENTER FOR AIDS RESEARCH

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

NEW ENGLAND PRIMATE RESEARCH CENTER BASE GRANT

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

INTEGRATED HUMAN ORGAN-ON-CHIP MICROPHYSIOLOGICAL SYSTEMS

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

MICROBIAL ECOLOGY, PROTEOGENOMICS AND COMPUTATIONAL OPTIMA

CENTER FOR INTEGRATED QUANTUM MATERIALS

HARVARD CLINICAL AND TRANSLATIONAL SCIENCE CENTER - PROJECT SUMMARY/ ABSTRACT CLINICAL AND TRANSLATIONAL RESEARCH (CTR) ACROSS HARVARD IS CONDUCTED AT 17 INDEPENDENT AND GEOGRAPHICALLY DISPERSED INSTITUTIONS, INCLUDING HARVARD MEDICAL SCHOOL (HMS), HARVARD T. H. CHAN SCHOOL OF PUBLIC HEALTH, AND 15 HMS-AFFILIATED ACADEMIC HEALTH CARE CENTERS. EACH OF THESE INSTITUTIONS IS FISCALLY AND OPERATIONALLY INDEPENDENT WITH THEIR OWN GOVERNANCE, FACULTY, IRB, AND ELECTRONIC HEALTH RECORDS. HARVARD CATALYST (HC) SERVES AS THE SOLE COORDINATING ENTITY FOR CTR AND HAS BROUGHT THESE INSTITUTIONS TOGETHER AS A FEDERATED CTR NETWORK. SINCE 2008, HC HAS DEVELOPED A SUBSTANTIAL PORTFOLIO OF EDUCATIONAL AND CTR RESOURCES TO MEET THE NEEDS OF THE CTR WORKFORCE AT HARVARD AND, WHEN THEIR VALUE HAS BEEN DEMONSTRATED AT HARVARD, DISSEMINATED THEM TO THE CTSA CONSORTIUM. MOVING FORWARD, HC’S OVERARCHING VISION IS TO PARTNER WITH OUR CTR WORKFORCE, INSTITUTIONS, AND COMMUNITIES TO BECOME A LIVING CLINICAL AND TRANSLATIONAL SCIENCE (CTS) LEARNING LABORATORY. THE CTS LEARNING LABORATORY WILL CONTINUOUSLY ASSESS AND REASSESS THE HUB’S CTR STRENGTHS AND WEAKNESSES, DEVELOPING AND IMPLEMENTING PROGRAMMATIC INNOVATIONS TO IMPROVE THE EFFICIENCY, QUALITY, EFFECTIVENESS, AND IMPACT OF CTR. USING THE PRINCIPLES AND METHODOLOGIES OF CTS AND GUIDED BY A LOGIC MODEL, HC IS COMMITTED TO ACHIEVING THESE GOALS AND OVERCOMING TRANSLATIONAL ROADBLOCKS. SEVEN TRANSLATIONAL ROADBLOCKS HAVE BEEN PRIORITIZED THAT CAN BE MITIGATED OR OVERCOME: 1) EDUCATIONAL RESOURCES ARE NOT REACHING ALL LEARNERS AND HAVE BEEN FOCUSED ON INVESTIGATORS, RATHER THAN INVESTIGATIONAL TEAMS; 2) EXTENSIVE RESEARCH RESOURCES ARE FREQUENTLY INVISIBLE AND DIFFICULT TO ACCESS; 3) SUBSTANTIAL STRUCTURAL AND REGULATORY BARRIERS LIMIT CROSS-INSTITUTIONAL COLLABORATIONS; 4) RESEARCH AND CLINICAL DATA NEED TO BE CONNECTED AND THEIR ACCESS DEMOCRATIZED; 5) CTR WORKFORCE IS NOT SUFFICIENTLY DIVERSE AND MUST BE GROWN IN ALL DOMAINS; 6) THERE IS LIMITED ACCESS TO AND PARTICIPATION BY DIVERSE POPULATIONS IN RESEARCH; AND 7) INSUFFICIENT MECHANISMS EXIST TO SUPPORT IMPLEMENTATION OF CTR EVIDENCE INTO PRACTICE. HC WILL ALSO FOCUS ON BETTER UNDERSTANDING AND MEETING THE NEEDS OF EARLY-STAGE AND UNDERREPRESENTED IN MEDICINE INVESTIGATORS AND THEIR TEAMS, AS WELL AS DIVERSE PATIENT POPULATIONS AND COMMUNITIES, WHILE WORKING TO DIVERSIFY THE WORKFORCE AND REDUCE HEALTH INEQUITIES. MULTIPLE INITIATIVES ARE PROPOSED TO ADDRESS FIVE SPECIFIC AIMS: 1) TRAIN AND DIVERSIFY THE CTR WORKFORCE; 2) CONNECT TRAINEES AND CTR TEAMS WITH HC RESOURCES; 3) PARTNER WITH COMMUNITY STAKEHOLDERS TO IMPROVE RESEARCH PARTICIPATION; 4) DEMOCRATIZE HEALTH INFORMATICS; AND 5) USE CTS TO OVERCOME SIGNIFICANT CTR ROADBLOCKS. HC IS EAGER TO LEARN FROM OTHER CTSA HUBS AND IS COMMITTED TO DISSEMINATION AND SHARING ACROSS THE CTSA CONSORTIUM. THE INSIGHTS DERIVED FROM EMPLOYING CTS APPROACHES WILL BE USED TO OVERCOME TRANSLATIONAL ROADBLOCKS AND ADVANCE THE COLLECTIVE NATIONAL GOAL OF IMPROVING HUMAN HEALTH.

STATISTICAL AND DATA MANAGEMENT CENTER FOR THE AIDS CLINICAL TRAILS GROUP

THE ROLE OF PRIVATE PLANS IN MEDICARE

NEW COSTIMULATORY PATHWAYS: FUNCTIONS AND INTERACTIONS

HEALTH AND AGING IN AFRICA: LONGITUDINAL STUDIES OF INDEPTH COMMUNITIES

SENSORIMOTOR PROCESSING, DECISION MAKING, AND INTERNAL STATES: TOWARDS A REALISTIC MULTISCALE CIRCUIT MODEL OF THE LARVAL ZEBRAFISH BRAIN

FLYBASE: A DROSOPHILA GENOMIC AND GENETIC DATABASE

MEDICAL SCIENTISTS TRAINING PROGRAM

HSPH NIEHS CENTER FOR ENVIRONMENTAL HEALTH

HARVARD CLINICAL AND TRANSLATIONAL SCIENCE CENTER (UL1)

GRADUATE RESEARCH FELLOWSHIP PROGRAM

COORDINATING CENTER FOR THE UNDIAGNOSED DISEASES NETWORK

THE HSPH EDUCATION AND RESEARCH CENTER FOR OCCUPATIONAL SAFETY AND HEALTH

INTEGRATED DISCOVERY AND DEVELOPMENT OF INNOVATIVE TB DIAGNOSTICS

FLYBASE: A DROSOPHILA GENOMIC & GENETIC DATABASE

COMPREHENSIVE SINGLE-CELL ATLAS OF THE DEVELOPING MOUSE BRAIN - PROJECT SUMMARY THE DEVELOPING MOUSE BRAIN IS A FOUNDATIONAL EXPERIMENTAL MODEL FOR INVESTIGATION OF THE ORIGINS OF CELL TYPES IN THE MAMMALIAN BRAIN. COMPREHENSIVE KNOWLEDGE OF MOUSE BRAIN DEVELOPMENT IS CRITICAL FOR COMPARATIVE STUDIES OF NEURODEVELOPMENTAL PROCESSES, WHICH ARE KEY TO UNDERSTANDING THE REMARKABLE EVOLUTIONARY INNOVATIONS THAT DISTINGUISH HUMANS FROM OTHER SPECIES. IN ADDITION, DEVELOPMENTAL INFORMATION ENABLES REFINING CELL TAXONOMY IN THE ADULT BRAIN BY INCORPORATING KNOWLEDGE OF CELL TYPE AND LINEAGE ORIGINS INTO ADULT CELL CLASSIFICATION. DESPITE THE TRANSFORMATIVE INSIGHTS ENABLED BY THE RECENTLY CREATED MOLECULAR ATLAS OF THE ADULT MOUSE BRAIN, WE CURRENTLY LACK A COMPREHENSIVE CENSUS OF CELL TYPES OF THE DEVELOPING MOUSE BRAIN, AND THE LINEAGE RELATIONSHIPS THAT LINK THEM TO THEIR ADULT COUNTERPARTS. HERE WE SEEK TO GENERATE A COMPREHENSIVE, SPATIALLY- AND TEMPORALLY-RESOLVED, CELLULAR-RESOLUTION ATLAS OF THE WHOLE DEVELOPING MOUSE BRAIN, SAMPLED AT HIGH RESOLUTION THROUGH THE ENTIRE PERIOD OF EMBRYONIC AND POSTNATAL BRAIN DEVELOPMENT (FROM E8.0 TO P28). WE WILL EMPLOY THREE COMPLEMENTARY APPROACHES TO GENERATE COMPREHENSIVE MULTI-OMIC SINGLE-CELL PROFILES: 10X GENOMICS SINGLE-CELL RNA-SEQ (SCRNA-SEQ), 10X GENOMICS MULTIOME (SIMULTANEOUS SINGLE-NUCLEUS RNA-SEQ AND ATAC-SEQ, FOR COMBINED TRANSCRIPTOMIC AND EPIGENOMIC PROFILING), AND SMART-SEQ3 (FOR FULL-LENGTH DEEP RNA-SEQUENCING). IN PARALLEL, WE WILL USE THE SPATIALLY RESOLVED TRANSCRIPTOMIC METHOD MERFISH ACROSS THE SAME DENSELY-SAMPLED TIMELINE, TO IDENTIFY THE SPATIAL DISTRIBUTION OF ALL CELL TYPES AND DYNAMIC CHANGES IN CELL STATES ACROSS THE ENTIRE MOUSE BRAIN. WE WILL APPLY COMPUTATIONAL METHODS TO PREDICT DEVELOPMENTAL LINEAGE RELATIONSHIPS FROM THESE SPATIALLY AND TEMPORALLY RESOLVED DATASETS, AND EXPERIMENTALLY VALIDATE LINEAGE RELATIONSHIPS THROUGH BOTH BARCODE-BASED IN VIVO LINEAGE TRACING AND BY FUNCTIONALLY TESTING CANDIDATE MOLECULAR EFFECTORS USING MULTIPLEXED IN UTERO CRISPR SCREENING (PERTURB-SEQ). FINALLY, WE WILL PILOT INTEGRATION OF DEVELOPMENTAL DATASETS ACROSS SPECIES, MAPPING SINGLE-CELL OMICS DATASETS FROM THE DEVELOPING HUMAN AND NON-HUMAN PRIMATE BRAINS ONTO THE COMPREHENSIVE MOUSE BRAIN DEVELOPING CELL TYPE ATLAS ESTABLISHED HERE, TO CREATE A COMPUTATIONAL ALIGNMENT OF DEVELOPMENTAL TIME THAT WILL ENABLE UNDERSTANDING OF DIFFERENTIAL REGULATION OF SPECIFIC DEVELOPMENTAL EVENTS ACROSS SPECIES. OVERALL, THIS PROJECT BRINGS TOGETHER A TEAM OF INVESTIGATORS WITH EXTENSIVE, DEMONSTRATED EXPERTISE IN BRAIN DEVELOPMENT, CIRCUITRY, SINGLE-CELL GENOMICS, AND ASSEMBLY OF BRAIN ATLASES TO PRODUCE A COMPREHENSIVE DEVELOPMENTAL BRAIN CELL ATLAS, INTENDED TO SERVE AS A FIRST-OF-ITS-KIND FOUNDATIONAL RESOURCE TO THE NEUROSCIENCE COMMUNITY FOR THE STUDY OF MECHANISMS OF MAMMALIAN BRAIN DEVELOPMENT AND NEURODEVELOPMENTAL DISORDERS. OUR PROPOSED PROJECT WILL CONTRIBUTE SUBSTANTIALLY TO THE OVERARCHING GOAL OF BICAN TO GENERATE FUNDAMENTAL KNOWLEDGE ON DIVERSE CELL TYPES AND THEIR THREE-DIMENSIONAL ORGANIZATIONAL PRINCIPLES IN THE BRAIN ACROSS LIFESPAN AND EVOLUTION.

MIDAS CENTER FOR COMMUNICABLE DISEASE DYNAMICS

STATISTICAL AND DATA MANAGEMENT CENTER-PEDIATRIC,ADOLESCENT, AND MATERNAL CTG

IMMGEN: A GENE EXPRESSION COMPENDIUM FOR IMMUNE CELLS

TIME-TOLERANT BIOSTASIS THERAPEUTICS

DIAGNOSING THE UNKNOWN FOR CARE AND ADVANCING SCIENCE (DUCAS) - PROJECT SUMMARY IN OUR CURRENT HEALTHCARE SYSTEM, IT OFTEN TAKES YEARS BEFORE PATIENTS WITH RARE CONDITIONS AND RARE PRESENTATIONS OF COMMON CONDITIONS RECEIVE A DIAGNOSIS. IN 2013, THE NATIONAL INSTITUTES OF HEALTH SUPPORTED THE CREATION OF THE UNDIAGNOSED DISEASES NETWORK (UDN) TO ADDRESS THE NEEDS OF THESE PATIENTS, TO FACILITATE THE DIAGNOSTIC PROCESS FOR THOSE WITH UNDIAGNOSED CONDITIONS AND GENERATE NEW KNOWLEDGE ABOUT UNDERLYING MECHANISMS OF DISEASE. THE UDN WAS SUCCESSFUL IN SOLVING MEDICAL MYSTERIES, SHORTENING DIAGNOSTIC ODYSSEYS, AND CONTRIBUTING TO BIOMEDICAL RESEARCH DISCOVERY. IN ORDER TO SERVE MORE PATIENTS, THE UDN PROCESS MUST BE SCALED AND INTEGRATED INTO BROADER HEALTHCARE AND RESEARCH ECOSYSTEMS. AS THE DATA MANAGEMENT COORDINATING CENTER (DMCC) FOR A NETWORK OF DIAGNOSTIC CENTERS OF EXCELLENCE, HARVARD MEDICAL SCHOOL WILL LEVERAGE EXPERIENCE IN THE UDN TO CREATE SUSTAINABLE, NATIONALLY SCALED INFRASTRUCTURE TO SUPPORT DIAGNOSIS, RESEARCH, AND CARE FOR THOSE WHO ARE UNDIAGNOSED. THIS WILL BE ACCOMPLISHED BY BRINGING TOGETHER EXPERTS IN TRANS-INSTITUTIONAL DATA SHARING, DATA ANALYSIS, CLINICAL CARE, BIOINFORMATICS, NOVEL DIAGNOSTICS, AND TRANSLATIONAL RESEARCH AND CREATING THREE DMCC CORES - ADMINISTRATIVE, DATA MANAGEMENT, AND CLINICAL RESEARCH SUPPORT - TO ADDRESS UNMET NEEDS OF THE UNDIAGNOSED. THE ADMINISTRATIVE CORE WILL UNITE THE DMCC AND SUPPORT ACTIVITIES OF ALL THREE CORES. TOGETHER, THE DMCC CORES WILL ACCOMPLISH FOUR AIMS: 1) SCALE UP UDN THROUGHPUT BY AT LEAST AN ORDER OF MAGNITUDE TO MEET A PRESSING NATIONAL NEED, 2) LEVERAGE PARTNERSHIPS FOR SUSTAINABLE COORDINATION OF DIAGNOSTIC PROCESSES TO INCREASE PATIENT AUTONOMY WHILE ADVANCING OPPORTUNITIES FOR INVESTIGATIVE SCIENCE, 3) MAXIMIZE DATA MOBILITY, INTERPRETABILITY, AND SHAREABILITY, AND 4) PROVIDE ANALYTIC SERVICE AND DATA STEWARDSHIP THROUGH THE DATA MANAGEMENT CORE AND CLINICAL RESEARCH SUPPORT CORES LED BY EXPERTS IN GENOMICS AND AI TEAMING WITH CLINICIANS AND RESEARCHERS.

INNOVATIVE PLATFORMS FOR ANTIMICROBIAL THERAPY AND VACCINE DEVELOPMENT

NEW ENGLAND PRIMATE RESEARCH CENTER BASE GRANT

4D NUCLEOME NETWORK DATA COORDINATION AND INTEGRATION CENTER

HSPH CENTER FOR EXCELLENCE TO PROMOTE A HEALTHIER WORKFORCE

THE PURPOSE OF THIS AGREEMENT IS TO FUND RESEARCH SUPPORTING THE DEFENSE ADVANCED RESEARCH PROJECTS AGENCY (DARPA) BIOLOGICAL TECHNOLOGIES OFFICE (BTO) PANACEA PROGRAM.

SMALL MOLECULE INHIBITORS OF ENVELOPED VIRUS ENTRY

LIFE COURSE CANCER EPIDEMIOLOGY COHORT IN WOMEN

MICROBIAL ECOLOGY, PROTEOGENO-MICS & COMPUTATIONAL OPTIMA

BRAIN CONNECTS: A CENTER FOR HIGH-THROUGHPUT INTEGRATIVE MOUSE CONNECTOMICS - PROJECT SUMMARY/ABSTRACT THE PROPOSED PROJECT WILL DEMONSTRATE THE FEASIBILITY OF GENERATING A COMPLETE SYNAPSE-LEVEL BRAIN MAP (CONNECTOME) BY DEVELOPING A SERIAL-SECTION ELECTRON MICROSCOPY PIPELINE THAT COULD SCALE TO A WHOLE MOUSE BRAIN. THIS WORK WILL IMAGE 10 CUBIC MILLIMETERS, ITSELF AN UNPRECEDENTEDLY LARGE DATASET THAT MAY EXCEED TENS OF PETABYTES. YET THE MOUSE BRAIN IS 50 TIMES LARGER. REACHING THIS AMBITIOUS GOAL WILL REQUIRE ADVANCES IN WHOLE-BRAIN STAINING, IMAGING, IMAGE-PROCESSING, ANALYSIS, AND DISSEMINATION TOOLS. WE WILL SCALE AND TEST THESE TOOLS BY PRODUCING A CONNECTOME OF THE HIPPOCAMPAL FORMATION, A CRITICAL BRAIN REGION FOR MEMORY AND SPATIAL NAVIGATION. SPECIFICALLY, WE WILL DEFINE OUR VOLUME OF INTEREST VIA MICROCT SCANNING OF A WHOLE BRAIN. THEN WE WILL CUT IT INTO SEMITHIN SERIAL SECTIONS AND IMAGE THEM WITH MULTIBEAM SCANNING ELECTRON MICROSCOPY AND ION BEAM MILLING. THIS TECHNIQUE IMAGES A THIN LAYER OF TISSUE AND THEN REMOVES IT TO REVEAL THE NEXT LAYER UNTIL EACH SECTION IS FULLY IMAGED, MINIMIZING DISTORTIONS CAUSED BY PREVIOUS ULTRA-THIN SECTIONING APPROACHES. THE IMAGING DATA WILL BE PROCESSED BY AN IMPROVED VERSION OF OUR STATE-OF-THE-ART PIPELINE. AFTER QUALITY MONITORING AND IMAGE COMPRESSION, OUR AUTOMATED SYSTEM WILL ASSEMBLE THE FULL VOLUME FROM IMAGED SLICES AND THEN LABEL TISSUE ELEMENTS: NEURONS, GLIA, BLOOD VESSELS, MYELIN, CELL BODIES, AND SYNAPSES. THIS RECONSTRUCTION WILL THEN BE PROOFREAD AND REGISTERED TO THE ALLEN INSTITUTE BRAIN ATLAS, ALLOWING US TO RELATE OUR DATA TO OTHER TYPES OF DATA. OUR ANALYSIS WILL IDENTIFY CELL TYPES BY REGION AND LAYER, AND REVEAL THE DETAILED CONNECTIVITY OF HIPPOCAMPAL FORMATION CIRCUITS. USING CUSTOM SOFTWARE, WE WILL INTEGRATE THESE STRUCTURAL RESULTS ON CELL TYPES WITH OTHER APPROACHES BASED ON LIGHT MICROSCOPY AND SINGLE-CELL GENE EXPRESSION, ALLOWING US TO RELATE OUR RESULTS TO THE EXTENSIVE LITERATURE ON HIPPOCAMPAL FORMATION STRUCTURE AND FUNCTION. TO PROMOTE DIVERSE PERSPECTIVES, WE WILL INVOLVE UNDERGRADUATES FROM UNDERREPRESENTED BACKGROUNDS IN THE PROOFREADING AND SCIENTIFIC DISCOVERY PHASES OF OUR WORK, OFFERING THEM MENTORING AS WELL AS RESEARCH EXPERIENCE. WE WILL TURN THESE DATA INTO A LASTING RESOURCE FOR THE SCIENTIFIC COMMUNITY AND THE PUBLIC BY SCALING UP FREE ACCESS VIA ONLINE SHARING TOOLS TO ALLOW ANY INTERESTED PARTY TO RENDER, PROOFREAD, OR OTHERWISE ANALYZE THE CELLS AND CIRCUITS IN THIS VOLUME. TO ILLUSTRATE HOW THIS RESOURCE CAN BE COMBINED WITH OTHER DISCOVERIES, WE WILL DEFINE CELL TYPES BASED ON THEIR MORPHOLOGY AND CONNECTIVITY, CHARACTERIZE THE RELATIONSHIP BETWEEN THESE ASSIGNMENTS AND TRANSCRIPTOMIC-BASED CLASSIFICATIONS, AND INTEGRATE THIS INFORMATION WITH PREVIOUS WORK. FINALLY, WE WILL DEFINE LOCAL AND LONG-RANGE MICROCIRCUIT MOTIFS IN OUR DATA AND USE IT TO IDENTIFY CIRCUIT PRINCIPLES AND MECHANISMS OF MEMORY AND SPATIAL COGNITION, BY TESTING AND IMPROVING MODELS OF THE HIPPOCAMPAL FORMATION. THROUGHOUT THE PROJECT, WE WILL MONITOR KEY PERFORMANCE PARAMETERS, SUCH AS IMAGING THROUGHPUT OF A SINGLE MICROSCOPE, TO EVALUATE THE FEASIBILITY AND COST OF SCALING UP TO A WHOLE MOUSE BRAIN CONNECTOME.

INTEGRATED MESOSCALE ARCHITECTURES FOR SUSTAINABLE CATALYSIS (IMASC)

DISSECTING THE ESTABLISHMENT AND REGULATION OF HUMAN PLURIPOTENCY

RESEARCH IN HIGH ENERGY PHYSICS

VIRAL AND HOST MECHANISMS THAT TILT THE HSV LYTIC/LATENT BALANCE

IMPACT EVALUATION OF COMBINATION HIV PREVENTION INTERVENTIONS IN BOTSWANA

CAUSAL TRANSCRIPTIONAL CONSEQUENCES OF HUMAN GENETIC VARIATION

BOSTON-AREA RESEARCH TRAINING PROGRAM IN BIOMEDICAL INFORMATICS

PROSPECTIVE STUDIES OF DIET AND CANCER IN MEN AND WOMEN

TOWARDS A UNIFIED FRAMEWORK FOR DOPAMINE SIGNALING IN THE STRIATUM

IMPRINTING A CONNECTOME: DEVELOPMENTAL CIRCUIT APPROACH TO MENTAL ILLNESS

WARM LIQUID CALORIMETRY, FRONT END ELECTRONICS, & SILICON DRIFT DETECTOR R&D FOR SSC.

PATIENT-CENTERED INFORMATION COMMONS

THE VENTRAL MEDULLA AND THE SUDDEN INFANT DEATH SYNDROME

NMR AND COMPUTATIONAL STUDIES OF BIOMOLECULES

MATERIALS RESEARCH SCIENCE AND ENGINEERING CENTER

INTEGRATING LIFECOURSE APPROACHES, BIOLOGIC AND DIGITAL PHENOTYPES IN SUPPORT OF HEART AND LUNG DISEASE EPIDEMIOLOGIC RESEARCH

DAMAGE OF A SINGLE ORGAN ACCOUNTS FOR THE MAJORITY OF HUMAN ILLNESSES WITH LIVER DISEASE AFFECTING OVER 500 MILLION PEOPLE AND ACCOUNTING FOR OVER 2 MILLION ANNUAL DEATHS WORLDWIDE. AT THIS TIME THE ONLY CURATIVE THERAPY IS ORTHOTOPIC TRANSPLANT OF A DONOR LIVER. HOWEVER DUE TO THE SEVERE SHORTAGE OF DONOR ORGANS TRANSPLANTS ARE LIMITED TO ONLY A FRACTION OF THE POPULATION WHO MIGHT BENEFIT FROM LIVER REPLACEMENT THERAPY LARGELY DUE TO THE LOW AVAILABILITY AND HIGH COST AND COMPLEX SURGERY AND LIFELONG IMMUNOSUPPRESSION REQUIREMENTS. AS SUCH MILLIONS OF PATIENTS ARE LEFT WITHOUT AN ACCESSIBLE SOLUTION.THE IMPLANT TEAM AIMS TO ADDRESS THIS CHALLENGE BY ESTABLISHING THE FIRST OFF THE SHELF ENGINEERED PRODUCT TO ADDRESS LIVER FAILURE. THE SOLUTION IS BUILT ON SEVERAL NEXT GENERATION TECHNOLOGIES INCLUDING TOOLS TO DRIVE INDUCIBLE PLURIPOTENT STEM CELL DIFFERENTIATION INTO ALL REQUIRED CELLS OF THE LIVER AND IMMUNE ENGINEERING TO ALLOW ALLOGENEIC CELLS TO EVADE IMMUNE REJECTION AND BIOREACTORS TO FACILITATE MANUFACTURING AND MATURATION OF CELLS AND ENGINEERED TISSUES AT LOW COST AND SIMPLE BIOFABRICATION TECHNOLOGIES TO BUILD CLINICAL SCALE CONSTRUCTS. IMPLANT WILL GENERATE A UNIVERSAL AND TRANSPLANT READY GRAFT THAT COOPERATES WITH THE NATIVE LIVER TO MAINTAIN HOMEOSTASIS AND SOMETIMES EVEN LEADING TO ITS RECOVERY AND REGENERATION THROUGH METABOLIC OFFLOADING AND BRINGING HOPE TO MILLIONS OF PATIENTS FOR WHOM THE CURRENT LIVER TRANSPLANT PARADIGM FAILS.THE PROJECT WILL CULMINATE WITH A GMP MANUFACTURED BIOBANK OF CELLS AND UNIVERSAL LIVER TISSUES WITH EFFECTIVENESS DEMONSTRATED IN HUMANIZED MICE AND HUMANIZED PIG MODELS TO SUPPORT TECHNOLOGY TRANSLATION TOWARDS CLINICAL TRIALS. BEYOND IMPLANT WE EXPECT THE PATH TO REGULATORY APPROVAL TO PROGRESS THROUGH A NARROW INDICATION ULTIMATELY INTO SERVING THE MILLIONS OF PATIENTS WITH SERIOUS LIVER DISEASES. OVERALL THIS PROJECT AIMS TO PROVIDE A SOLUTION THAT WILL REVOLUTIONIZE THE TREATMENT OF LIVER DISEASE AND SERVING ALL POPULATIONS MANY OF WHOM ARE CURRENTLY EXCLUDED FROM TRANSPLANT.

RISK FACTORS FOR BREAST CANCER IN YOUNGER NURSES

NEUROPSYCHIATRIC GENOME-SCALE AND RDOC INDIVIDUALIZED DOMAINS (N-GRID)

CANCER EPIDEMIOLOGY COHORT IN MALE HEALTH PROFESSIONALS

LIFE COURSE CANCER EPIDEMIOLOGY COHORT IN WOMEN

INNOVATION PLATFORM FOR SUBSTITUTABLE APPS WITH ACCESS TO NETWORKED HEALTHCARE DATA

NETWORKING RESEARCH RESOURCES ACROSS AMERICA

CORE GRANT FOR VISION RESEARCH

BACTERIAL DETERMINANTS OF TREATMENT RESPONSE IN MYCOBACTERIA TUBERCULOSIS

MECHANISMS OF PROTECTIVE IMMUNITY INDUCED BY LIVE ATTENUATED SIV VACCINES

HEALTH OUTCOMES AROUND PREGNANCY AND EXPOSURE TO HIV/ARV (HOPE): EXTENDING THE REACH OF PHACS TO EXAMINE WOMEN'S HEALTH

MEDICAL SCIENTIST TRAINING PROGRAM - PROJECT SUMMARY THE MISSION OF THE HARVARD/MIT MD-PHD PROGRAM IS TO PROVIDE AN ACADEMIC AND SOCIAL ENVIRONMENT THAT INCULCATES IN OUR STUDENTS THE VITAL IMPORTANCE OF RIGOROUS CLINICAL AND SCIENTIFIC KNOW-HOW, THE HIGHEST ETHICAL STANDARDS, COMMITMENT TO INCLUSION AND DIVERSITY, AND MOST OF ALL, THE DRIVE TO HARNESS THEIR REMARKABLE TALENTS TO PROMOTE HEALING OVER THE SHORT AND LONG TERM. A KEY COMPONENT OF OUR MISSION IS THE RECOGNITION THAT EACH STUDENT BRINGS TO THE TABLE A UNIQUE BACKGROUND, SKILL SET, AND VISION FOR THEIR FUTURE CAREER. FOR THIS REASON, WE PROMOTE AN INTEGRATED TRAINING CURRICULUM THAT AFFORDS ESSENTIAL STANDARDS COMPLEMENTED BY OPERATIONAL FLEXIBILITY. OUR STUDENTS PURSUE EITHER (1) A TRULY UNIQUE HEALTH SCIENCES AND TECHNOLOGY (HST) CURRICULUM THAT REPRESENTS A HARVARD AND MIT COLLABORATION EMPHASIZING THE MECHANISMS OF MEDICINE AND THE IMPACT OF MATHEMATICS, PHYSICS AND ENGINEERING ON OUR FUNDAMENTAL UNDERSTANDING OF PHYSIOLOGY AND OPPORTUNITIES TO INNOVATE; OR (2) A PATHWAYS CURRICULUM THAT FEATURES A “FLIPPED CLASSROOM” APPROACH IN WHICH MULTIDIMENSIONAL THINKING AND HANDS-ON LEARNING RULES THE DAY AND A LIBERAL ARTS CULTURE OF “ANY AND EVERY MEDICAL CAREER ROUTE IS POSSIBLE” IS PALPABLE. THE ACADEMIC CHOICES AVAILABLE TO OUR STUDENTS AT THE GRADUATE RESEARCH PHASE ARE EQUALLY ROBUST, SPANNING A REMARKABLE BREADTH OF INSTITUTIONS, BASIC AND SOCIAL SCIENCE GRADUATE PROGRAMS, AND RESEARCH SPECTRA THAT INCORPORATE ESSENTIALLY ANY AND EVERY TRAINING DISCIPLINE AVAILABLE AT HARVARD UNIVERSITY (HU), HARVARD MEDICAL SCHOOL (HMS), AND THE MASSACHUSETTS INSTITUTE OF TECHNOLOGY (MIT). AS AN MD-PHD TRAINING PROGRAM THAT SITS AT THE INTERSECTION OF SUCH RENOWNED INSTITUTIONS AND HOSPITALS, OUR MISSION IS BASED ON FIVE KEY PILLARS: (1) SELECTING AND RECRUITING THE NATION’S MOST PROMISING AND DIVERSE YOUNG TALENT; (2) PROVIDING AN INTEGRATED AND EVIDENCE-BASED MD-PHD CURRICULUM THAT FEATURES COMPREHENSIVE DUAL-DEGREE TRAINING; (3) ASSEMBLING AND TRAINING THE IDEAL CONSTELLATION OF FACULTY LEADERS, ADVISORS, AND ROLE MODELS WHO EMBODY THE BREADTH AND DEPTH OF CLINICAL AND RESEARCH DISCIPLINES; (4) FOSTERING AN INCLUSIVE, DIVERSE, AND DYNAMIC MD-PHD TRAINING COMMUNITY THAT IS ENRICHED BY TAILORED ACADEMIC, SOCIAL, AND CAREER DEVELOPMENT PROGRAMMING; AND (5) DEVELOPING THE FUNDING BASE TO MAXIMALLY SUPPORT OUR ENROLLED STUDENTS AND ENABLE THE CONTINUED GROWTH OF OUR PROGRAM SO THAT WE CAN CONTRIBUTE TO BUILDING A LARGER, MUCH-NEEDED MD-PHD WORKFORCE TO SERVE THE CRITICAL HEALTH CARE AND BIOMEDICAL TECHNOLOGY NEEDS OF THE NATION AND WORLD. TO EXECUTE THE PROPOSED TRAINING PROGRAM, WE HAVE ASSEMBLED A QUARTET OF ACADEMIC LEADERS WITH COMPLEMENTARY EXPERTISE AND INSTITUTIONAL REPRESENTATION, SPANNING HMS BASIC SCIENCE AND CLINICAL CARE, MIT BASIC SCIENCE, HU/HMS SOCIAL SCIENCE, AND EDUCATION EVALUATION, MULTICULTURALISM, AND UNDER-REPRESENTED MINORITY STUDENT AND FACULTY RECRUITMENT. OUR LEADERS HAVE ESTABLISHED A BOLD SET OF 9 ACADEMIC AND INTEGRATIVE TRAINING OBJECTIVES TO PROMOTE THE PERSONAL AND PROFESSIONAL DEVELOPMENT OF BUDDING PHYSICIAN-SCIENTISTS WHO ARE BALANCED, FULFILLED, AND MAXIMALLY PREPARED TO MAKE THEIR MARK AS MULTI-TALENTED, MULTI-DIMENSIONAL, AND MULTI-DISCIPLINARY CAREGIVERS, RESEARCHERS, AND EDUCATORS.

GH16-002, BOTSWANA: IMPACT EVALUATION OF COMBINATION HIV PREVENTION INTERVENTIONS

BIOLOGICAL DIVERSITY: GENERATION, CONTROL AND EXPLOITATION

IDENTIFYING PATHOGENIC BACTERIA BY PHENOTYPING INDIVIDUAL CELLS

SEAL (STOPPING ATOPIC DERMATITIS AND ALLERGY) STUDY: PREVENT ALLERGY BY ENHANCING THE SKIN BARRIER

TRAINING IN THE MOLECULAR BIOLOGY OF NEURODEGENERATION

ATOMIC RESOLUTION IN BIOLOGICAL ELECTRON MICROSCOPY

TRAINING FOR SPEECH AND HEARING SCIENCES

MATERIALS RESEARCH SCIENCE AND ENGINEERING CENTER

DECODING THE ROLES OF CRITICAL GENES OF UNKNOWN FUNCTION IN M. TUBERCULOSIS

PHARMACO RESPONSE SIGNATURES AND DISEASE MECHANISM

IMPLEMENTATION OF PROGRAMS FOR THE PREVENTION CARE AND TREATMENT OF HIV/AIDS IN

INVESTING IN INNOVATION -- VALIDATION GRANTS

CYTOTXIC T-CELL MEDIATED IMMUNITY TO CHLAMYDIA

DEFINING REGULATORS OF IMMUNITY TO ACUTE INFECTION USING CRISPR SCREENS

MATERIALS RESEARCH SCIENCE AND ENGINEERING CENTER

PHYSICS OF COLLECTIVE CELLULAR MIGRATION IN LUNG HEALTH AND DISEASE

THE BOSTON LUNG CANCER SURVIVAL COHORT

COOPERATIVE AGREEMENT "ENTANGLED NEUTRAL ATOMS FOR LOGICAL QUANTUM TELEPORTATION (ENAQT)"

CENTER FOR GENOME IMAGING - PROJECT SUMMARY/ABSTRACT CENTER FOR GENOME IMAGING (CGI) OBJECTIVES: THREE-DIMENSIONAL (3D) GENOME ORGANIZATION IS A MAJOR CONTRIBUTOR TO GENOME FUNC- TION, AND YET, WE ARE ONLY AT THE VERY DAWN OF DISCOVERING THE STRUCTURAL SIGNATURES THAT UNDERLIE THAT ORGANIZATION. THUS, THE GOAL OF THE PROPOSED STUDIES IS TO DEVELOP AND APPLY TOOLS THAT WILL ENABLE SE- QUENCE-SPECIFIC IMAGING OF HUMAN GENOMES, IN THEIR ENTIRETY, WITH HIGH GENOMIC RESOLUTION. IN PARTICU- LAR, THE PROPOSED WORK WILL INNOVATE METHODS FOR FIXED AND LIVE CELL IMAGING USING DIFFRACTION-LIMITED LIGHT MICROSCOPY AND SUPER-RESOLUTION MICROSCOPY AS WELL AS DEVELOP NEW TOOLS FOR IMAGE ANALYSIS AND GE- NOME MODELING. TO THIS END, IT WILL INVOLVE THE CONTINUED COLLABORATION OF FOUR LABORATORIES, WHOSE COL- LECTIVE BREADTH OF EXPERTISE COVERS THE FIELDS OF CLASSICAL AND MOLECULAR GENETICS, CHROMOSOME DYNAM- ICS, IMAGING, HI-C ANALYSIS, CONVOLUTIONAL NEURAL NETWORKS, AND POLYMER PHYSICS-BASED AND RESTRAINT- BASED MODELING. AN EQUALLY IMPORTANT OBJECTIVE OF THE PROPOSED STUDIES IS TO ENSURE A GENERATION OF RE- SEARCHERS WHOSE PERSONAL BREADTH OF EXPERTISE WILL COME TO MATCH THAT OF THE ENTIRE CURRENT TEAM. HEALTH RELATEDNESS: WILL A SOLID GRASP OF 3D GENOME ORGANIZATION HAVE IMPLICATIONS FOR UNDER- STANDING HUMAN DEVELOPMENT? WILL IT CONTRIBUTE TO THE PROTECTION OF HUMAN HEALTH? WILL IT CONTRIBUTE TO STRATEGIES FOR EARLY DIAGNOSTICS AND PERHAPS EVEN THE DEVELOPMENT OF NEW THERAPIES? THE ANSWER TO ALL THESE QUESTIONS IS ALMOST CERTAINLY A RESOUNDING YES, AS KNOWLEDGE OF 3D GENOME ORGANIZATION WILL EN- HANCE OUR CAPACITY TO ADDRESS BOTH FUNDAMENTAL BIOLOGICAL PROCESSES AS WELL AS DISEASE. INNOVATION: AN ABUNDANCE OF STUDIES ARGUE THAT GENOMES FUNCTION AS INTEGRATED UNITS AND, YET, NO EXTANT TECHNOLOGIES ENABLE SEQUENCE-SPECIFIC IMAGING OF ENTIRE GENOMES AT HIGH GENOMIC RESOLUTION. THUS, THE CAPACITY OF RESEARCHERS TO FATHOM THE INTERPLAY BETWEEN 3D GENOME ORGANIZATION AND GE- NOME FUNCTION HAS BEEN LIMITED TO DISJOINTED SNAPSHOTS OF LOCALIZED EVENTS. ACCORDINGLY, FIRST THREE AIMS WILL DEVELOP THE NEXT TIER OF TOOLS TO PUT ENTIRE GENOMES WITHIN REACH. THEY WILL ADVANCE A NEW METHOD, OLIGOFISSEQ, AND THEN INTEGRATE IT WITH OLIGOSTORM AND OLIGODNA-PAINT TO FINALLY ACHIEVE HIGH- THROUGHPUT IMAGING AT BOTH CONVENTIONAL AND SUPER-RESOLUTION. THEY WILL ALSO TACKLE TWO GENOMIC FEA- TURES THAT HAVE BEEN PROHIBITIVELY DIFFICULT TO CAPTURE – PRESENCE OF HOMOLOGS IN DIPLOID CELLS AND HIGHLY REPEATED SEQUENCES – AS WELL AS INNOVATE STRATEGIES FOR HIGH VOLUME DATA STORAGE, IMAGE PROCESSING AND ANALYSIS, AND MODELING. FINALLY, A FOURTH AIM WILL IMPLEMENT METHODS FOR DISSEMINATING OUR TOOLS. 1. SCALING TECHNOLOGIES TOWARD WHOLE GENOME IMAGING 2. FILLING IN GAPS TO VISUALIZE CHROMOSOMES END-TO-END – TACKLING HOMOLOGS AND REPEATS 3. PROBE DESIGN, IMAGE ANALYSIS, MODELING, AND INTEGRATION OF EPIGENETIC DATA 4. TRAINING, RESOURCES, AND OPPORTUNITIES FOR ENGAGING COLLEAGUES IN WHOLE GENOME IMAGING

ANTI-VIRAL IMMUNE RESPONSES IN LYMPH NODE

IMPLEMENTATION SCIENCE CENTER IN CANCER CONTROL EQUITY: A COMPETITIVE REVISION TO ACCELERATE COVID TESTING IN VULNERABLE COMMUNITIES

PHD TRAINING IN NEUROSCIENCE

PROGRAM FOR TRAINING IN CANCER EPIDEMIOLOGY

COVID 19. THE PURPOSE OF THIS AGREEMENT IS TO FUND RESEARCH SUPPORTING THE DEFENSE ADVANCED RESEARCH PROJECTS AGENCY DARPA BIOLOGICAL TECHNOLOGIES OFFICE BTO PROGRAM PREEMPTIVE EXPRESSION OF PROTECTIVE ALLELES AND RESPONSE ELEMENTS PREPARE. THIS EFFORT SHALL BE CARRIED OUT GENERALLY AS SET FORTH IN EXHIBIT B, RESEARCH DESCRIPTION DOCUMENT, DATED APRIL 2020, AND IN THE RECIPIENTS PROPOSAL TITLED, ULTRA-RAPID DRUG REPURPOSING FOR COVID19 THERAPEUTICS.

MEMBRANE PROTEIN STRUCTURES BY SOLUTION NMR

SPLEE-ON-A-CHIP SEPSIS THERAPEUTIC DEVICE

BOTSWANA-HARVARD SCHOOL OF PUBLIC HEALTH AIDS INITIATIVE PARTNERSHIP CTU

CANCER EPIDEMIOLOGY COHORT IN MALE HEALTH PROFESSIONALS

GENERATE A CORPS OF SCIENTISTS, ENGINEERS, AND TECHNICAL EXPERTS TRAINED IN INTERNATIONAL DEVELOPMENT PROGRAMMING AND POLICY AND IMPROVE DEVELOPMENT OUTCOMES BY INTEGRATING SCIENTIFIC AND TECHNICAL EXPERTISE ACROSS USAID PROGRAMMING.

IMAGING INFLAMMATION IN AUTOIMMUNE DISEASE

BIOCHEMICAL STUDIES OF MITOSIS

TRAINING PROGRAM IN BIOINFORMATICS AND INTEGRATIVE GENOMICS

A DEFEND AND DESTROY APPROACH TO CURING HIV

DIETARY ETIOLOGIES OF HEART DISEASE AND CANCER

PARTNERSHIP FOR GLOBAL HEALTH RESEARCH TRAINING PROGRAM

SYSTEMS PHARMACOLOGY OF THERAPEUTIC AND ADVERSE RESPONSES TO IMMUNECHECKPOINT AND SMALL MOLECULE DRUGS

THE HMS LABORATORY OF SYSTEMS PHARMACOLOGY

DECODING AND TARGETING THE PI3K-MTOR SIGNALING NETWORK IN CANCER

ELECTRONIC SEQUENCING IN NANOPORES

NETWORKS AND NEIGHBORHOODS

LUNG CANCER DISPARTIES CENTER: JOINTLY ADDRESSING RACE & SOCIOECONOMIC STATUS

TRAINING IN MOLECULAR, CELLULAR, AND CHEMICAL BIOLOGY

DISCOVERY BIOLOGY AND RISK OF INHERITED VARIANTS IN BREAST CANCER

TRAINING IN INTERDISCIPLINARY PULMONARY SCIENCES

CENTER FOR GENOMICALLY ENGINEERED ORGANS

DEVELOPMENTAL REGULATION OF BONE MORPHOGENESIS

SUPERFUND METAL MIXTURES, BIOMARKERS AND NEURODEVELOPMENT

EXPLOITING MEMBRANE TARGETS TO OVERCOME ANTIBIOTIC RESISTANCE - PROJECT SUMMARY – OVERALL ANTIBIOTIC RESISTANCE IS A MAJOR PUBLIC HEALTH CONCERN WORLDWIDE. THIS CARB (COMBATING ANTIBIOTIC RESISTANT BACTERIA) PROPOSAL WAS CONCEIVED IN RESPONSE TO THIS URGENT GLOBAL THREAT. THE THEME OF OUR PROGRAM, “EXPLOITING MEMBRANE TARGETS TO OVERCOME ANTIBIOTIC RESISTANCE,” ADDRESSES IMPORTANT GAPS IN CURRENT KNOWLEDGE TO FACILITATE TRANSLATION OF DISCOVERIES INTO STRATEGIES TO COMBAT ANTIBIOTIC-RESISTANT INFECTIONS. A TEAM OF HIGHLY COLLABORATIVE AND PRODUCTIVE SCIENTISTS FROM DIVERSE FIELDS – CHEMISTRY, BIOCHEMISTRY, STRUCTURAL BIOLOGY, AND MOLECULAR GENETICS – HAS JOINED FORCES IN THIS EFFORT. THE CELL ENVELOPE, THE INTERFACE BETWEEN HOST AND PATHOGEN, IS A MAJOR POINT OF VULNERABILITY FOR BACTERIA. INTERFERING WITH CELL ENVELOPE ASSEMBLY OR FUNCTION CAN INHIBIT BACTERIAL GROWTH, PROMOTE LYSIS, DECREASE RESISTANCE TO HOST IMMUNE DEFENSES, AND INCREASE SUSCEPTIBILITY TO OTHER ANTIBIOTICS TO OVERCOME RESISTANCE. IDENTIFYING AND EXPLOITING NEW WAYS OF DISRUPTING ENVELOPE ASSEMBLY PATHWAYS TO ENABLE THERAPEUTIC DISCOVERY HAS BEEN AN IMPORTANT GOAL IN THE FIELD. HOWEVER, PROGRESS IN THIS AREA HAS BEEN HAMPERED BY THE MANY CHALLENGES POSED BY ENVELOPE TARGETS. BIOSYNTHETIC AND REGULATORY PROCESSES THAT GOVERN CELL ENVELOPE BIOGENESIS TAKE PLACE AT A MEMBRANE INTERFACE AND OFTEN INVOLVE PROTEINS THAT CONTAIN MULTIPLE MEMBRANE-SPANNING SEGMENTS, FUNCTION IN MULTI-PROTEIN COMPLEXES, AND USE COMPLICATED SUBSTRATES THAT ARE NOT COMMERCIALLY AVAILABLE. ADVANCING OUR UNDERSTANDING OF THESE CELL ENVELOPE TARGETS REQUIRES THE CONCERTED EFFORTS OF AN INTERDISCIPLINARY TEAM WITH EXPERTISE THAT SPANS BROAD AREAS OF CHEMISTRY AND BIOLOGY. RECENT TECHNOLOGICAL ADVANCES AND BIOLOGICAL DISCOVERIES, MANY MADE BY THE CARB PROJECT TEAM, HAVE TRANSFORMED OUR UNDERSTANDING OF CELL ENVELOPE BIOLOGY AND OPENED THE DOOR TO FUNDAMENTALLY NEW APPROACHES TO THERAPEUTIC TARGETING OF THIS ESSENTIAL STRUCTURE. TO BUILD ON THESE SUCCESSES, WE HAVE CREATED A COLLABORATIVE, INTERDISCIPLINARY PROJECT TO IDENTIFY, CHARACTERIZE, AND VALIDATE NOVEL VULNERABILITIES IN ENVELOPE BIOGENESIS AND MAINTENANCE PATHWAYS. THE THREE PROPOSED PROJECTS ARE NOT ONLY CONNECTED BY THE SHARED FOCUS OF THE INVESTIGATORS ON CELL ENVELOPE BIOLOGY, THEIR COMMITMENT TO MOLECULAR MECHANISM AS THE FOUNDATION OF TRANSLATIONAL RESEARCH, AND OVERLAPPING THEMES AND GOALS, BUT ALSO BY SYNERGISTIC COLLABORATION AMONG MULTIPLE INVESTIGATORS WITHIN AS WELL AS BETWEEN EACH PROPOSAL. PROJECT 1 WILL DEFINE THE STRUCTURAL BASIS FOR ENZYMATIC ACTIVITY OF THE BROADLY CONSERVED SEDS FAMILY CELL WALL POLYMERASES AND DETERMINE HOW SEDS PROTEINS FUNCTION WITHIN LARGE MACROMOLECULAR COMPLEXES DURING GROWTH AND DIVISION. PROJECT 2 WILL FOCUS ON IDENTIFYING AND EXPLOITING VULNERABILITIES IN THE GRAM-POSITIVE CELL ENVELOPE. PROJECT 3 WILL FOCUS ON CHARACTERIZING AND EXPLOITING VULNERABILITIES IN THE GRAM-NEGATIVE CELL ENVELOPE. A STREAMLINED ADMINISTRATIVE CORE WILL COORDINATE ACTIVITIES TO MAXIMIZE SYNERGIES, DATA SHARING, AND USE OF ALL PROGRAM ASSETS WHILE PROVIDING RESPONSIBLE FISCAL OVERSIGHT.

FUNCTIONAL GENOMIC ANALYSIS USING RNAI SCREEN IN DROSOPHILA

THE CENTER WILL INVESTIGATE THE SOURCES, COMPOSITION, TRENDS, AND EFFECTS OF REGIONAL AIR POLLUTANT MIXTURES ACROSS THE US OVER A PERIOD SPANNING PAS

THE NATIONAL CENTER ON RURAL EDUCATION RESEARCH NETWORKS

STATISTICAL METHODS FOR ANALYSIS OF MASSIVE GENETIC AND GENOMIC DATA IN CANCER RESEARCH

CHEMIGENOMIC DRUG DISCOVERY FOR TUBERCULOSIS

EDUCATION RESEARCH AND DEVELOPMENT CENTERS

TRAINING PROGRAM IN ENVIRONMENTAL EPIDEMIOLOGY

QUANTUM OPTIMIZATION WITH PROGRAMMABLE SIMULATORS BASED ON ATOM ARRAYS

SYNTHESIS AND STUDY OF NATURAL AND NON-NATURAL ANTIPROLIFERATIVE AGENTS

DROSOPHILA TRANSGENIC RNAI RESOURCE PROJECT

ACTIVE CONTEXT

AIR POLLUTION DISRUPTS INFLAMMASOME REGULATION IN HEART AND LUNG TOTAL HEALTH (AIRHEALTH) - ABSTRACT: OVERALL COMPONENT EXPOSURE TO AIR POLLUTION FROM AUTOMOBILE EXHAUST AND FOREST FIRES IS A SIGNIFICANT, RAPIDLY GROWING GLOBAL PUBLIC HEALTH BURDEN THAT CONTRIBUTES TO CARDIOPULMONARY PATHOGENESIS. PRODUCED BY EPITHELIAL AND INFLAMMATORY CELLS, INTERLEUKIN-1 BETA (IL-1SS) IS KEY TO THIS INFLAMMATORY RESPONSE WITHIN BLOOD, LUNG, CARDIAC, AND VASCULAR TISSUES, AND PRIMARILY ASSOCIATED WITH ACUTE AND CHRONIC INFLAMMATION UPON EXPOSURE TO POLLUTANTS. ACCORDINGLY, UNDERSTANDING THE MECHANISMS OF THE IL-1SS AND OTHER PATHWAYS WILL SIGNIFICANTLY BENEFIT CARDIOPULMONARY HEALTH SINCE THERAPIES ARE AVAILABLE TO BLOCK THIS PATHWAY AND SINCE KNOWLEDGE OF DIRECT MECHANISMS OF HOW AIR POLLUTION LEADS TO CARDIOPULMONARY DISEASES IS NEEDED TO SHAPE POLICY IN PUBLIC HEALTH. OUR CENTRAL OBJECTIVE IS TO TEST DISTINCT BUT INTERTWINED MECHANISTIC ASPECTS OF IL-1SS AND OTHER PATHWAY REGULATION IN INFLAMMATION-ASSOCIATED CARDIOPULMONARY PATHOLOGY LINKED TO AIR POLLUTION. WE WILL TEST THE HYPOTHESIS THAT THE IMMUNOPATHOLOGY OF CARDIOVASCULAR AND PULMONARY DISEASES ARE LINKED TO IL-1SS AND/OR OTHER PATHWAYS, AS WE HAVE PRELIMINARY DATA DEMONSTRATING ACTIVATION OF IL-1SS AND INFLAMMASOME, AND OTHER PATHWAYS IN AIR POLLUTION EXPOSURE, PARTICULARLY PM2.5. WE UNDERSTAND THERE ARE OTHER PATHWAYS OTHER THAN IL-1SS INVOLVED AND TO THIS END, WE HAVE PROPOSED UNBIASED, AGNOSTIC EXPERIMENTS IN ALL PROJECTS AND CORES, ESPECIALLY THE SYSTEMS BIOLOGY APPROACH OF PROJECT 2. FURTHERMORE, OUR DATA SHOW THE LINK OF IMMUNE PATHWAYS TO CLINICAL OUTCOMES, SUCH AS INCREASE SYSTOLIC BLOOD PRESSURE, IN YOUNG CHILDREN AND ADOLESCENTS EXPOSED TO AIR POLLUTION. WE HAVE CREATED SYNERGY AND DEPENDENCY OF ALL THE PROJECTS AND CORES SINCE WE USE ALL THE SAME SAMPLES FROM THE SAME COHORTS, WE SHARE DATA TO BE ABLE TO CREATE COMPOSITE BIOLOGICAL BIOMARKERS TO LINK PATHOLOGY TO DISEASE (I.E. ASTHMA OR INCREASED BLOOD PRESSURE). AS AN EXAMPLE OF OUR INNOVATION TOGETHER, WE HAVE PROPOSED USING INDUCED PLURIPOTENT STEM CELLS (IPSCS) IN BOTH LUNG AND HEART MODELS (PROJECTS 1 AND 3) TO SCREEN AND IDENTIFY AGENTS THAT BLOCK IL-1SS AND OTHER PATHWAY EFFECTS. OUR AIMS ARE: 1. DESCRIBE THE MECHANISMS UNDERLYING HEART, LUNG, AND IMMUNE DISEASES ASSOCIATED WITH AIR POLLUTION (PM2.5) EXPOSURE. WE WILL IDENTIFY AND CHARACTERIZE BIOMARKERS OF ACUTE AND CHRONIC ENVIRONMENTAL EXPOSURE TO AIR POLLUTION THAT PREDICT CARDIOPULMONARY DISEASES. 2. ENSURE THE EFFORTS OF THE THREE SCIENTIFIC PROJECTS AND PROJECT CORES WILL BE SYNERGISTIC, COORDINATED, AND INTEGRATED. WE DESCRIBE SPECIFICALLY HOW THE THREE PROJECTS AND CORES ARE SYNERGISTIC AND HOW WE WILL INTEGRATE OUR STUDY FINDINGS WITH OTHER EFFORTS TO INVESTIGATE IL-1SS AND OTHER PATHWAYS. 3: PROVIDE A HIGHLY INTERACTIVE, COLLABORATIVE, AND MULTI-DISCIPLINARY TEAM OF INVESTIGATORS AND RESOURCES TO SUPPORT OUR GOALS. WE DESCRIBE OUR MULTI-DISCIPLINARY FACILITIES AND INVESTIGATORS THAT WILL CONTRIBUTE TO THE OVERALL SUCCESS OF THE PPG, CALLED AIRHEALTH. IF OUR PROGRAM AND OVERALL AIMS ARE MET, WE WILL DEFINE THE MECHANISTIC LINKS OF LUNG AND HEART DISEASES WITH IL-1SS AND OTHER PATHWAYS, WHICH WILL LIKELY LEAD TO CLINICAL APP. OF BIOLOGICALS AND OTHER DRUGS IN INDIVIDUALS EXPOSED TO ACUTE AND/OR CHRONIC AIR POLLUTION.

PHARMACO RESPONSE SIGNATURES AND DISEASE MECHANISM

MECHANISMS AND IMMUNOLOGICAL CONSEQUENCES OF HOST-VIRUS INTERACTIONS

MECHANISMS OF YEAST TRANSCRIPTIONAL INITIATION

MOLECULAR BIOPHYSICS TRAINING GRANT

SENSORY TRANSDUCTION IN BACTERIAL CHEMOTAXIS

NEURODEVELOPMENTAL MECHANISMS UNDERLYING STRESS VULNERABILITY DURING ADOLESCENCE

MAPPING TRANSCRIPTIONAL NETWORKS IN CARDIAC DEVELOPMENT

OUTER MEMBRANE BIOGENESIS: NEW ANTIBIOTIC TARGETS

ASSURED MICROBIAL PRESERVATION IN HARSH OR REMOTE AREAS PROGRAM (AMPHORA)

HARVARD TRANSDISCIPLINARY RESEARCH IN ENERGETICS AND CANCER CENTER

BIOSTATISTICS/EPIDEMIOLOGY TRAINING GRANT IN BIOSTATISTICS

PROTEIN TRANSPORT ACROSS MEMBRANES

HIGH RESOLUTION CONNECTOMICS OF MAMMALIAN NEURAL CIRCUITS

COLLABORATIVE RESEARCH: ROBOBEES: A CONVERGENCE OF BODY, BRAIN AND COLONY

MRNA CAPPING ENZYME

BIOSTATISTICS/EPIDEMIOLOGY TRAINING GRANTS IN AIDS

MECHANISTIC PHARMACOLOGY OF ANTI-MITOTICS AND APOPTOSIS REGULATION

MEIOTIC CHROMOSOME SYNAPSIS AND RECOMBINATION IN YEAST

THE LONGITUDINAL AGING STUDY IN INDIA

PROJECT TITLE: PROSPECT: PUERTO RICO OBSERVATIONAL STUDY OF PSYCHOSOCIAL, ENVIRONMENTAL, AND CHRONIC DISEASE TRENDS

STATISTICAL METHODS FOR STUDIES OF RARE VARIANTS

MOLECULAR AND CELLULAR MECHANISMS OF VASCULAR ANOMALIES

COOPERATIVE AGREEMENT

PRE-CANCER ATLASES OF CUTANEOUS AND HEMATOLOGIC ORIGIN (PATCH CENTER)

A PROTEOMICS APPROACH TO PROTEIN UBIQUITINATION

GRADUATE TRAINING IN BIOSTATISTICS

CHIRAL CATALYSTS DESIGNED TO CATALYZE ORGANIC REACTIONS

CELLULAR AND DEVELOPMENTAL BIOLOGY

RANDOMIZED TRIAL OF HIGH-DOSE RIFAMPIN IN PATIENTS WITH NEW SMEAR-POSITIVE TB

INSTITUTIONAL CAREER DEVELOPMENT CORE

GENETIC DISSECTION OF AUDITORY CIRCUIT ASSEMBLY

UBIQUITIN-MEDIATED PROTEOLYSIS AND CELL CYCLE CONTROL

ENGINEERING A BACTERIAL REVERSE FUEL CELL

METALS AND METAL MIXTURES: COGNITIVE AGING, REMEDIATION AND EXPOSURE SOURCES (MEMCARE)

SCIENCE OF NANOSCALE SYSTEMS AND THEIR DEVICE APPLICATIONS NSEC

PEPTIDOGLYCAN BIOGENESIS IN ESCHERICHIA COLI

MAPPING PROTEIN COMMUNICATION BETWEEN ORGANS IN HOMEOSTASIS AND DISEASE

MOLECULAR BASIS OF VIRAL INFECTIVITY

CHARACTERIZATION OF THE INSULIN TO AUTOPHAGY PATHWAY IN MUSCLES

MULTI-ALLELIC COPY NUMBER VARIATION OF THE HUMAN GENOME

TAS::89 0222::TAS; NEW; ACTUATION OF BIOINSPIRED, ADAPTIVE "HAIRS" POWERED BY RESPONSIVE HYDROGELS; PI- JOANNA AIZENBERG

PEDIATRIC HIV/AIDS COHORT STUDY (PHACS): RESEARCH ON IMMUNE AGING, SUPPORTING REPRODUCTIVE HEALTH, AND PERINATAL ACQUISITION: ELUCIDATING RELATIONSHIPS IN HIV (RISE) - CUMULATIVE STRESS BURDEN OVER THE LIFE COURSE MAY ELEVATE THE RISK OF COMORBIDITIES, IMMUNE AGING, REPRODUCTIVE AGING, AND ADVERSE REPRODUCTIVE HEALTH OUTCOMES THAT OFTEN AFFECT PEOPLE WITH HIV (PWH), AND ESPECIALLY MEN AND WOMEN WITH PERINATALLY-ACQUIRED HIV (PHIV). THE CONCEPT OF ALLOSTATIC LOAD (AL) REFERS TO BIOLOGICAL RESPONSES TO CHRONIC STRESS, INCLUDING EXPOSURE TO ADVERSE NON-MEDICAL FACTORS. AL MAY EXPLAIN THE DEVELOPMENT OF ACCELERATED AGING AND COMORBIDITIES AMONG PWH, INCLUDING THOSE WITH PHIV, AS WELL AS THE ADVERSE HEALTH CONDITIONS EXPERIENCED BY POPULATIONS WITH EXPOSURE TO CHRONIC STRESS. FEW HIV RESEARCH PROGRAMS HAVE JOINTLY INVESTIGATED DRIVERS OF AGING AND POOR REPRODUCTIVE HEALTH IN YOUNGER PWH, INCLUDING THOSE WITH PHIV, THROUGH AN INTEGRATED APPROACH, APPLYING THE LENS OF CUMULATIVE STRESS (AL) AND NON-MEDICAL FACTORS. WITH THE PHACS RESEARCH ON IMMUNE AGING, SUPPORTING REPRODUCTIVE HEALTH, AND PERINATAL ACQUISITION: ELUCIDATING RELATIONSHIPS IN HIV (RISE) U19 PROGRAM, WE WILL CLOSE THIS GAP THROUGH TWO LINKED PROJECTS (PROJECT 1 – IMMUNE AGING; PROJECT 2 – REPRODUCTIVE HEALTH). THESE CUTTING-EDGE PROJECTS WILL BE SUPPORTED BY TWO CORES (SCIENTIFIC AND ADMINISTRATIVE CORE; DATA MANAGEMENT AND ANALYSIS CORE) TO PROMOTE HIGH-IMPACT SCIENCE THAT IMPROVES THE HEALTH OF PWH ACROSS THE LIFESPAN. AIM 1 OF THE PHACS RISE PROGRAM IS TO ASSEMBLE A PROSPECTIVE COHORT OF OVER 700 MEN AND WOMEN WITH PHIV AND WOMEN PWH (BOTH PHIV AND NON-PHIV [NPHIV]) ACROSS 7 US SITES. AIM 2 IS TO ELUCIDATE PATHWAYS OF CHRONIC STRESS (AS REFLECTED BY AL), IMMUNE AGING, AND COMORBIDITIES IN THE CONTEXT OF HIV, ART, PERINATAL HIV ACQUISITION, AND HIV VIRAL RESERVOIR BURDEN (PROJECT 1). AIM 3 IS TO ELUCIDATE PATHWAYS OF CHRONIC STRESS (AL), ADVERSE PREGNANCY OUTCOMES, REPRODUCTIVE AGING, AND HUMAN PAPILLOMA VIRUS PERSISTENCE IN THE CONTEXT OF HIV, ART, AND PERINATAL HIV ACQUISITION (PROJECT 2). THROUGH A CONSORTIUM OF SEVEN EXPERIENCED U.S.-BASED CLINICAL SITES AND AN EXPERT MULTIDISCIPLINARY TEAM OF INVESTIGATORS, WE WILL BUILD ON YEARS OF NIH INVESTMENT AND FOUNDATIONAL COHORTS IN PHACS. WE HAVE RE-DESIGNED THE PHACS NETWORK TO ESTABLISH A NEW, UNIFIED, AND STREAMLINED PROTOCOL, PHACS RISE. BY LEVERAGING WELL-CURATED EXISTING DATA, COMPREHENSIVELY PHENOTYPED COHORTS OF MEN AND WOMEN WITH PHIV, RICH SPECIMEN REPOSITORIES, AND THE ROBUST RESEARCH INFRASTRUCTURE OF PHACS, WE WILL ADVANCE RESEARCH IN PWH, INCLUDING THOSE WITH PHIV, TOWARDS DISCOVERY OF INSIGHTS AROUND THE DOWNSTREAM REPERCUSSIONS OF MODIFIABLE FACTORS. PHACS RISE AIMS TO BRIDGE GAPS IN KNOWLEDGE AROUND OUR CENTRAL THEME – THE INTERPLAY OF HIV, CHRONIC STRESS, AGING, AND REPRODUCTIVE HEALTH – AND INFORM FUTURE STUDIES AROUND PREVENTION AND POTENTIAL INTERVENTIONS AGAINST HIV AGING-RELATED COMORBIDITES AND ADVERSE REPRODUCTIVE HEALTH.

HARVARD PREVENTION RESEARCH CENTER ON NUTRITION AND PHYSICAL ACTIVITY-CATEGORY 1

BIOMATERIALS TO CREATE T CELL IMMUNITY

THE PRIMARY OBJECTIVE OF THE CENTER IS TO INVESTIGATE HEALTH EFFECTS OF AIR POLLUTION MIXTURES SOURCES AND INDIVIDUAL POLLUTANTS ACROSS LIFE STAGES

SCALING A NATIONAL MODEL OF READING ENGAGEMENT (MORE) TO IMPROVE FIRST TO FOURTH-GRADE STUDENTS’ READING COMPREHENSION

COMPARATIVE MODELING TO INFORM CERVICAL CANCER CONTROL POLICIES

GENETIC ANALYSIS OF TOXINOGENESIS IN VIBRIO CHOLERAE

RAPID TESTS FOR VIRUS GENES THAT SUPPRESS THE HOST ANTIVIRAL DEFENSES

DEFINING PATHWAYS FROM GENE MUTATION TO HEART FAILURE

GENOMIC TARGETS OF ONCOPROTEINS AND TUMOR SUPPRESSORS

THERE IS A COMPELLING NEED FOR INTENSIVE STUDY OF CONVECTIVE IMPACTS ON THE SUMMER STRATOSPHERE OVER NORTH AMERICA. EACH SUMMER THE NORTH AMERICAN MONSOON ANTICYCLONE (NAMA) DOMINATES THE CIRCULATION OF THE NORTH-WESTERN HEMISPHERE AND ACTS TO PARTIALLY CONFINE AND ISOLATE AIR FROM THE SURROUNDING ATMOSPHERE. STRONG CONVECTIVE STORMS IN THE NAMA REGULARLY PENETRATE DEEP INTO THE LOWER STRATOSPHERE (LS) WITH SOME ASCENDING ABOVE 20 KM (~450 K POTENTIAL TEMPERATURE). THE UNIQUENESS OF THE NAMA REGION IS MOST EASILY SEEN IN SATELLITE MEASUREMENTS OF WATER VAPOR WHICH SHOW A LARGE ENHANCEMENT IN THE LS OVER NORTH AMERICA NOT SEEN EITHER IN MAGNITUDE OR AT SUCH HIGH LATITUDES ELSEWHERE AROUND THE GLOBE. BUT THE COUPLING OF TROPOPAUSE-PENETRATING CONVECTION WITH LARGE-SCALE MONSOONAL MOTION IS POORLY UNDERSTOOD AS IS THE IMPACT OF CONVECTION ON THE CHEMICAL COMPOSITION OF THE LS BOTH IN MONSOON REGIONS AND IN THE GLOBAL STRATOSPHERE WHICH RECEIVES INPUTS OF MOIST AND POLLUTED MONSOON AIR FROM THE NAMA. THE DYNAMICS AND CHEMISTRY OF THE SUMMER STRATOSPHERE (DCOTSS) PROPOSAL DIRECTLY ADDRESSES THIS KNOWLEDGE GAP.

LINKING ASSESSMENT AND MEASUREMENT TO PERFORMANCE IN PHEP SYSTEMS (LAMPS)

FUNCTIONAL COUPLING OF STEPS IN GENE EXPRESSION

ENGINEERING SKELETAL MUSCLE WITH BIODEGRADABLE HYDROGELS

PREMENOPAUSAL HORMONE LEVELS AND RISK OF BREAST CANCER

MECHANISMS AND FUNCTIONS OF SYNAPSES AND CIRCUITS

REGIONAL AND GENETIC DIVERSITY OF CORTICAL INTERNEURONS

MURI FY21 TUNNELING PHENOMENA IN INTERFACE SUPERCONDUCTORS

"(MURI) NEW APPROACHES TO QUANTUM CONTROL WITH INDIVIDUAL MOLECULE SENSITIVITY" DATED 12 SEP 2019 (THE GRANTEE'S TECHNICAL PROPOSAL) IS HEREBY INCORPO

NEXT-GENERATION MATERIALS FOR OXYGEN GENERATION, TRANSPORT, AND STORAGE IN THE UNDERSEA ENVIRONMENT

QUANTUM OPTO-MECHANICS WITH ATOMS AND NANOSTRUCTURED DIAMOND: QOMAND

PCBS, PHTHALATES AND MALE REPRODUCTIVE HEALTH

"(MURI-FY07) QUANTUM SIMULATIONS OF CONDENSED MATTER SYSTEMS USING ULTRA-COLD ATOMIC GASSES METAMEDIA" (THE GRANTEE'S TECHNICAL PROPOSAL DATED 9 NOV

CHROMOSOME ORGANIZATION AND FUNCTION IN TIME AND SPACE: MEIOSIS, MITOSIS AND E.COLI