Trustees Of The University Of Pennsylvania

ABRAMSON CANCER CENTER OF THE U OF P CORE SUPPORT GRANT

INSTITUTIONAL CLINICAL AND TRANSLATIONAL SCIENCE AWARD

ALZHEIMER'S DISEASE GENETICS CONSORTIUM

CENTER FOR AIDS RESEARCH

INSTITUTIONAL CLINICAL AND TRANSLATIONAL SCIENCE AWARD

ARCHES: AUTONOMOUS RESILIENT COGNITIVE HETEROGENEOUS SWARMS

SCIENCE AND TECHNOLOGY CENTER FOR ENGINEERING MECHANO-BIOLOGY

THE NIA GENETICS OF ALZHEIMER'S DISEASE DATA STORAGE SITE

RESEARCH IN HIGH ENERGY PHYSICS AT THE UNIVERSITY OF PENNSYLVANIA

HUMAN PANCREAS ANALYSIS PROGRAM FOR TYPE 1 DIABETES - HPAP-T1D - THE HUMAN PANCREAS ANALYSIS PROGRAM FOR TYPE 1 DIABETES (HPAP-T1D) ABSTRACT IN 2016, THE NIH NIDDK SELECTED A MULTI-DISCIPLINARY TEAM OF INVESTIGATORS FROM THREE INSTITUTIONS (UPENN, VANDERBILT, UNIVERSITY OF FLORIDA) TO ESTABLISH THE PILOT PHASE OF THE HUMAN PANCREAS ANALYSIS PROGRAM (HPAP). OVER THE PAST THREE YEARS, TYPE 1 DIABETES (T1D)-RELEVANT TISSUES FROM MORE THAN 50 ORGAN DONORS WERE PROFILED AT THE ANATOMIC, PHYSIOLOGIC, METABOLIC, IMMUNOLOGIC, GENOMIC AND EPIGENOMIC LEVELS. THE RESULTING DATA WERE COMPILED AND ORGANIZED INTO THE PUBLICLY ACCESSIBLE PANC-DB DATABASE AND WEBSITE. HERE, WE PROPOSE NOT ONLY TO CONTINUE, BUT TO EXPAND OUR EFFORTS TO APPLY AND DEVELOP STATE-OF-THE-ART TECHNOLOGIES DESIGNED TO PHENOTYPE AND MOLECULARLY PROFILE HUMAN TISSUES RELEVANT TO THE ETIOLOGY OF T1D THROUGH A SERIES OF INNOVATIVE EFFORTS BY SIX CORES. CORE A (PANCREAS PROCUREMENT AND ISLET ISOLATION) WILL PROCURE/PROCESS PANCREATIC ISLETS, PANCREAS AND LYMPHOID ORGANS, EXPAND DONOR OUTREACH (IN COLLABORATION WITH THE WELL-ESTABLISHED NPOD PROGRAM) AND INCREASE THE COLLECTION OF NON-PANCREATIC TISSUES. CORE B (PHYSIOLOGICALPHENOTYPING)WILL PROVIDE A COMPREHENSIVE METABOLIC PROFILE AND PROBE THE KEY REGULATORY STEPS THAT GOVERN HORMONE SECRETION FROM THE MAJOR PANCREATIC ENDOCRINE CELL TYPES. CORE C (IMMUNOBIOLOGY) WILL DEVELOP AN IMMUNE ATLAS OF PERIPANCREATIC LYMPHOID POPULATIONS, OBTAIN TRANSCRIPTOMIC PROFILES OF THE T1D- SPECIFIC T CELLS, AND PERFORM IMMUNE REPERTOIRE PROFILING OF B AND T CELLS IN ASSOCIATION WITH SINGLE CELL AND ANTIGEN-SPECIFIC CELL APPROACHES. CORE D (ADVANCED MOLECULAR PROFILING) WILL PERFORM RNASEQ, ATACSEQ AND DNA METHYLOME ANALYSIS ON SORTED ALPHA-CELL, BETA-CELL AND EXOCRINE CELL POPULATION AS WELL AS SCRNASEQ AND SCATACSEQ AND CARRY OUT WHOLE GENOME SEQUENCING. IN ADDITION, ISLET ENDOCRINE AND MAJOR LYMPHOCYTE POPULATIONS WILL BE QUANTIFIED PRECISELY USING FLOW CYTOF. CORE E (TISSUE ANALYSIS & BIOBANKING) WILL ANALYZE PANCREATIC TISSUE ARCHITECTURE AND IMMUNE CELL/EPITHELIAL CELL INTERACTIONS USING MULTIPLE MODALITIES INCLUDING IMAGING MASS CYTOMETRY, MULTI-SPECTRAL IMAGING AND CODEX. COMPLETE IMAGE DATA WILL BE MADE AVAILABLE VIA PANCREATLASTM AND PANC-DB. FINALLY, CORE F (PANC-DB, DATA ANALYSIS AND INTEGRATION) WILL EXPAND THE PANC-DB RESOURCE BY ADDING NEW FEATURES THAT WILL MAKE THE PUBLIC WEB PAGE EVEN MORE USEFUL, AS WELL AS ADD A COMPUTATIONAL BIOLOGY AND DATA SCIENCE UNIT FOR APPLYING STATE-OF-THE-ART ANALYTICAL TOOLS, ALLOWING FOR THE INTEGRATION AND VISUALIZATION OF GENERATED DATASETS USING DIFFERENT EXPERIMENTAL MODALITIES SUCH AS MULTI-SPECTRAL IMAGING AND OMICS TECHNOLOGIES. IN ADDITION, CORE F WILL CONTINUE TO EXPAND ITS OUTREACH ACTIVITIES, EXEMPLIFIED VIA THE DEPOSITION OF TRANSCRIPTOME AND EPIGENOME DATA INTO THE DIABETES EPIGENOME ATLAS (DGA). HPAP-T1D WILL BE DIRECTED BY AN EXPERIENCED, COLLABORATIVE MULTI-PI TEAM THAT CONFERS WEEKLY AND WILL MEET IN-PERSON ON A BIANNUAL BASIS IN COORDINATION WITH NIDDK LEADERSHIP TO REVIEW THE PROGRESS OF THE ENTIRE PROGRAM.

INSTITUTIONAL CLINICAL AND TRANSLATIONAL SCIENCE AWARD

MID-SCALE RI-2: ADVANCED MILLIMETER SURVEY INSTRUMENTATION IN CHILE -LARGE SCALE MILLIMETER-WAVE SURVEYS OF THE SKY AT HIGH RESOLUTION, DESIGNED TO EXPLORE THE ORIGIN AND EVOLUTION OF THE UNIVERSE, CAN ADDRESS A WIDE RANGE OF PRESSING SCIENCE QUESTIONS. THE NEXT GENERATION OF COSMIC MICROWAVE BACKGROUND (CMB) INSTRUMENTS WILL REVEAL MUCH ABOUT THE ORIGIN AND EVOLUTION OF THE UNIVERSE, ABOUT THE FUNDAMENTAL PHYSICS DRIVING ITS BIRTH AND GROWTH, AND ABOUT ITS DYNAMIC CONTENTS AS THEY INTERACT AND CHANGE. ACHIEVING THESE GOALS REQUIRES A SIGNIFICANT IMPROVEMENT BOTH IN INSTRUMENTAL CAPABILITIES AND IN DATA PIPELINES. BUILDING ON SIGNIFICANT INVESTMENT BY THE SIMONS FOUNDATION (SF) IN THE SIMONS OBSERVATORY (SO), THIS AWARD PROVIDES THREE ADVANCED SO (ASO) DELIVERABLES, WHICH WILL INCREASE THE SCIENTIFIC REACH, INCREASE ACCESS TO THE WIDER COMMUNITY NOT EXPERT IN THE INSTRUMENTATION, AND DECREASE THE ENVIRONMENTAL IMPACT OF THE FACILITY AND IMPROVE RELATIONS WITH THE HOST COUNTRY OF CHILE. THERE ARE EXTENSIVE PLANS FOR PUBLIC OUTREACH AND THE TRAINING OF EARLY CAREER RESEARCHERS DURING THE SURVEY ACTIVITY ONCE ASO IS OPERATIONAL. MEANWHILE, IMPLEMENTATION OF THE INFRASTRUCTURE INVOLVES MORE THAN A DOZEN GRADUATE STUDENTS AND AROUND TEN POSTDOCS, AS KEY PLAYERS. THERE WILL BE OPPORTUNITIES FOR YOUNG PHYSICISTS TO WORK WITH SO SCIENTISTS ON SUMMER ACTIVITIES, AND EXTENSIVE TRAINING ON THE ASO INFRASTRUCTURE, MENTORED BY SO SCIENTISTS IN A COLLABORATION WITH THE SIMONS FOUNDATION AND THE NATIONAL SOCIETY OF BLACK PHYSICISTS. THE CONTRIBUTIONS FROM THIS AWARD ARE: (I) 30,000 NEW DETECTORS AND ASSOCIATED OPTICS FOR THE SO SIX-METER DIAMETER LARGE APERTURE TELESCOPE, DOUBLING ITS MAPPING SPEED AND ENABLING THE DETECTION OF TRANSIENT OBJECTS; (II) AN END-TO-END DATA PIPELINE TO PRODUCE AND VALIDATE MAPS OF ALL SO DATA, AND GENERATE DAILY LIGHT-CURVES OF VARIABLE SOURCES CONCURRENT WITH OTHER SURVEYS SUCH AS THOSE FROM THE RUBIN OBSERVATORY, AND (III) A PHOTOVOLTAIC POWER SYSTEM THAT DIRECTLY INCREASES SYSTEM SENSITIVITY WHILE REDUCING OPERATING COSTS AND ENVIRONMENTAL IMPACT. THIS INFRASTRUCTURE IS CRUCIAL TO THE SURVEY GOAL, TO PRODUCE MILLIMETER-WAVE MAPS OF THE SKY ON A REGULAR CADENCE. SUCH MAPS ARE A CRITICAL PART OF THE SEARCH FOR PRIMORDIAL GRAVITATIONAL WAVES, BUT ALSO HELP UNDERSTANDING OF GALAXY EVOLUTION AND THE ROLE OF MAGNETIC FIELDS. ANALYSIS WILL: (1) REVEAL PHYSICAL CONDITIONS IN THE EARLY UNIVERSE AND CONSTRAIN ANY NEW LIGHT PARTICLES; (2) MEASURE THE DISTRIBUTION OF MASS, ELECTRON PRESSURE, AND ELECTRON MOMENTUM IN THE MORE RECENT UNIVERSE, AND COMBINE WITH LARGE-SCALE STRUCTURE SURVEYS TO DETERMINE THE NEUTRINO MASS AND THE EFFECTS OF DARK ENERGY; (3) MEASURE THE DISTRIBUTION OF ELECTRON DENSITY AND PRESSURE AROUND GALAXY GROUPS AND CLUSTERS; (4) USE THE THERMAL SUNYAEV-ZEL?DOVICH EFFECT TO FIND MORE THAN 30,000 GALAXY CLUSTERS AND MORE THAN 100,000 EXTRAGALACTIC MILLIMETER SOURCES; (5) MEASURE THE ALIGNMENT OF DUST BY MAGNETIC FIELDS IN OUR GALAXY; AND (6) REVEAL NEW FEATURES OF THE TRANSIENT UNIVERSE CONCURRENT WITH OPTICAL OBSERVATIONS. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.

SHIV/HIV ENV-ANTIBODY COEVOLUTION AS A GUIDE TO ITERATIVE VACCINE DESIGN

GLOBAL AUTONOMOUS LANGUAGE EXPLOITATION (GALA)

UNIV OF PENNSYVANIA DIABETES ENDOCRINOLOGY RES CTR

MEDICAL SCIENTIST TRAINING PROGRAM

PENN PREVENTION CLINICAL TRIALS UNIT

COORDINATING CENTER FOR GENETICS AND GENOMICS OF ALZHEIMER'S DISEASE (CGAD)

TESTERONE TRIAL

CENTER WITHOUT WALLS FOR IMAGING PROTEINOPATHIES WITH PET (CW2IP2)

NSF ENGINEERING RESEARCH CENTER FOR THE INTERNET OF THINGS FOR PRECISION AGRICULTURE (IOT4AG)

ASIAN COHORT FOR ALZHEIMER'S DISEASE (ACAD) - OVERALL ABSTRACT ALZHEIMER’S DISEASE (AD) AFFECTS 5.8 MILLION PEOPLE IN THE UNITED STATES AND IS AN IMMENSE BURDEN ON OUR ECONOMY, PATIENTS AND CAREGIVERS. GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE SUCCESSFULLY LED TO 25 GENOME-WIDE SIGNIFICANT LOCI ASSOCIATED WITH AD RISK AND MANY MORE ASSOCIATIONS WITH KEY CLINICAL COVARIATES. MOST OF THESE FINDINGS ARE MADE ON PARTICIPANTS WITH EUROPEAN ANCESTRY, ALTHOUGH EFFORTS TO STUDY OTHER MINORITY POPULATIONS ARE TAKING OFF. KNOWLEDGE ABOUT AD GENETICS AMONG ASIAN AMERICANS IS ESPECIALLY LIMITED DUE TO LACK OF PARTICIPANTS. COMPRISING 6% OF THE US POPULACE, ASIAN AMERICANS ARE UNDER-SAMPLED AND DESERVE MORE SCIENTIFIC INVESTMENT. WE PROPOSE THE ASIAN COHORT FOR ALZHEIMER’S DISEASE (ACAD), THE FIRST LARGE ALZHEIMER’S DISEASE (AD) GENETICS COHORT FOR ASIANS IN UNITED STATES (US) AND CANADA. TO ADDRESS RECRUITMENT BARRIERS, WE ASSEMBLED A TEAM OF SCIENTISTS, CLINICIANS, AND COMMUNITY PARTNERS WITH COLLABORATIVE HISTORY AND EXPERTISE IN AD RESEARCH, HUMAN GENETICS, AND ASIAN COMMUNITY OUTREACH. WE PROPOSE TO RECRUIT 5,081 PARTICIPANTS AGED 60 YEARS OR OLDER AND OF CHINESE, KOREAN, AND VIETNAMESE ANCESTRY FROM METROPOLITAN AREAS ACROSS US AND CANADA IN COLLABORATION WITH COMMUNITY HEALTH PROVIDERS OR LONG-TERM CARE FACILITIES THAT SERVE ASIAN COMMUNITIES. WE WILL COLLECT DNA AND PLASMA BIOMARKERS AND USE VALIDATED, TRANSLATED DATA COLLECTION FORMS AND CLINICAL/DIAGNOSTIC PROTOCOLS. TO SUPPORT THESE RECRUITMENT AND DATA COLLECTION ACTIVITIES, WE WILL FORM SIX CORES THAT PROVIDE ADMINISTRATIVE OVERSITE, OUTREACH, CLINICAL EXPERTISE, DATA MANAGEMENT, BIOSAMPLE MANAGEMENT, AND TRAINING AND QUALITY ASSURANCE TO SUPPORT RECRUITMENT AND ANALYSIS ACTIVITIES. ALL SAMPLES WILL BE GENOTYPED USING SNP ARRAYS AND IMPUTED USING A LARGE ASIAN-SPECIFIC REFERENCE PANEL OF WHOLE GENOME SEQUENCING DATA FROM INTERNATIONAL ASIAN COHORTS. WE PROPOSE TWO RESEARCH PROJECTS THAT WILL ANALYZE GENETIC, BIOMARKER AND CLINICAL DATA TO INVESTIGATE IMPACT OF LIFESTYLE RISK FACTORS, GENETIC VARIANTS FOR AD RISK, EVALUATE DIFFERENTIAL EFFECTS OF SEX AND APOE GENOTYPES ON AD RISK, AND PREDICT CLINICAL DIAGNOSIS OF AD USING GENETIC AND LIFESTYLE RISK SCORES. WE WILL REPLICATE THESE FINDINGS THROUGH META-ANALYSIS COLLABORATIONS WITH INTERNATIONAL ASIAN COHORTS AND AD STUDIES FROM OTHER POPULATIONS.

SCIENTIFIC AND DATA COORDINATING CENTER(SDCC) FOR THE P*

CENTER OF EXCELLENCE IN ENVIRONMENTAL TOXICOLOGY

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP) -THE NATIONAL SCIENCE FOUNDATION (NSF) GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP) IS A HIGHLY COMPETITIVE, FEDERAL FELLOWSHIP PROGRAM. GRFP HELPS ENSURE THE VITALITY AND DIVERSITY OF THE SCIENTIFIC AND ENGINEERING WORKFORCE OF THE UNITED STATES. THE PROGRAM RECOGNIZES AND SUPPORTS OUTSTANDING GRADUATE STUDENTS WHO ARE PURSUING RESEARCH-BASED MASTER'S AND DOCTORAL DEGREES IN SCIENCE, TECHNOLOGY, ENGINEERING, AND MATHEMATICS (STEM) AND IN STEM EDUCATION. THE GRFP PROVIDES THREE YEARS OF FINANCIAL SUPPORT FOR THE GRADUATE EDUCATION OF INDIVIDUALS WHO HAVE DEMONSTRATED THEIR POTENTIAL FOR SIGNIFICANT RESEARCH ACHIEVEMENTS IN STEM AND STEM EDUCATION. THIS AWARD SUPPORTS THE NSF GRADUATE FELLOWS PURSUING GRADUATE EDUCATION AT THIS GRFP INSTITUTION. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.

EPIGENETICS OF AGING AND AGE-ASSOCIATED DISEASES

RESEARCH IN HIGH-ENERGY PHYICS

FRONTOTEMPORAL DEMENTIAS: GENOTYPES AND PHENOTYPES

ALZHEIMER'S DISEASE CORE CENTER

THE HUMAN PANCREAS ANALYSIS PROGRAM FOR TYPE 2 DIABETES

ENDOPHENOTYPES OF SLEEP APNEA AND ROLE OF OBESITY

CENTER FOR DIGESTIVE AND LIVER DISEASES

MATERIALS RESEARCH SCIENCE AND ENGINEERING CENTER

DNA VIRUS AS VECTORS FOR CARDIOVASCULAR DISEASES

HEERF FUNDING - INSTITUTIONAL

PENN MENTAL HEALTH AIDS RESEARCH CENTER

CENTER OF EXCELLENCE FOR MATERIALS RESEARCH AND INNOVATION

ENHANCING CHIMERIC ANTIGEN RECEPTOR T CELL THERAPIES FOR HEMATOLOGIC MALIGNANCIES: BEYOND CART 19

PENN ARTIFICIAL INTELLIGENCE AND TECHNOLOGY COLLABORATORY FOR HEALTHY AGING - THE OVERARCHING GOAL OF OUR PROPOSED PENN ARTIFICIAL INTELLIGENCE AND TECHNOLOGY (PENNAITECH) COLLABORATORY IS TO IDENTIFY, DEVELOP, EVALUATE, COMMERCIALIZE, AND DISSEMINATE INNOVATIVE TECHNOLOGY FOR MONITORING AGING ADULTS AND THOSE WITH ALZHEIMER’S DISEASE (AD) AND ALZHEIMER’S DISEASE RELATED DEMENTIAS (ADRD) IN THEIR HOME ENVIRONMENT AND THE ARTIFICIAL INTELLIGENCE (AI) METHODS AND SOFTWARE FOR ANALYZING DATA GENERATED BY THOSE TECHNOLOGIES. THE COLLABORATORY IS MOTIVATED BY THE NEED FOR A COMPREHENSIVE PIPELINE FROM TECHNOLOGY-BASED MONITORING OF AGING ADULTS IN THE HOME, COLLECTION AND PROCESSING MONITORING DATA, INTEGRATION OF THOSE DATA WITH CLINICAL DATA FROM ELECTRONIC HEALTH RECORDS, ANALYSIS WITH CUTTING-EDGE AI METHODS AND SOFTWARE, AND DEPLOYMENT OF VALIDATED AI MODELS AT POINT OF CARE FOR DECISION SUPPORT. WE HAVE ASSEMBLED A TEAM OF EXPERTS WITH EXPERIENCE BUILDING AND IMPLEMENTING EACH COMPONENT OF THIS PIPELINE AND WILL PROMOTE THIS VISION AND EXISTING TOOLS AND SOFTWARE (AIM 1). A CENTRAL FOCUS OF THE PENNAITECH COLLABORATORY IS TO ADVANCE THIS VISION THROUGH THE SOLICITATION, REVIEW, AND FUNDING OF PILOT GRANTS FOCUSED ON TECHNOLOGY AND AI DEVELOPMENT TO ADVANCE THE SCIENCE OF CARE MANAGEMENT AND AGING IN PLACE FOR VULNERABLE OLDER ADULTS OR THOSE WITH AD/ADRD RECEIVING SKILLED HOME AND COMMUNITY-BASED SERVICES (AIM 2). FUNDED PILOT PROJECTS WILL BE SUPPORTED IN AIM 3 THROUGH CORES FOCUSED ON ADMINISTRATION (CORE A), STAKEHOLDER ENGAGEMENT (CORE B), TECHNOLOGY IDENTIFICATION AND TRAINING (CORE C), CLINICAL TRANSLATION AND VALIDATION (CORE D), NETWORKING (CORE E), AND ETHICAL AND POLICY ISSUES (CORE H). FINALLY, THE COLLABORATORY WILL WORK CLOSELY WITH THE PLANNED COORDINATING CENTER TO FACILITATE THE SUCCESS AND TRANSLATION OF ALL COLLABORATORY PROJECTS (AIM 4). WE ARE COMMITTED TO IMPROVING THE HEALTH OF AGING ADULTS AND THOSE WITH AD/ADRD THROUGH THESE SPECIFIC AIMS.

MEMORY ENHANCEMENT WITH MODELING, ELECTROPHYSIOLOGY, AND STIMULATION (MEMES)

CONTINUATION OF THE COORDINATING CENTER FOR THE CHRONIC RENAL INSUFFICIENCY COHORT (CRIC) STUDY

REGULATION OF PLATELET AND ENDOTHELIAL CELL FUNCTION

GRADUATE RESEARCH FELLOWSHIP PROGRAM(GRFP)

AUTOLOGOUS CHIMERIC ANTIGEN RECEPTOR ENGINEERED T CELL IMMUNOTHERAPY FOR DESENSITIZATION IN PATIENTS AWAITING KIDNEY TRANSPLANTATION - ABSTRACT KIDNEY TRANSPLANT IS THE TREATMENT OF CHOICE FOR PATIENTS WITH END-STAGE RENAL DISEASE (ESRD), AS IT EXTENDS SURVIVAL, IMPROVES QUALITY OF LIFE AND IS HIGHLY COST-EFFECTIVE. HOWEVER, FOR ABOUT A THIRD OF PATIENTS ON THE WAITLIST, PRE-EXISTING ANTI-HLA ANTIBODIES (I.E. ALLO-SENSITIZATION) PRESENTS A MAJOR BARRIER TO SUCCESSFUL TRANSPLANT. HLA ANTIBODY RESPONSES ARE MAINTAINED BY MEMORY B CELLS (BMEM) AND PLASMA CELLS (PC). UNFORTUNATELY, DESENSITIZATION APPROACHES HAVE BEEN LARGELY INEFFECTIVE DUE TO INCOMPLETE DEPLETION OF ALLO-SPECIFIC B CELLS AND PCS. WE HYPOTHESIZE THAT STRINGENT DEPLETION OF DONOR-SPECIFIC B CELLS AND PCS IS REQUIRED FOR A CLINICALLY SIGNIFICANT REDUCTION OF ALLO-ANTIBODIES NECESSARY TO ACHIEVE SUCCESSFUL KIDNEY TRANSPLANTATION. WE HAVE SHOWN THAT ENGINEERED T CELL IMMUNOTHERAPIES EMPLOYING SYNTHETIC CHIMERIC ANTIGEN RECEPTORS (CARS) CAN INDUCE DURABLE REMISSION OF B CELL LINEAGE AND PLASMA CELL MALIGNANCIES. TWO CAR-T CELL THERAPIES THAT TARGET CD19 (CART-19) AND B CELL MATURATION ANTIGEN (CART-BCMA) RESULT IN DEPLETION OF MALIGNANT CELLS BUT ALSO PHYSIOLOGIC B CELLS AND PCS. IMPORTANTLY, WE HAVE SHOWN THAT CART-BCMA AND CART-19 CAN BE SAFELY ADMINISTERED TOGETHER. BASED ON THIS EXPERIENCE, OUR GOAL IS TO LEVERAGE THIS INNOVATIVE PLATFORM TO TARGET BMEM AND PCS AND PROMOTE REDUCTION OF PREFORMED ANTI-HLA ANTIBODIES, THUS PROVIDING A WINDOW OF OPPORTUNITY FOR TRANSPLANTATION. SPECIFICALLY, WE PROPOSE A SINGLE-ARM PROOF-OF-CONCEPT CLINICAL TRIAL THAT COMBINES CART-19 WITH CART-BCMA AS A NOVEL DESENSITIZATION MEASURE IN KIDNEY TRANSPLANT CANDIDATES WITH A CPRA =99.9%. MECHANISTIC STUDIES WILL EVALUATE THE CELLULAR, HUMORAL AND MOLECULAR IMMUNE CORRELATES OF CART-19 + CART-BCMA IMMUNOTHERAPY IN HIGHLY SENSITIZED KIDNEY TRANSPLANT CANDIDATES. THESE ARE FOCUSED ON THE CAR T CELLS, T- AND B-CELL IMMUNITY (BOTH ALLO-SPECIFIC AND PROTECTIVE) AND, IN THE EVENT OF SUCCESSFUL TRANSPLANTATION, THE ALLOGRAFT BIOLOGY. AN INFECTIOUS DISEASE STUDY PROPOSAL WILL EVALUATE VACCINE RESPONSE AND IMMUNE FUNCTION IN OUR RENAL TRANSPLANT CANDIDATES, INCLUDING OUR STUDY COHORT. THE MULTI-CENTER TEAM (PENN, NYU, MGH) BRINGS TOGETHER INVESTIGATORS WITH EXTENSIVE EXPERIENCE IN CART THERAPY, DESENSITIZATION, AND OUTSTANDING DEPTH OF LABORATORY EXPERTISE TO CARRY OUT ROBUST MECHANISTIC STUDIES.

PARKINSON'S DISEASE AND DEMENTIA

EXAMINING THE EFFECTS OF ADVERTISING, PACKAGING AND LABELING ON PERCEPTIONS, USE AND EXPOSURE OF COMBUSTIBLE TOBACCO PRODUCTS

PERSONALIZATION OF THERAPEUTIC EFFICACY AND RISK

UPENN TCORS: TOBACCO PRODUCT MESSAGING IN A COMPLEX COMMUNICATION ENVIRONMENT

PRIMARY OPEN ANGLE AFRICAN-AMERICAN GLAUCOMA GENETICS (POAAGG)

INSTITUTIONAL RESEARCH AND ACADEMIC CAREER DEVELOPMENT AWARD

HEERF FUNDING - STUDENT SUPPORT

PENN INTEGRATED HUMAN PANCREAS PROCUREMENT AND ANALYSIS PROGRAM

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

PHOTODYNAMIC THERAPY FOR NEOPLASTIC DISEASES INVOLVING SEROSAL SURFACES

MAPP RESEARCH NETWORK

CENTER ON ALPHA-SYNUCLEIN STRAINS IN ALZHEIMER DISEASE & RELATED DEMENTIAS

PHARMACOGENETICS OF NICOTINE ADDICTION AND TREATMENT

PENN-CHOP ECHO - EARLY EXPOSURES AFFECT HEALTH ACROSS THE LIFE COURSE. EXTENSIVE HEALTHCARE EFFORTS HAVE BEEN MADE TO PREVENT ADVERSE PREGNANCY OUTCOMES AND TO OPTIMIZE CHILD GROWTH, HEALTH, AND NEURODEVELOPMENT. HOWEVER, BIRTH AND CHILDHOOD OUTCOMES REMAIN MAJOR AREAS OF PUBLIC HEALTH CONCERN. MACROENVIRONMENTAL HEALTH PROMOTING FACTORS (GREENSPACE, WALKABILITY) AND HEALTH THREATENING FACTORS (NEIGHBORHOOD CONDITIONS) MAY AFFECT HEALTH DIRECTLY THROUGH INFLAMMATORY AND IMMUNOLOGIC PATHWAYS. MACROENVIRONMENTS MAY ALSO CONTRIBUTE TO LIVED EXPERIENCES OF INCOME POTENTIAL AND EDUCATIONAL ATTAINMENT. COMBINED WITH INTERPERSONAL INDIVIDUAL EXPOSURES, MACROENVIRONMENTS MAY ALTER INDIVIDUALS’ MICROENVIRONMENTAL HEALTH FACTORS SUCH AS DIET, PHYSICAL ACTIVITY, PSYCHOSOCIAL STRESS, AND SLEEP. WHILE MACRO- AND MICROENVIRONMENTAL EXPOSURES HAVE BEEN STUDIED INDIVIDUALLY, THE IMPACT OF NEIGHBORHOOD ENVIRONMENTS ON COMPLEX HEALTH DISORDERS IN PREGNANCY AND EARLY CHILDHOOD REMAINS UNDERSTUDIED AND THE INTERPLAY WITH MICROENVIRONMENTAL FACTORS IS UNKNOWN. WE PROPOSE A CAUSAL INFERENCE FRAMEWORK TO EVALUATE THE ROLE OF SPECIFIC MACROENVIRONMENT FACTORS (AIM 1) TO REDUCE THE RISKS OF ABNORMAL FETAL GROWTH, PRETERM BIRTH, OBESITY, ASTHMA, AND NEURODEVELOPMENTAL DELAYS BY AGE 3. WE WILL ALSO IDENTIFY OPTIMAL COMPONENTS OF MICROENVIRONMENTAL FACTORS OF DIET, PHYSICAL ACTIVITY, AND SLEEP, DURING PREGNANCY (AIM 2) AND AMONG COUPLES DURING PRECONCEPTION (AIM 4), THAT CAN BEST BE UTILIZED TO MAXIMIZE REDUCTIONS IN ADVERSE MATERNAL AND CHILD HEALTH OUTCOMES. WE HAVE ASSEMBLED A MULTIDISCIPLINARY TEAM OF EXPERTS AT THE UNIVERSITY OF PENNSYLVANIA AND CHILDREN’S HOSPITAL OF PHILADELPHIA WHO ARE WELL-POSITIONED TO COMPLETE THE STUDY AND RECRUIT UP TO 2500 PREGNANT WOMEN, PARTNERS, AND OFFSPRING, WITH RETENTION OF AT LEAST 75% AT AGE 3 IN A POPULATION REFLECTIVE OF THE PHILADELPHIA COMMUNITY (AIM 3). THE CULTURE OF CLINICAL RESEARCH AND EXCELLENT SCIENTIFIC ENVIRONMENT MAKES PENN AND CHOP THE IDEAL PLACE TO INNOVATE IN THE FIELD OF MATERNAL-CHILD HEALTH. THE PENN-CHOP ECHO STUDY TEAM IS COMMITTED TO THE SUCCESS OF THIS WORK AND LOOKS FORWARD TO WORKING COLLABORATIVELY WITH THE OTHER ECHO STUDY SITES, COORDINATING CENTERS, AND CORES.

FROM CELLS TO COMPLEX SYNDROMES: USING NETWORKS TO UNDERSTAND HETEROGENEITY IN TDP-RELATED FRONTOTEMPORAL DEGENERATION AND AGING

PENN ALZHEIMER'S DISEASE RESEARCH CENTER (ADRC) - PENN ADRC OVERALL PROJECT SUMMARY THE MISSION OF THE UNIVERSITY OF PENNSYLVANIA’S ALZHEIMER’S DISEASE RESEARCH CENTER (PENN ADRC) IS TO INCREASE RESEARCH AND EDUCATION ON ALZHEIMER’S DISEASE (AD) AND ITS LINKS TO RELATED DEMENTIAS (ADRD) WITH THE GOAL OF IDENTIFYING THE CAUSES OF AND CURES FOR AD/ADRD. TO DO SO, THE PENN ADRC WILL ADDRESS ONE OF THE FUNDAMENTAL BARRIERS TO EFFECTIVE TREATMENT OR PREVENTION, WHICH IS THE SIGNIFICANT PHENOTYPIC, PATHOLOGICAL, AND SOCIODEMOGRAPHIC HETEROGENEITY OF AD. WE WILL EMBRACE AND SEEK TO CHARACTERIZE AND UNDERSTAND THIS HETEROGENEITY TO ULTIMATELY ACHIEVE A PRECISION MEDICINE APPROACH LEADING TO TARGETED INTERVENTIONS THAT WILL FACILITATE REALIZATION OF THE NATIONAL ALZHEIMER’S PROJECT ACT’S (NAPA) AMBITIOUS GOAL OF EFFECTIVE PREVENTION OR TREATMENT BY 2025. INDEED, THE PENN ADRC IS CONSTRUCTED TO DIRECTLY CONTRIBUTE TO A NUMBER OF THE MILESTONES OF NAPA NECESSARY TO ACHIEVE THIS GOAL. EMERGING FROM THE 30-YEAR HISTORY OF THE PENN ALZHEIMER’S DISEASE CORE CENTER (ADCC), THE PENN ADRC BENEFITS FROM A RICH SCIENTIFIC MILIEU IN WHICH THERE IS SIGNIFICANT INTEGRATION AND COLLABORATION ACROSS PENN’S NEURODEGENERATIVE DISEASE CENTERS. THIS CONSTRUCTION IS CRITICAL TO THE UNDERSTANDING OF AD HETEROGENEITY WHICH IS DRIVEN, IN PART, BY OVERLAPPING PATHOLOGIES AND MECHANISMS, SUCH THAT CROSS-DEGENERATIVE DISEASE STUDIES ARE OF INCREASING IMPORTANCE IN CAPTURING THE FULL SPECTRUM OF DISEASE. THIS ENVIRONMENT HAS LED TO A HISTORY OF TRANSFORMATIVE RESEARCH THAT HAS INFLUENCED UNDERSTANDING OF DISEASE DEFINITION AND MECHANISMS, DIAGNOSTIC APPROACHES AND BIOMARKER DEVELOPMENT, STATISTICAL AND BIOINFORMATICS METHODOLOGY, AND ETHICAL, SOCIAL AND LEGAL PERSPECTIVES OF THOSE SUFFERING FROM THIS CONDITION AND THEIR CARE PARTNERS. IT HAS ALSO CREATED AN INTELLECTUAL, CULTURAL, AND PHYSICAL SETTING DEDICATED TO TRAINING THE NEXT GENERATION OF INVESTIGATORS AND CLINICIANS, AS WELL AS PARTNERING AND EDUCATING THE COMMUNITY. TO ACHIEVE OUR MISSION, THE PENN ADRC WILL BRING TOGETHER EIGHT CORES (ADMINISTRATIVE; BIOMARKER; CLINICAL; DATA MANAGEMENT AND STATISTICAL; GENOMICS; NEUROIMAGING; NEUROPATHOLOGY; OUTREACH, RECRUITMENT, AND ENGAGEMENT) AND THE RESEARCH EDUCATION COMPONENT (REC). THESE HIGHLY INTEGRATED CORES WILL SUPPORT DEVELOPMENT OF A PHENOTYPICALLY, PATHOLOGICALLY, AND ETHNO-RACIALLY DIVERSE COHORT WHICH WILL BE DEEPLY CHARACTERIZED THROUGH COGNITIVE ASSESSMENTS, MEASURES OF SOCIAL DETERMINANTS OF HEALTH, GENETICS, BIOFLUID AND NEUROIMAGING BIOMARKERS, AND AUTOPSY. ALL THESE DATA WILL BE STORED WITHIN THE INTEGRATED NEURODEGENERATIVE DISEASE DATABASE (INDD), WHICH IS LINKED TO THE OTHER NEURODEGENERATIVE CENTERS AT PENN AND WILL CONTRIBUTE TO OUR UNDERSTANDING OF THE UPSTREAM FACTORS AND PROCESSES THAT LEAD TO AD HETEROGENEITY AND ITS DOWNSTREAM MANIFESTATIONS. FURTHER, THE ADRC SUPPORTS ROBUST SHARING OF THESE DATA AND PARTICIPATION IN LARGER NIA AND NATIONAL PROGRAMS. THE REC LEVERAGES THESE CORES AND THEIR RESEARCH PROGRAMS FOR TRAINING NEW INVESTIGATORS. TOGETHER, THE PENN ADRC WILL ADVANCE OUR ULTIMATE MISSION TO REDUCE THE TREMENDOUS BURDEN OF AD.

MOLECULAR MOTORS IN CELL BIOLOGY

IMPLEMENTATION OF PROLONGED EXPOSURE IN THE ARMY: IS CONSULTATION NECESSARY FOR EFFECTIVE DISSEMINATION

DIFFERENTIATED FUNCTION OF TISSUES INVOLVED IN NUTRITION AND METABOLISM

COMPLEMENT IN CELL PROLIFERATION AND INJURY-THERAPEUTIC INTERVENTIONS

MRSEC: MATERIALS RESEARCH SCIENCE AND ENGINEERING CENTER

PENN INNOVATION IN SUICIDE PREVENTION IMPLEMENTATION RESEARCH (INSPIRE) CENTER - THIS PROPOSAL IS TO DEVELOP THE UNIVERSITY OF PENNSYLVANIA’S INNOVATION IN SUICIDE PREVENTION IMPLEMENTATION RESEARCH (INSPIRE) CENTER. SUICIDE IS A LEADING CAUSE OF DEATH IN THE US THAT DISPROPORTIONATELY AFFECTS MINORITY AND DISENFRANCHISED POPULATIONS, INCLUDING BLACKS, HISPANICS AND SEXUAL/GENDER MINORITIES. YET, THESE GROUPS OFTEN ARE NOT INCLUDED IN SUICIDE PREVENTION RESEARCH. GUIDED BY A CONCEPTUAL MODEL BASED ON THE INTEGRATED BEHAVIOR MODEL, WHICH POSITS THAT ORGANIZATIONAL CULTURE, POLICIES, AND RESOURCES (OR LACK THEREOF) IMPACT THE PROVIDER’S ATTRIBUTES AND BEHAVIORS, INSPIRE BRINGS TOGETHER PSYCHOLOGY, IMPLEMENTATION SCIENCE, HEALTH ECONOMICS, MACHINE LEARNING, HEALTH INFORMATION TECHNOLOGY, PSYCHIATRY AND PARTICIPATORY RESEARCH EXPERTS TO APPLY INNOVATIVE INTERDISCIPLINARY APPROACHES TO SUICIDE PREVENTION. INSPIRE’S OVERARCHING GOALS ARE TO DEVELOP AND ADAPT PRACTICE-BASED AND OTHER SUICIDE PREVENTION INTERVENTIONS FOR UNDERSERVED GROUPS AND TO DESIGN AND TEST IMPLEMENTATION STRATEGIES TO OPTIMIZE HOW EVIDENCE-BASED PRACTICES CAN BE BROUGHT TO SCALE EFFICIENTLY AND WITH HIGH FIDELITY, FOR OPTIMAL EFFECTIVENESS. INSPIRE WILL PRIORITIZE STRATEGIES THAT CAN BE RAPIDLY DEPLOYED IN A RANGE OF PRACTICE SETTINGS, INCLUDING THOSE WITH LIMITED RESOURCES, THEREBY INCREASING THEIR REACH AND PUBLIC HEALTH IMPACT. PENN INSPIRE WILL USE STATE-OF-THE-SCIENCE METHODS FROM PARTICIPATORY RESEARCH TO ACTIVELY ENGAGE STAKEHOLDERS FROM MANY SECTORS – INCLUDING PATIENTS, PROVIDERS, AND PAYERS – AT EVERY LEVEL OF ITS WORK TO ACCOMPLISH ITS SPECIFIC AIMS. INSPIRE WILL APPLY INNOVATIVE, INTERDISCIPLINARY BEHAVIOR CHANGE AND IMPLEMENTATION SCIENCE METHODS TO DEVELOP, ADAPT, AND EVALUATE COST EFFECTIVE INTERVENTIONS. A SIGNATURE PROJECT WILL USE A STEPPED WEDGE STUDY DESIGN TO TEST AN INNOVATIVE ORGANIZATIONAL STRATEGY THAT LEVERAGES TELEHEALTH TO DELIVER HIGH QUALITY SAFETY PLANNING INTERVENTION AND FOLLOW-UP SERVICES IN EMERGENCY DEPARTMENTS. THREE EXPLORATORY PROJECTS WILL TEST NOVEL STRATEGIES FOR SUICIDE PREVENTION ACROSS INDIVIDUAL, CLINICIAN, AND ORGANIZATIONAL LEVELS AND WITH SPECIFIC VULNERABLE POPULATIONS THAT WILL LAY THE FOUNDATION FOR MORE DEFINITIVE STUDIES. INSPIRE WILL ALSO SUPPORT 10 PILOT PROJECTS AND AN INNOVATIVE METHODS CORE THAT WILL DEVELOP AND TEST NEW METHODS TO ADVANCE RESEARCH AT THE INTERSECTION OF SUICIDE PREVENTION AND IMPLEMENTATION SCIENCE. THE SUICIDE PREVENTION SCHOLARS PROGRAM WILL EXPAND THE CADRE OF SUICIDE PREVENTION RESEARCHERS BY ENGAGING BOTH EMERGING INVESTIGATORS AND ESTABLISHED SCIENTISTS WHO DO NOT CURRENTLY WORK ON SUICIDE PREVENTION – PARTICULARLY THOSE FROM GROUPS UNDER-REPRESENTED IN RESEARCH – THROUGH CONTENT, DESIGN. AND METHODOLOGICAL MENTORING AND CAPACITY-BUILDING. BY CATALYZING INTERDISCIPLINARY, CROSS-SECTOR COLLABORATIONS AND ADVANCING SUICIDE PREVENTION RESEARCH, CARE, AND POLICY BOTH LOCALLY AND NATIONALLY, WE WILL DEVELOP COST-EFFECTIVE, PRACTICAL, AND EFFICIENT WAYS TO IMPLEMENT EVIDENCE-BASED SUICIDE PREVENTION INTERVENTIONS. INSPIRE IS POISED TO BE TRANSFORMATIONAL FOR SUICIDE PREVENTION.

TECHNICAL ASISTANCE FOR IN-SERVICE TRAINING OF HEALTH CARE PROVIDERS IN BOTSWANA

NEURODEVELOPMENTAL GENOMICS: TRAJECTORIES OF COMPLEX PHENOTYPES

MODELS OF HEREDITARY RETINAL DEGENERATIONS

SIGNAL TRANSDUCTION IN ATHEROSCLEROSIS

IPSC-BASED PLATFORM DEVELOPMENT FOR MAJOR PSYCHIATRIC DISORDER MODELING AND DISCOVERY

INSTITUTIONAL CLINICAL AND TRANSLATIONAL SCIENCE AWARD

PENN CENTER FOR STUDY OF EPIGENETICS IN REPRODUCTION

NEW GRANT. UNIVERSITY OF PENNSYLVANIA. GRANT NO. W31P4Q-13-1-0003. ARPA ORDER I501/00. PAN RTW 9F-12. IMMEDIATE AND PERSISTENT E-DNA PROTECTION AGAIN

TRANSLATIONAL RESEARCH FOR RETINAL DEGENERATION THERAPIES

CORE GRANT FOR VISION RESEARCH

ENGINEERING T CELLS TO PROVIDE DURABLE CONTROL OF HIV-1 REPLICATION

THE MECHANISMS OF ALTERATIONS IN SLEEP WITH AGE

INTERACTION OH INHALATIONAL ANESTHETICS WITH MACROMOLECULES

TRANSLATIONAL RESEARCH AT PENN: ADVANCING CURES THROUGH INTERDISCIPLINARY SCIENCE

CANCER CELL ADAPTATION TO METABOLIC STRESS

THE WHOLE HEALTH STUDY: COLLABORATIVE CARE FOR OUD AND MENTAL HEALTH CONDITIONS

NOVEL SIVSMM STRAINS FOR ANALYSIS OF MUCOSAL TRANSMISSION AND VACCINE PROTECTION

PROSPECTIVE RENAL INSUFFICIENCY COHORT EVALUATION: PRICE

CONSORTIUM FOR ALZHEIMERS SEQUENCE ANALYSIS (CASA)

VASCULITIS CLINICAL RESEARCH CONSORTIUM

A RANDOMIZED TRIAL OF BEHAVIORAL ECONOMIC INTERVENTIONS TO REDUCE CVD RISK

RAPID AB ISOLATION AND DELIVERY BY RECOMBINANT AAV TECHNOLOGY (RAID-RAT)

DEVELOPMENT OF NOVEL SMALL MOLECULES FOR DELAYING THE PROGRESSION OF MUSCULAR DY

STUDIES OF PHYSIOLOGIC AND PATHOLOGIC PLATELET PLUG FORMATION

DEVELOPMENT OF A MULTILEAF COLLIMATOR FOR PROTON RADIOTHERAPY PHASE 4 - PROTON THERAPY DOSE CHARACTERIZATIONA VERIFICATION

ENGINEERING T CELLS TO PROVIDE DURABLE CONTROL OF HIV-1 REPLICATION

MEDICAL SCIENTIST TRAINING PROGRAM - PROJECT SUMMARY THE UNIVERSITY OF PENNSYLVANIA MD/PHD AND VMD/PHD PROGRAMS WERE ESTABLISHED IN 1958 AND 1969, AND UNITED AS A SINGLE MEDICAL SCIENTIST TRAINING PROGRAM IN 1977. THE PROGRAM CURRENTLY ENROLLS 218 MD/PHD AND 22 VMD/PHD STUDENTS, 95% OF WHOM ARE TRAINING GRANT ELIGIBLE. PROGRAM GUIDANCE IS PROVIDED BY A COMMITTED TEAM OF FACULTY AND STAFF THAT HAS BEEN IN PLACE SINCE 2014 AND WAS RECENTLY JOINED BY AN EXPERIENCED MEDICAL EDUCATOR TO ASSIST IN PROGRAM EVALUATION. OUR PRIMARY GOAL IS TO IDENTIFY, TRAIN AND MENTOR A DIVERSE GROUP OF OUTSTANDING PHYSICIAN-SCIENTISTS WHO WILL BECOME LEADERS OF BIOMEDICAL RESEARCH AND TRANSLATIONAL MEDICINE, AS WELL AS BEING SUCCESSFUL CLINICIANS, ROLE MODELS AND MENTORS. TO MEET THIS GOAL, WE HAVE ESTABLISHED FLEXIBLE, EVIDENCE-BASED TRAINING PLANS THAT INTEGRATE RESEARCH AND CLINICAL TRAINING IN PREPARATION FOR CAREERS THAT USE BOTH. PENN'S INSTITUTIONAL COMMITMENT IS REFLECTED IN A LARGE ANNUAL INVESTMENT THAT PROVIDES RESOURCES, ENRICHMENT ACTIVITIES, AND SUPPORT FOR PROGRAM ADMINISTRATION, AS WELL AS AN INSTITUTIONAL CULTURE THAT VALUES PHYSICIAN-SCIENTISTS, SUPPORTS DIVERSITY AND INCLUSIVITY, PROMOTES SCIENTIFIC RIGOR AND A SAFE LEARNING ENVIRONMENT, AND EXPECTS GOOD MENTORSHIP. ADMISSION IS OPEN TO RECENT COLLEGE GRADUATES AND CURRENT PENN MD, VMD AND PHD STUDENTS. ADMISSION DECISIONS ARE HOLISTIC, EMPHASIZING RESEARCH EXPERIENCE, CREATIVITY, AND COMMITMENT TO A PHYSICIAN-SCIENTIST CAREER AS WELL AS ACADEMIC EXCELLENCE. THE AVERAGE TIME TO DEGREE IS 8.1 YEARS. THERE ARE 12 AFFILIATED GRADUATE PROGRAMS: 7 IN BIOMEDICAL GRADUATE STUDIES PLUS ENGINEERING, ECONOMICS, CHEMISTRY, HISTORY & SOCIOLOGY OF SCIENCE, AND ANTHROPOLOGY, WITH PROTOCOLS TO ADD MORE WHEN APPROPRIATE. THE DIVERSE TRAINING FACULTY INCLUDES 161 JUNIOR AND SENIOR SCIENTISTS AND PHYSICIAN-SCIENTISTS INCLUDING 3 NIH INTRAMURAL INVESTIGATORS WHO HOLD ADJUNCT FACULTY APPOINTMENTS AT PENN. POLICIES ARE IN PLACE TO ACQUIRE AND MAINTAIN TRAINING FACULTY MEMBERSHIP AND TO RESOLVE CONFLICTS. EACH STUDENT'S INDIVIDUALIZED CURRICULUM EMPHASIZES THE INTEGRATION OF CLINICAL AND RESEARCH TRAINING, RESPONSIBLE CONDUCT OF RESEARCH, SCIENTIFIC RIGOR AND REPRODUCIBILITY, AND MENTORSHIP. IT ALSO INCLUDES MSTP-DIRECTED COURSES IN YEARS 1 AND 2, CLINICAL CONNECTIONS DURING GRADUATE SCHOOL, RETURN TO RESEARCH IN THE FINAL YEAR AND, BECAUSE OUR RESPONSIBILITIES DO NOT END WITH GRADUATION, THE HAND OVER CURRICULUM, WHICH GUIDES STUDENTS IN THE SELECTION OF PHYSICIAN-SCIENTIST-FRIENDLY RESIDENCIES AND CAREERS. 81% OF RECENT GRADUATES WHO HAVE COMPLETED FURTHER TRAINING ARE EMPLOYED BY ACADEMIC CENTERS, RESEARCH INSTITUTES, THE BIOTECH AND PHARMACEUTICAL INDUSTRIES, THE NIH, AND FEDERAL AGENCIES. MOST HAVE RESEARCH FUNDING FROM THE NIH AND OTHER SOURCES. OUR OBJECTIVES FOR THE NEXT 5 YEARS INCLUDE: 1) FOSTERING THE NEXT GENERATION OF PHYSICIAN-SCIENTISTS, 2) ASSISTING TRAINEES IN EXPLORING PHYSICIAN-SCIENTIST CAREER OPTIONS IN ADDITION TO ACADEMIA, 3) MANAGING UPWARD PRESSURE ON TOTAL TRAINING TIME, 4) IMPROVING MENTORSHIP SKILLS FOR FACULTY AND TRAINEES, AND 5) EXTENDING OUR SUCCESSFUL EFFORTS TO INCREASE DIVERSITY. THESE OBJECTIVES ARE LINKED TO AN OUTCOMES RUBRIC THAT DEFINES SUCCESS AND A LOGIC MODEL WHOSE METRICS WILL ENABLE CONTINUOUS IMPROVEMENT.

BIOFOUNDRY: ARTIFICIAL INTELLIGENCE-DRIVEN RNA BIOFOUNDRY -THE ARTIFICIAL INTELLIGENCE-DRIVEN RNA BIOFOUNDRY (AIRFOUNDRY) ADDRESSES CRITICAL CHALLENGES IN RNA TECHNOLOGY RESEARCH BY ESTABLISHING A USER-FRIENDLY, OPEN-ACCESS PLATFORM. THIS INITIATIVE INTEGRATES CUTTING-EDGE AI FOR RNA DESIGN, SYNTHESIS, AND DELIVERY, WHILE ALSO PROMOTING KNOWLEDGE SHARING AND REPRODUCIBILITY. AIRFOUNDRY HARNESSES THE POTENTIAL OF RNA BY EXTENDING ITS IMPACT BEYOND HEALTHCARE TO FIELDS SUCH AS AGRICULTURE, BIOTECHNOLOGY, AND ENVIRONMENTAL REMEDIATION. AIRFOUNDRY COMBINES AI TOOLS, AUTOMATION, AND MICROFLUIDICS TO UNCOVER FUNDAMENTAL DESIGN PRINCIPLES THAT WILL ACCELERATE RNA-BASED INNOVATIONS. AIRFOUNDRY SERVES THREE KEY FUNCTIONS: 1) OPTIMIZING RNA DESIGN, SYNTHESIS, AND EFFICIENCY; 2) GUIDING AND ASSISTING RESEARCHERS IN DEVELOPING EFFECTIVE DELIVERY VEHICLES, LIKE LIPID NANOPARTICLES, TO TRANSPORT RNA TO INTENDED TARGETS; AND 3) GENERATING NEW KNOWLEDGE TOWARDS ESTABLISHING RELATIONSHIPS BETWEEN RNA DESIGN, DELIVERY VEHICLES, AND THEIR ACTIVITY IN BIOLOGICAL SYSTEMS. FURTHERMORE, AIRFOUNDRY EMPHASIZES EDUCATION AND SEEKS TO BROADEN PARTICIPATION IN RNA RESEARCH BY TRAINING THE NEXT GENERATION OF SCIENTISTS FROM DIVERSE TECHNICAL AND GEOGRAPHICAL BACKGROUNDS WHILE ENSURING THAT ITS ADVANCED TECHNOLOGIES ARE ACCESSIBLE TO A WIDE RANGE OF USERS, FROM ACADEMIC RESEARCHERS TO SMALL BUSINESSES. THIS COLLABORATIVE, MULTIDISCIPLINARY ENVIRONMENT FOSTERS INNOVATION, ACCELERATES ADVANCEMENTS IN RNA RESEARCH, AND DEMOCRATIZES RNA TECHNOLOGY, ULTIMATELY EMPOWERING A DIVERSE WORKFORCE TO ADDRESS GLOBAL CHALLENGES LIKE CLIMATE CHANGE AND FOOD SECURITY. THE ARTIFICIAL INTELLIGENCE-DRIVEN RNA BIOFOUNDRY (AIRFOUNDRY) DIRECTLY ADDRESSES CRITICAL ROADBLOCKS IN RNA RESEARCH BY ESTABLISHING A COMPREHENSIVE FRAMEWORK THAT INTEGRATES CUTTING-EDGE ARTIFICIAL INTELLIGENCE (AI) TO UNCOVER, SHARE, AND APPLY FUNDAMENTAL DESIGN PRINCIPLES OF RNA AND DELIVERY VEHICLES. AIRFOUNDRY OPERATES THROUGH THREE DISTINCT MULTIDISCIPLINARY RESEARCH GROUPS (MRGS) WORKING IN TANDEM WITH TECHNOLOGY INNOVATION GROUPS (TIGS) THAT SERVE A WIDE RANGE OF USERS, FROM ACADEMIC RESEARCHERS TO SMALL BUSINESSES. MRG-1 OPTIMIZES RNA DESIGN AND SYNTHESIS THROUGH INTEGRATION OF CUTTING-EDGE BIOCHEMICAL METHODS AND BAYESIAN OPTIMIZATION MODELS TO EFFICIENTLY NAVIGATE THE VAST DESIGN SPACE OF RNA MOLECULES, RAPIDLY IDENTIFYING OPTIMAL SEQUENCES FOR DESIRED FUNCTIONALITIES. MRG-2 ADVANCES THE FIELD OF DELIVERY VEHICLES BY EMPLOYING AI-REFINED DESIGN RULES FOR LIPID NANOPARTICLES (LNPS). BY ESTABLISHING THE FUNDAMENTAL STRUCTURE-ACTIVITY RELATIONSHIPS FOR LNPS, RESEARCHERS CAN TAILOR THESE DELIVERY SYSTEMS FOR SPECIFIC RNA CARGOS AND TARGET CELLS, ENSURING EFFICIENT CELLULAR UPTAKE AND MAXIMIZING PERFORMANCE ACROSS A BROAD SET OF APPLICATIONS. MRG-3 LEVERAGES AI TO AUGMENT HUMAN EXPERTISE AND DECISION-MAKING ACROSS THE ENTIRE RNA DESIGN, SYNTHESIS, AND DELIVERY WORKFLOW. AI ALGORITHMS WILL BE TRAINED ON LARGE DATASETS THAT COMPRISE RNA SEQUENCES, LNP COMPOSITIONS, AND BIOLOGICAL RESPONSES. THIS KNOWLEDGE BASE WILL EMPOWER RESEARCHERS TO MAKE INFORMED DECISIONS AT EVERY STAGE OF DEVELOPMENT, ACCELERATING DISCOVERY AND OPTIMIZING RNA-BASED TECHNOLOGIES. COMPLEMENTING THESE MRGS, A SET OF TIGS FOCUSES ON TRANSLATING FUNDAMENTAL RESEARCH INTO TECHNOLOGIES TO SUPPORT THE AIRFOUNDRY AND ITS USERS. TIG-1 FOCUSES ON AUTOMATING RNA PRODUCTION, INTEGRATING ROBOTICS AND CHROMATOGRAPHY TO ENHANCE THE HIGH-THROUGHPUT SYNTHESIS AND SCALABILITY OF DIVERSE RNA MOLECULES FOR RESEARCH AND APPLICATION. TIG-2 TACKLES THE DEVELOPMENT OF ROBUST AND RAPID PRODUCTION OF MULTIPLE LNPS WITH PRECISELY CONTROLLED STRUCTURES, ENABLING HIGH-THROUGHPUT SCREENING AND OPTIMIZATION OF LNP PROPERTIES FOR TARGETED RNA DELIVERY. TIG-3 FOCUSES ON DEVELOPING CROSS-CUTTING TOOLS THAT INTEGRATE KNOWLEDGE SHARING, SIMULATIONS, DATA MANAGEMENT AND IN-LINE SENSING FOR SEAMLESS COLLABORATION WITHIN THE AIRFOUNDRY PLATFORM. BY HARNESSING THE COLLECTIVE EXPERTISE OF SCIENTISTS AND ENGINEERS FROM DIVERSE FIELDS SUCH AS RNA BIOLOGY, AI, MICROFLUIDICS, PROCESS ENGINEERING, AND DATA MANAGEMENT, AIRFOUNDRY AIMS TO ESTABLISH A PREEMINENT PLATFORM FOR RNA TECHNOLOGY ADVANCEMENT AND DEMOCRATIZATION. INTEGRATING AI-DRIVEN DISCOVERY AND OPTIMIZATION WITH CUTTING-EDGE MICROFLUIDICS AND AUTOMATION, AIRFOUNDRY PROMISES TO REVOLUTIONIZE RNA RESEARCH AND TO OPEN A WIDE VARIETY OF NEW APPLICATIONS. THIS PROJECT IS JOINTLY SUPPORTED BY DIVISIONS OF EMERGING FRONTIERS (EF), BIOLOGICAL INFRASTRUCTURE (DBI), AND MOLECULAR AND CELLULAR BIOSCIENCES (MCB) IN THE DIRECTORATE FOR BIOLOGICAL SCIENCES (BIO), DIVISION OF CHEMISTRY (CHE) IN THE DIRECTORATE FOR MATHEMATICAL AND PHYSICAL SCIENCES (MPS), AND THE DIRECTORATE FOR TECHNOLOGY, INNOVATION AND PARTNERSHIPS (TIP). THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.- SUBAWARDS ARE PLANNED FOR THIS AWARD.

TAS::97 0400::TAS REORIENT: RESOURCES FOR OPERATIONALLY RELEVANT INFORMATION EXTRACTION FROM NON-EXPLICIT TEXT

NSEC ON MOLECULAR FUNCTION AT THE NANO/BIO INTERFACE

TRANSLATIONAL STUDIES IN FLASH PARTICLE RADIOTHERAPY - PROJECT SUMMARY RADIATION THERAPY (RT) IS USED IN THE CURATIVE SETTING FOR MANY CANCERS INCLUDING SARCOMAS AND LUNG AND PANCREATIC CANCER. DESPITE SIGNIFICANT IMPROVEMENTS OVER THE PAST FEW DECADES, THERE IS STILL MUCH ROOM FOR IMPROVEMENT AS PATIENTS STILL DEVELOP RT-INDUCED INJURIES OR SECOND MALIGNANT NEOPLASMS. FLASH RADIOTHERAPY, WHICH DELIVERS A LARGE DOSE OF RADIATION AT AN ULTRA-HIGH DOSE RATE COULD POTENTIALLY REDUCE TOXICITY. OUR OVERALL HYPOTHESIS IS THAT PROTON/CARBON PARTICLE FLASH RT IS SUPERIOR TO STANDARD PARTICLE RT IN PROTECTING NORMAL TISSUES WHILE THE TWO MODALITIES WILL BE EQUIPOTENT IN CONTROLLING MALIGNANT GROWTH. PROJECT 1, WHICH FOCUSES ON PANCREATIC CANCER, WILL DEFINE THE DOSIMETRIC AND BIOPHYSICAL PARAMETERS THAT WILL MAXIMALLY SPARE NORMAL INTESTINE TISSUES USING FLASH PROTON THERAPY (F-PRT) WITHOUT COMPROMISING ANTITUMOR EFFECTS. IT WILL DELINEATE MECHANISTIC ASPECTS OF DIFFERENTIAL RESPONSE OF NORMAL INTESTINAL TISSUES, BY FOCUSING ON THE RELATIVE SPARING OF THE STEM/PROGENITOR CELL POPULATION. PROJECT 1 WILL ALSO EMPLOY P53+/- TRANSGENIC MOUSE MODELS TO DISSECT THE GENETIC DETERMINANTS OF DIFFERENTIAL GI TOXICITY OF STANDARD PROTON THERAPY (S-PRT) VS F-PRT. PROJECT 2 WILL EXPLORE THE ABILITY OF F-PRT TO AMELIORATE ADVERSE EVENTS (INFLAMMATION, FIBROSIS, LYMPHEDEMA, CHANGES TO BONE STRUCTURE, RADIATION-INDUCED CANCERS) THAT POSE BARRIERS TO THE TREATMENT OF SARCOMAS WITH RT. WE WILL ALSO CARRY OUT A PHASE 1/2 TRIAL THAT WILL TREAT CANINE PATIENTS WITH OSTEOSARCOMAS DEFINITIVELY WITH F-PRT. PROJECT 3 WILL COMPARE THE EFFICACY OF FLASH-RT GIVEN WITH CARBON ION RADIOTHERAPY (C- RT) VS. STANDARD DOSE RATE AND COMPARE IT TO ELECTRON F-RT. STUDIES WILL FOCUS ON THE MITIGATION OF NORMAL TISSUE INJURY IN NSCLC WITH AN EMPHASIS ON THE IMPACT OF NORMAL TISSUE AND INTRATUMORAL HYPOXIA TO RESPONSE FOLLOWING C-RT. LASTLY, PROJECT 4 WILL DEVELOP AND VALIDATE THE USE OF PENCIL BEAM SCANNING (PBS) TECHNOLOGY FOR PARTICLE F-RT. IT WILL ANALYZE SPATIOTEMPORAL VARIATIONS AND SOBP (SPREAD OUT BRAGG PEAK) VS. SHOOT THROUGH PBS AND DEVELOP DOSE DELIVERY ALGORITHMS FOR MODELING BIOLOGICAL EFFECTS FOR PBS-BASED FLASH PROTON THERAPY. THESE TOOLS WILL BE INCORPORATED IN THE EXPERIMENTAL PLANS OF PROJECT 1-3. THESE PROJECTS ARE SUPPORTED BY 4 CORES INCLUDING AN ADMINISTRATIVE CORE (CORE A), PHYSICS-DOSIMETRY CORE (CORE B), WHICH WILL OFFER INFRASTRUCTURE SERVICES TO HARMONIZE DOSIMETRY BETWEEN VARIOUS SITES AND A COMPARATIVE PATHOLOGY CORE (CORE C) FOR TISSUE PREPARATION FOR HISTOPATHOLOGICAL EVALUATION. STATISTICAL SERVICES WILL BE PROVIDED BY CORE D. COLLECTIVELY, THIS HIGHLY INTEGRATED EFFORT LED BY RECOGNIZED LEADERS IN RADIATION AND TUMOR BIOLOGY, AIMS TO DEFINE THE BIOLOGICAL, DOSIMETRIC AND BIOPHYSICAL PARAMETERS AND MOLECULAR MECHANISMS UNDER WHICH FLASH RT IS MOST EFFECTIVE IN TUMORS AND TISSUES WE DEEM THE MOST LIKELY TO BE FIRST TESTED IN CLINICAL TRIALS. IT IS OUR BELIEF THAT ONLY BY ACQUIRING THIS KNOWLEDGE WILL THIS EXCITING AND NOVEL MODALITY BE USHERED INTO THE CLINIC IN A SAFE AND EFFECTIVE MANNER TO IMPROVE THERAPEUTIC OUTCOME AND QUALITY OF LIFE OF CANCER PATIENTS.

POST GWA STUDIES IN TESTICULAR GERM CELL TUMORS

HEMATOLOGY CLINICAL RESEARCH TRAINING PROGRAM

COORDINATING CENTER FOR THE COMPARISON OF AMD TREATMENTS TRIALS

RADIATION AND CHECKPOINT BLOCKADE FOR CANCER IMMUNE THERAPY

PLATELET SIGNALS AND THEIR INTERFACE WITH THE EXTERNAL ENVIRONMENT

ASBESTOS FATE, EXPOSURE, REMEDIATION, AND ADVERSE HEALTH EFFECTS

CELLULAR MOLECULAR BIOLOGICS IN CLINICAL CANCER RESEARCH

A RESOURCE FOR MAGNETIC RESONANCE AND OPTICAL IMAGING

CENTER FOR SUB-CELLULAR GENOMICS

DELAWARE VALLEY NODE OF THE CLINICAL TRIALS NETWORK

THE UNFOLDED PROTEIN RESPONSE IN CANCER

INSTITUTIONAL CLINICAL AND TRANSLATIONAL SCIENCE AWARD - PROJECT SUMMARY THE PENN-CHOP CLINICAL AND TRANSLATIONAL SCIENCE AWARD (CTSA) HUB PROPOSES A TRANSFORMATIVE VISION TO CATALYZE A DYNAMIC CLINICAL AND TRANSLATIONAL SCIENCE (CTS) ECOSYSTEM THAT ACCELERATES THE DELIVERY OF INNOVATIVE, LIFE-ALTERING THERAPIES TO INDIVIDUALS ACROSS THE LIFESPAN. ALIGNED WITH THE NCATS MISSION TO BRING MORE TREATMENTS TO ALL PEOPLE MORE QUICKLY, OUR HUB WILL LEVERAGE ITS NATIONALLY-RECOGNIZED STRENGTHS IN TRANSLATIONAL THERAPEUTICS, DATA SCIENCE, COMMUNITY ENGAGEMENT, AND WORKFORCE DEVELOPMENT TO ADVANCE THE SCIENCE AND PRACTICE OF CLINICAL TRANSLATION. WE PROPOSE FOUR INTEGRATED AIMS: (1) INNOVATE NOVEL APPROACHES TO ADVANCING THE DEVELOPMENT AND DISSEMINATION OF TRANSLATIONAL THERAPEUTICS; (2) ACCELERATE THE APPLICATION OF STATE-OF-THE-ART DATA SCIENCE RESOURCES AND DYNAMIC DATA ECOSYSTEMS TO ENABLE A PENN-CHOP ACADEMIC LEARNING HEALTH SYSTEM (ALHS) FRAMEWORK AND CATALYZE GROUNDBREAKING CTS; (3) INTEGRATE OUR HUB WITH OUR COMMUNITIES AND STAKEHOLDERS TO PROMOTE COMMUNITY-PARTNERED AND COLLABORATIVE RESEARCH WITHIN FAMILIES AND ACROSS THE LIFESPAN; (4) EDUCATE, TRAIN, ADVANCE, AND RETAIN A SKILLED MULTIDISCIPLINARY WORKFORCE READY TO MEET THE DEMAND OF AN EVER-EVOLVING CTS AND AND CTR LANDSCAPE. OUR HUB WILL SERVE AS A NATIONAL MODEL FOR INTEGRATED, COMMUNITY-ENGAGED, AND DATA-DRIVEN TRANSLATIONAL SCIENCE. THROUGH RIGOROUS EVALUATION, CONTINUOUS QUALITY IMPROVEMENT, AND DISSEMINATION OF BEST PRACTICES, WE AIM TO CONTRIBUTE MEANINGFULLY TO THE CTSA CONSORTIUM'S COLLECTIVE IMPACT ON PUBLIC HEALTH.

ROLE OF SINGLE CELL MRNA VARIATION IN SYSTEMS ASSOCIATED ELECTRICALLY EXCITABLE C

SHAPING ANTIVIRAL IMMUNITY BY THE INFLAMMATORY REGULATORY AND TISSUE ENVIRONMENT

IMMUNOBIOLOGY OF NORMAL AND NEOPLASTIC LYMPHOCYTES

GRASSROOTS RIGOR: MAKING RIGOROUS RESEARCH PRACTICES ACCESSIBLE, MEANINGFUL, AND BUILDING A COMMUNITY AROUND THEM - PROJECT SUMMARY: THROUGHOUT BIOMEDICAL RESEARCH, PROGRESS IS IMPEDED DUE TO A LACK OF RIGOR, WHICH COULD BE AMELIORATED WITH BETTER TRAINING AND WITH COMMUNITY BUY-IN. WHILE MANY PAPERS HAVE BEEN WRITTEN AND COUNTLESS PRESENTATIONS DELIVERED ON RIGOROUS PRACTICES, THE AVERAGE SCIENTIST FAILS TO CONSISTENTLY FOLLOW THE RELEVANT PRINCIPLES. WE STRUCTURE OUR PROPOSAL BASED ON THREE INSIGHTS. (1) ADOPTION OF THE PRINCIPLES OF RIGOROUS SCIENCE IS A QUESTION OF CULTURE, WHICH CAN ONLY BE CHANGED BY A BROAD COMMUNITY EFFORT. THIS WORK REQUIRES BUY-IN FROM ALL STAKEHOLDERS, INCLUDING STUDENTS, PROFESSORS, AND OTHER CHAMPIONS OF RIGOR. (2) TO ENABLE THIS CULTURAL CHANGE, MATERIALS MUST BE ENGAGING, HIGH QUALITY, AND INSPIRING FOR LEARNERS. ABOVE ALL, THESE MATERIALS NEED TO SERVE THE COMMUNITY; THEY MUST BE AVAILABLE FOR DIRECT CONSUMPTION, FOR INCORPORATION INTO TEACHING BY MANY PROFESSORS, AND THEIR STRUCTURE SHOULD BE A TEMPLATE FOR RESEARCH ITSELF. (3) THE DEVELOPMENT AND ROLLOUT OF SUCH HIGH-QUALITY MATERIALS NECESSITATES A TIGHT FEEDBACK LOOP WITH THE COMMUNITY; BY EVALUATING THEIR USE, WE CAN SEE HOW THESE MATERIALS ACTUALLY INFLUENCE SCIENTIFIC RIGOR. THE GRASS-ROOTS, COMMUNITY-DRIVEN MOVEMENT TOWARD A MORE RIGOR-INFUSED SCIENTIFIC CULTURE THAT WE ENVISION REQUIRES EXCELLENT AND VISUALLY ENGAGING MATERIALS WITH THE FOLLOWING KEY FEATURES: LEARNING BY DOING, SHORT LECTURES, OPEN LANGUAGES, EASY DELIVERY MECHANISM, ADAPTABLE CONTENT, SIMPLE INTERFACES, GROUP-BASED LEARNING, OPEN-SOURCE BIDIRECTIONAL COLLABORATION WITH THE COMMUNITY, AND THOROUGHLY EVALUATED. OUR MAIN GOAL IS TO ENABLE THE PRINCIPLES UNDERLYING SCIENTIFIC RIGOR TO BECOME PART OF EVERYDAY CULTURE IN SCIENCE.

MOLECULAR THERAPY FOR CF AND GENETIC DISEASES

LIVER CANCER: PRE-MALIGNANT STIFFENING, MEMBRANE TRANSDUCTION, & NUCLEAR RHEOLOGY

DEVELOPMENTAL TRAJECTORIES OF NEGATIVE SYMPTOMS IN SCHIZOPHRENIA

PENN-CHOP ECHO - PROJECT SUMMARY HEALTH DISPARITIES START EARLY IN LIFE, WITH BLACK INFANTS (10.6 PER 1,000) TWICE AS LIKELY TO DIE COMPARED TO WHITE INFANTS (4.5 PER 1,000). ADVERSE PREGNANCY OUTCOMES ARE RESPONSIBLE FOR THE MAJORITY OF THE BLACK-WHITE INFANT MORTALITY DISPARITY. EXTENSIVE HEALTHCARE EFFORTS HAVE BEEN TAKEN TO PREVENT ADVERSE PREGNANCY OUTCOMES AND TO OPTIMIZE CHILD GROWTH, HEALTH, AND NEURODEVELOPMENT. HOWEVER, BIRTH AND CHILDHOOD OUTCOMES REMAIN MAJOR AREAS OF PUBLIC HEALTH CONCERN WITH ONGOING INEQUITIES. MACROENVIRONMENTAL HEALTH PROMOTING FACTORS (GREENSPACE, WALKABILITY) AND HEALTH THREATENING FACTORS (POLLUTION, NEIGHBORHOOD VIOLENCE, EXTREME TEMPERATURES) MAY AFFECT HEALTH DIRECTLY THROUGH INFLAMMATORY AND IMMUNOLOGIC PATHWAYS. MACROENVIRONMENTS MAY ALSO CONTRIBUTE TO LIVED EXPERIENCES OF INCOME POTENTIAL AND EDUCATIONAL ATTAINMENT. COMBINED WITH INTERPERSONAL INDIVIDUAL EXPOSURES SUCH AS RACISM AND VIOLENCE, MACROENVIRONMENTS MAY ALTER INDIVIDUALS' MICROENVIRONMENTAL HEALTH FACTORS SUCH AS DIET, PHYSICAL ACTIVITY, PSYCHOSOCIAL STRESS, AND SLEEP. WHILE MACRO- AND MICROENVIRONMENTAL EXPOSURES HAVE BEEN STUDIED INDIVIDUALLY, THE IMPACT OF NEIGHBORHOOD ENVIRONMENTS ON COMPLEX HEALTH DISORDERS IN PREGNANCY AND EARLY CHILDHOOD REMAINS UNDERSTUDIED AND THE INTERPLAY WITH MICROENVIRONMENTAL FACTORS TO REDUCE DISPARITIES IS COMPLETELY UNKNOWN. WE PROPOSE A CAUSAL INFERENCE FRAMEWORK TO EVALUATE THE ROLE OF SPECIFIC MACROENVIRONMENT FACTORS (AIM 1) TO REDUCE THE RISKS OF ABNORMAL FETAL GROWTH, PRETERM BIRTH, OBESITY, ASTHMA, AND NEURODEVELOPMENTAL DELAYS BY AGE 3, AS WELL AS WHETHER SUCH FACTORS MAY IMPROVE RACIAL DISPARITIES IN THESE OUTCOMES. WE WILL ALSO IDENTIFY OPTIMAL COMPONENTS OF MICROENVIRONMENTAL FACTORS OF DIET, PHYSICAL ACTIVITY, AND SLEEP, DURING PREGNANCY (AIM 2) AND AMONG COUPLES DURING PRECONCEPTION (AIM 4), THAT CAN BEST BE UTILIZED TO MAXIMIZE REDUCTIONS IN HEALTH DISPARITIES. WE HAVE ASSEMBLED A MULTIDISCIPLINARY TEAM OF EXPERTS AT THE UNIVERSITY OF PENNSYLVANIA AND CHILDREN'S HOSPITAL OF PHILADELPHIA WHO ARE WELL-POSITIONED TO COMPLETE THE STUDY AND RECRUIT UP TO 2500 PREGNANT PEOPLE, PARTNERS, AND OFFSPRING, WITH RETENTION OF AT LEAST 75% AT AGE 3, AMONG WHOM 1250 WILL BE RECRUITED INTO THE PRECONCEPTION PILOT (AIM 3). THE HEALTH SYSTEM AT PENN/CHOP SERVES A POPULATION UNDERREPRESENTED IN OTHER PREGNANCY AND PEDIATRIC COHORTS IN THE US (LARGELY MEDICAID-INSURED AND PLURALITY BLACK). THE CULTURE OF CLINICAL RESEARCH, EXCELLENT SCIENTIFIC ENVIRONMENT, AND DIVERSE POPULATION MAKES PENN AND CHOP THE IDEAL PLACE TO INNOVATE IN THE FIELD OF MATERNAL-CHILD HEALTH EQUITY. THE PENN-CHOP ECHO STUDY TEAM IS COMMITTED TO THE SUCCESS OF THIS WORK AND LOOKS FORWARD TO WORKING COLLABORATIVELY WITH THE OTHER ECHO STUDY SITES, COORDINATING CENTERS, AND CORES.

EXTENDING CHIMERIC ANTIGEN (CAR) T CELL THERAPY TO THORACIC CANCERS

CHANGING THE TRAJECTORY OF MILD COGNITIVE IMPAIRMENT WITH CPAP TREATMENT OF OBSTRUCTIVE SLEEP APNEA

LONG TERM FOLLOW UP OF THE LUNG TRANSPLANT OUTCOMES GROUP COHORT

DATA COORDINATING CENTER FOR THE PREMATURITY AND RESPIRATORY OUTCOMES PROGRAM

SEDATION MANAGEMENT IN PEDIATRIC PATIENTS WITH ACUTE RESPIRATORY FAILURE

INSTITUTIONAL CLINICAL AND TRANSLATIONAL SCIENCE AWARD

EDUCATION RESEARCH AND DEVELOPMENT CENTERS

TAS::89 0222::TAS THE LOW ENERGY NEUTRINO PHYSICS RESEARCH PROGRAM AT PENN

PENN CMU ROYBAL CENTER ON BEHAVIORAL ECONOMICS AND HEALTH

GENE THERAPY FOR UREA CYCLE DISORDERS

CENTER FOR RESEARCH ON IMPROVING THE TREATMENT OF DRUG ABUSE

LIPIDS AS MODULATORS OF THE RESPONSE TO VASCULAR INJURY

TRAINING IN AGE-RELATED NEURODEGENERATIVE DISEASES

FERROXIDASES IN RPE IRON TRANSPORT

RECORDING NEURAL ACTIVITIES ONTO DNA

CENTER ON THE DEMOGRAPHY OF AGING

PENN PET ADDICTION CENTER OF EXCELLENCE (PENN PACE)

IMMUNO/IMMUNOGENE THERAPIES FOR THORACIC MALIGNANCIES

LOOK AHEAD: ACTION FOR HEALTH IN DIABETES

INNOVATIVE APPROACHES FOR COCAINE PHARMACOTHERAPY

CONNECT-TBI

BIOLOGY OF THE ORPHAN RECEPTOR REV-ERBALPHA

BIOGENESIS OF VOLTAGE-GATED K+ CHANNELS

OLIGODENDROCYTE DAMAGE AND DYSFUNCTION IN HIV ASSOCIATED NEUROCOGNITIVE DISORDER

COMBINATION IMMUNOTHERAPY WITH GENE MODIFIED CD4 AND CD8 T CELLS AND STEM CELLS

TRAINING PROGRAM IN GASTROINTESTINAL SCIENCES

CARDIOLOGY & PULMONARY RESEARCH TRAINING GRANT

REDUCING HIV VULNERABILITY THROUGH A MULTILEVEL LIFE SKILLS INTERVENTION FOR ADOLESCENT MEN

INTEGRATIVE GENOMICS OF HUMAN HEART FAILURE

TIME-OF-FLIGHT PET FOR IMPROVED WHOLE-BODY IMAGING

TRAINING PROGRAM IN CARDIOVASCULAR BIOLOGY AND MEDICINE

COOPERATIVE HUMAN TISSUE NETWORK EASTERN DIVISION

FUNCTIONAL INTERROGATION OF T2D-ASSOCIATED GENES IN HUMAN STEM CELL-DERIVED MODELS AND MICE

PENN'S CENTER OF EXCELLENCE IN CANCER COMMUNICATION RESEARCH

MATERIALS RESEARCH SCIENCE AND ENGINEERING CENTERS (MRSEC) UPENN -NON-TECHNICAL ABSTRACT THE LABORATORY FOR RESEARCH ON THE STRUCTURE OF MATTER (LRSM) AT THE UNIVERSITY OF PENNSYLVANIA IS A CENTER OF EXCELLENCE FOR MATERIALS RESEARCH AND EDUCATION. IT FACILITATES COLLABORATION BETWEEN RESEARCHERS FROM DIFFERENT DISCIPLINES ? PHYSICS, CHEMISTRY, ENGINEERING, AND BIOLOGY ? TO ADVANCE TRANSFORMATIVE SCIENTIFIC PROJECTS AND SOLVE SOCIETAL CHALLENGES. ONE RESEARCH EFFORT TAKES INSPIRATION FROM THE BRAIN?S ABILITY TO LEARN, DESIGNING NEW MATERIALS THAT CAN ADAPT TO THEIR SURROUNDINGS AND COMPLEX STIMULI. POTENTIAL APPLICATIONS RANGE FROM MAKING FLEXIBLE MATERIALS THAT CAN DEFLECT THE ENERGY OF A HAMMER BLOW TO CREATING SOFT ROBOTS THAT CAN PERFORM COMPLEX TASKS. THESE ADVANCES WILL RESULT IN THE DESIGN OF NEW MATERIALS WITH PROPERTIES NOT FOUND IN NATURALLY OCCURRING SYSTEMS, ENABLING ENTIRELY NEW TECHNOLOGIES. A SECOND RESEARCH EFFORT TAKES ADVANTAGE OF HOW MATERIALS NATURALLY SEPARATE INTO DISTINCT PHASES LIKE OIL AND WATER. THE RESEARCH TEAM LEVERAGES THE PHYSICS OF DEMIXING TO MANIPULATE THE ASSEMBLY OF PROTEINS, CELLS, AND OTHER SOFT MATERIALS TO ENGINEER LIVING MATTER. POTENTIAL APPLICATIONS INCLUDE NEW AVENUES FOR PARTITIONING AND CONTROLLED RELEASE OF KEY MOLECULES INSIDE CELLS, AKIN TO DRUG DELIVERY, AND CREATING NEW TISSUE-LIKE MATERIALS, THEREBY SIGNIFICANTLY ADVANCING SYNTHETIC BIOLOGY, BIOTECHNOLOGY, AND MEDICINE. THE LRSM EDUCATES AND INSPIRES THE NEXT GENERATION OF MATERIALS SCIENTISTS AND ENGINEERS, BROADENING PARTICIPATION IN THE MATERIALS RESEARCH ENTERPRISE. THE LRSM OFFERS PROGRAMS AND ACTIVITIES FOR STUDENTS AT ALL LEVELS, FROM ELEMENTARY SCHOOL TO GRADUATE SCHOOL, AND PROVIDES PROFESSIONAL TRAINING AT THE POST-DOCTORAL LEVEL. THESE ACTIVITIES INCLUDE SUMMER CAMPS AND WORKSHOPS THAT INTRODUCE STUDENTS TO THE EXCITING WORLD OF MATERIALS SCIENCE THROUGH HANDS-ON EXPERIMENTS AND DEMONSTRATIONS, RESEARCH OPPORTUNITIES AND MENTORSHIP THAT ALLOWS STUDENTS TO PARTICIPATE IN SCIENTIFIC PROJECTS AND LEARN FROM EXPERTS IN THE FIELD, AND OUTREACH EVENTS AND ONLINE RESOURCES THAT HIGHLIGHT THE DIVERSITY AND IMPACT OF MATERIALS SCIENCE TO THE BROADER PUBLIC. THE LRSM ALSO PROVIDES ACCESS TO STATE-OF-THE-ART FACILITIES AND EQUIPMENT FOR MATERIALS RESEARCH, ALLOWING RESEARCHERS AT PENN, REGIONAL AND NATIONAL UNIVERSITIES, GOVERNMENT LABORATORIES, AND INDUSTRIES TO ADVANCE THEIR OWN RESEARCH ACTIVITIES. TECHNICAL ABSTRACT IRG-1: LEARNING METAMATERIALS (NSF BIG IDEAS: UNDERSTANDING THE RULES OF LIFE, HARNESSING THE DATA REVOLUTION) DEVELOPS AND EXPLOITS LEARNING STRATEGIES THAT MIMIC HOW THE BRAIN USES LOCAL RULES TO CHANGE ITS STRUCTURE TO CREATE AND DESTROY SYNAPSES FOR DISTRIBUTED AND ROBUST LEARNING. THE RESEARCH TEAM ADVANCES AND APPLIES LOCAL ADAPTIVE LEARNING TO CREATE NOVEL MICROFLUIDIC METAMATERIALS AND SOFT ROBOTS, UNDERSTAND HOW BIOPOLYMER NETWORKS FUNCTION IN VIVO, AND DEVELOP MECHANICAL METAMATERIALS WITH FUNCTIONAL AND COMPLEX DEFORMATION AND STRESS REDISTRIBUTION BEHAVIOR. RESEARCH ACTIVITY ALSO ADVANCES THE THEORY OF LEARNING BY EXPLORING NEW LEARNING STRATEGIES THAT CAPITALIZE ON THE ROLE OF DYNAMICS AND NON-LINEARITIES. IRG-2: BIOINSPIRED ENGINEERING OF CONDENSED PROTEIN MESOPHASES AND CELL COLLECTIVES (NSF BIG IDEAS: UNDERSTANDING THE RULES OF LIFE) DISCOVERS RULES OF LIFE FOR CONDENSED MESOPHASES COMPOSED OF POLYPEPTIDE OR CELLULAR BUILDING BLOCKS AND USES THESE PRINCIPLES TO ENGINEER THE STRUCTURE AND DYNAMICS OF SYNTHETIC BIOMATERIALS OVER MICRON TO CENTIMETER LENGTH SCALES. THE RESEARCH TEAM UNDERSTANDS AND UTILIZES PHASE PARTITIONING TO CREATE STRUCTURAL ORGANIZATION OVER MULTIPLE LENGTH SCALES IN LIVING MATTER, INCLUDING HOW MACROMOLECULES CAN BE SEGREGATED INTO BIOCHEMICAL COMPARTMENTS IN CELLS AND HOW CELLS CAN SEGREGATE FROM ONE ANOTHER IN TISSUES. LRSM IS A NATIONAL LEADER IN DEVELOPING A COMPETITIVE AND DIVERSE SCIENCE AND ENGINEERING WORKFORCE IN DEMAND BY ACADEMIA, GOVERNMENT, AND INDUSTRY. IT PROVIDES A WIDE RANGE OF EDUCATION, OUTREACH, AND HUMAN RESOURCE DEVELOPMENT PROGRAMS THAT TARGET PEOPLE AT ALL LEVELS, WITH EMPHASIS ON UNDERREPRESENTED MINORITIES, WOMEN, PERSONS WITH DISABILITIES, AND FIRST-GENERATION/LOW-INCOME STUDENTS, FROM K-16 TO PH.D. STUDENTS, POST-DOCS, TEACHERS, SCIENTISTS IN ACADEMIA, INDUSTRY, & GOVERNMENT, AND THE GENERAL PUBLIC. LRSM WILL CURATE AND SHARE ITS RESEARCH, EDUCATION, AND OUTREACH DATA. IN ADDITION, THE LRSM PROVIDES UNIQUE INTERDISCIPLINARY TRAINING FOR DOCTORAL STUDENTS AND POST-DOCTORAL RESEARCHERS IN CRITICAL FIELDS FOR US TECHNOLOGICAL COMPETITIVENESS. IT DEVELOPS AND FACILITATES THE USE OF UNIQUE SCIENTIFIC EXPERIMENTAL FACILITIES BY THE LOCAL, REGIONAL, AND NATIONAL SCIENTIFIC COMMUNITY. THE DISCOVERIES AND UNDERSTANDING GENERATED BY THE IRGS & SEEDS WILL PROVIDE FUNDAMENTALLY NEW WAYS TO HARNESS ACTIVE LEARNING TO BUILD NOVEL METAMATERIALS AND WILL EXPLOIT THE THERMODYNAMICS AND KINETICS OF PHASE PARTITIONING TO SYNTHESIZE BIOMATERIALS WITH UNPRECEDENTED CONTROL. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.

EARLY EVENTS IN KSVH INFECTION OF PRIMARY B-CELLS

ACHIEVING MATERNAL EQUITY AND TRANSFORMING HEALTH THROUGH IMPLEMENTATION SCIENCE AND TRAINING (AMETHIST@PENN) - PROJECT SUMMARY (ABSTRACT) ACHIEVING MATERNAL EQUITY AND TRANSFORMING HEALTH THROUGH IMPLEMENTATION SCIENCE AND TRAINING (AMETHIST@PENN) THE NIH IMPLEMENTING A MATERNAL HEALTH AND PREGNANCY OUTCOMES VISION FOR EVERYONE (IMPROVE) INITIATIVE AIMS TO REDUCE MATERNAL MORTALITY, IMPROVE PREGNANCY, PERINATAL AND POSTPARTUM CARE, AND TO ADDRESS THE FACTORS THAT HAVE LED TO SEVERE DISPARITIES IN OUTCOMES FOR MARGINALIZED GROUPS. THE UNIVERSITY OF PENNSYLVANIA (PENN) PROPOSES CREATING THE ACHIEVING MATERNAL EQUITY AND TRANSFORMING HEALTH THROUGH IMPLEMENTATION SCIENCE AND TRAINING (AMETHIST@PENN) IMPLEMENTATION SCIENCE HUB TO SUPPORT IMPROVE MATERNAL HEALTH RESEARCH CENTERS OF EXCELLENCE (COES) AND OTHER IMPROVE INVESTIGATORS, AND TO COORDINATE WITH NIH STAFF SCIENTISTS, PROJECT STAFF, AND THE DATA INNOVATION AND COORDINATING HUB. AMETHIST@PENN WILL BE LED BY MPIS MEGHAN LANE FALL, MD, MSHP, AND REBECCA HAMM, MD, MSCE, WHO BRING COMPLEMENTARY AND NECESSARY STRENGTHS IN IMPLEMENTATION SCIENCE (IS) AND MATERNAL HEALTH. DR. LANE-FALL IS EXECUTIVE DIRECTOR OF THE PENN IMPLEMENTATION SCIENCE CENTER AT THE LEONARD DAVIS INSTITUTE OF HEALTH ECONOMICS (PISCE@LDI). SHE IS AN INTERNATIONALLY RECOGNIZED ACUTE CARE IS EXPERT WITH AN INDEPENDENT IS RESEARCH PROGRAM. SHE HAS 8 YEARS OF EXPERIENCE AS A COLLABORATOR AND CONSULTANT ADVISING INVESTIGATORS ON: SELECTION OF IS THEORIES, MODELS, AND FRAMEWORKS, INCLUDING THOSE FOCUSED ON EQUITY; IMPLEMENTATION MAPPING AND STRATEGY SELECTION; IMPLEMENTATION OUTCOME SELECTION; DATA INTEGRATION ACROSS MULTIPLE TYPES AND SOURCES; AND ADVANCED ANALYTIC PROCEDURES TO ELUCIDATE CHANGE MECHANISMS. DR. HAMM IS A MATERNAL FETAL MEDICINE SPECIALIST WHO HAS ESTABLISHED HERSELF NATIONALLY AS A RESEARCHER AT THE CROSSROADS OF OBSTETRICS AND IS. TOGETHER THEY WILL ORCHESTRATE THE WORK OF AMETHIST@PENN, LEADING AN INTERDISCIPLINARY, INTERPROFESSIONAL GROUP OF MORE THAN 45 SCIENTISTS AND COMMUNITY PARTNERS. THE AMETHIST@PENN HUB WILL COMPRISE FIVE CORES, EACH WITH TWO CO-LEADS AND 2-4 CORE INVESTIGATORS: 1) ADMINISTRATION, LEADERSHIP, AND EVALUATION; 2) EQUITY, COMMUNITY AND STAKEHOLDER ENGAGEMENT (WITH AN EQUITY ADVISORY AND OVERSIGHT BOARD TO ADVISE AND HOLD INVESTIGATORS ACCOUNTABLE FOR INCORPORATING EQUITY INTO THEIR RESEARCH); 3) DESIGN, METHODS, AND ANALYSIS (INCLUDING A CONSULTANT PANEL WITH METHODS, EQUITY, AND CLINICAL SUBPANELS TO MEET THE ANTICIPATED CONSULTATION AND TECHNICAL ASSISTANCE NEEDS OF THE COES); 4) POLICY, DISSEMINATION, AND COMMUNICATION (WITH SKILLS BUILDING IN MESSAGING AND MEDIA TRAINING); AND 5) TRAINING AND CAPACITY BUILDING (FEATURING AN INNOVATIVE ACADEMIC-COMMUNITY PARTNER TRAINING PROGRAM AND A COMPREHENSIVE MENTORED RESEARCH EXPERIENCE FOR BOTH NEW AND ESTABLISHED INVESTIGATORS). IN ADDITION TO ESTABLISHING AND ADMINISTERING THE HUB, A RESEARCH AIM INCLUDES PROSPECTIVE MIXED METHODS RESEARCH ON IS INVESTIGATORS, COMMUNITY PARTNERS, AND INSTITUTIONS TO CHARACTERIZE PREDICTORS OF PROJECT-BASED IMPLEMENTATION SUCCESS AND MULTILEVEL BARRIERS TO AND FACILITATORS OF THE CONDUCT OF MATERNAL HEALTH IS RESEARCH. THE AMETHIST@PENN HUB WILL ADVANCE PUBLIC HEALTH AND MATERNAL HEALTH EQUITY BY FACILITATING RIGOROUS IMPLEMENTATION RESEARCH THAT CENTERS THE NEEDS AND PERSPECTIVES OF PATIENTS, COMMUNITIES, AND HEALTH DISPARITY POPULATIONS.

CENTER FOR INTERDISCIPLINARY RESEARCH ON NICOTINE ADDICTION (CIRNA)

IPS-DERIVED HEPATOCYTES FOR INTERROGATION OF LIPID PHENOTYPES

OVERALL: RESOURCE-BASED CENTER FOR MUSCULOSKELETAL DISORDERS RESEARCH

METABOLIC TUMOR SUPPRESSORS IN RENAL CANCER: UNPRECEDENTED ROLES IN DISEASE PROGRESSION

TRAINING PROGRAM IN SLEEP AND RESPIRATORY NEUROBIOLOGY

COMPLEMENTING BROADLY NEUTRALIZING ANTIBODIES AND AUTOLOGOUS RESPONSES TO RESTRICT VIRUS ESCAPE AND DURABLY SUPPRESS HIV-1 - PROJECT SUMMARY/ABSTRACT. ADVANCES IN B CELL BIOLOGY AND MOLECULAR VIROLOGY HAVE ENABLED THE DISCOVERY, CHARACTERIZATION, AND COMMERCIAL DEVELOPMENT OF SEVERAL CLASSES OF BROADLY NEUTRALIZING ANTIBODIES (BNABS), WITH APPLICATIONS FOR PREVENTION, TREATMENT, AND CURE OF HIV DISEASE ARE UNDER STUDY. YET, VIRUS RESISTANCE REMAINS THE CENTRAL VULNERABILITY OF EFFECTIVE BNAB USE. THIS APPLICATION PROPOSES TO ADDRESS THE PROBLEM OF BNAB ESCAPE BY RATIONALLY SELECTING COMBINATION BNAB THERAPY THAT LIMITS VIRUS ESCAPE. WE PROPOSE TO APPLY LESSONS FROM THE SUCCESSFUL DEVELOPMENT OF COMBINATION ANTIRETROVIAL THERAPY (CART), WHEREBY BIDIRECTIONAL PHENOTYPIC ANTAGONISM WAS EXPLOITED. OUR MULTIDISCIPLINARY TEAM HAS SECURED PLASMA VIRUS OR VIRUS SEQUENCES FROM RECENT OR ONGOING PREVENTION AND TREATMENT STUDIES OF VRC01-CLASS CD4 BINDING SITE (CD4BS)-TARGETING MONOTHERAPY, AS WELL AS COMBINATION THERAPY WITH V3 GLYCAN-TARGETING (TABLE 1). WE WILL LEVERAGE THESE UNIQUE SAMPLES TO MAP THE IN VIVO ESCAPE PATHWAYS OF VIRUS REPLICATING IN THE PRESENCE OF SUB-SUPPRESSIVE LEVELS OF THESE CLINICALLY RELEVANT BNABS (AIM 1). USING THE EVOLVING ESCAPE VARIANTS, WE WILL IDENTIFY PUTATIVE COMPLEMENTARY BNABS WITH MAINTAINED OR INVERSE ANTIBODY SENSITIVITIES FROM RATIONALLY DESIGNED PANELS OF CANDIDATE BNABS (AIM 1). WE WILL THEN CHARACTERIZE THE AUTOLOGOUS NEUTRALIZING ANTIBODY (ANAB) RESPONSE IN THE TREATMENT COHORTS, TO DETERMINE THE CAPACITY OF ANABS TO IMPEDE VIRUS ESCAPE FROM ADMINISTERED BNABS (AIM 2). FINALLY, WE WILL TEST THE MOST PROMISING COMPLEMENTARY BNABS TO RESTRICT VIRUS ESCAPE IN VIVO IN A VALIDATED BARCODED TF SHIV/NHP MODEL (AIM 3). OUR SCIENTIFIC PREMISE IS THAT IN VIVO MAPPING OF VIRUS ESCAPE FROM BNABS, IDENTIFICATION OF COMPLEMENTARY BNABS, DEFINING THE ROLE OF AUTOLOGOUS ANTIBODIES, AND RIGOROUS IN VIVO TESTING IN AN AUTHENTIC NHP MODEL WILL ELUCIDATE BASIC MECHANISMS OF VIRUS RESISTANCE TO BNABS AND INFORM MORE EFFECTIVE USE OF BNABS ACROSS THE HIV PREVENTION, TREATMENT AND CURE FIELDS. IF ACCOMPLISHED WE WILL (I) HAVE DEFINED THE SENSITIVITIES OF ESCAPED VIRUSES FROM CLINICAL TRIALS TO ALTERNATE BNABS, (II) IDENTIFIED BNABS THAT CANNOT MUTUALLY ESCAPE USING THE SAME PATHWAY, (III) DEFINED THE ROLE OF ANABS IN BNAB ESCAPE AND (IV) TESTED THE ABILITY OF COMPLEMENTARY BNABS TO IMPROVE THERAPY IN AN AUTHENTIC NHP MODEL.

INTRAOPERATIVE NEAR INFRARED MOLECULAR IMAGING OF LUNG CANCER - PROJECT SUMMARY/ABSTRACT NON-SMALL CELL LUNG CANCER (NSCLC) IS A DEVASTATING DISEASE WITH A POOR OUTCOME. WHEN A PATIENT IS FIRST DIAGNOSED WITH NSCLC, THE PERSON WOULD TYPICALLY UNDERGO DIAGNOSTIC BRONCHOSCOPY AND/OR THERAPEUTIC SURGERY. THESE TWO PROCEDURES HAVE TECHNICAL CHALLENGES THAT LIMIT THEIR SUCCESS SUCH AS INACCURATE BIOPSIES, FAILURE TO LOCATE NODULES AND LYMPH NODES, MISSED OCCULT TUMORS, AND POSITIVE MARGINS. AS A CONSEQUENCE, THERE IS A 40% FAILURE RATE FOR THESE PROCEDURES. THIS PROJECT WILL USE OPTICAL IMAGING IN THE NEAR-INFRARED (NIR) RANGE TO GENERATE PRACTICAL SOLUTIONS TO THESE PROBLEMS AND MAKE THESE TWO COMMON PROCEDURES SAFER, MORE EFFICIENT, AND HAVE IMPROVED OUTCOMES. THE GOAL OF THIS PROJECT IS TO TEST THE HYPOTHESIS THAT INTRAOPERATIVE IMAGING IN THE NIR SPECTRUM WITH TARGETED MOLECULAR TRACERS CAN IDENTIFY TUMOR CELLS IN ORDER TO IMPROVE PROCEDURES THAT ARE UTILIZED FOR THE MANAGEMENT OF PATIENTS WITH NSCLC. THE INNOVATION OF THIS PROGRAM PROJECT WILL BE IN THE MATRIX OF COCKTAIL DYE DEVELOPMENT, NEW NIR CAMERA DEVICES, AND CLINICAL TRANSLATION. THERE ARE THREE SPECIFIC GOALS OF THIS PROJECT. FIRST, TO DEVELOP A SET OF TARGETED NEAR-INFRARED MOLECULAR IMAGING CONTRAST AGENTS THAT ARE SENSITIVE AND SPECIFIC TO A RANGE OF DISTINCT TARGETS ON NSCLC. SECOND, TO DEVELOP AND INTEGRATE HIGHLY NIR SPECTRAL SENSITIVE IMAGING PLATFORMS INTO COMMONLY USED WHITE LIGHT IMAGING DEVICES SO THEY CAN BE UTILIZED DURING CLINICAL PROCEDURES. AND THIRD, TO APPLY THESE INNOVATIONS TO SOLVE COMMON CLINICAL PROBLEMS IN ORDER TO IMPACT PATIENT CARE. IF SUCCESSFUL, THE MOLECULAR OPTICAL IMAGING SOLUTION PRESENTED IN THIS PROPOSAL WOULD BE IMMEDIATELY APPLICABLE TO SEVERAL HUNDRED THOUSAND LUNG CANCER PATIENTS EACH YEAR.

DNA VACCINE FOR INDUCTION OF MUCOSAL IMMUNITY

1/2 PROSPECT: PRONE AND OSCILLATION PEDIATRIC CLINICAL TRIAL (CCC)

BIOCHEMISTRY OF LEUKEMIA VIRUS CORE BINDING FACTOR

ADVANCED TRAINING IN NURSING OUTCOMES RESEARCH

COMBINING PREGABALIN WITH LOFEXIDINE: CAN IT INCREASE THE SUCCESS OF TRANSITION TO NALTREXONE? - EXTENDED-RELEASE NALTREXONE (XR-NTX) REDUCES OVERDOSE RISK AND IS FILLING A NICHE FOR OPIOID ADDICTED PATIENTS THAT DO NOT WANT AGONIST MAINTENANCE OR CANNOT ACCESS IT. HOWEVER TRANSITIONING TO NALTREXONE REQUIRES DETOXIFICATION, WHICH IS A MAJOR HURDLE. METHADONE OR BUPRENORPHINE TAPERS ARE EFFECTIVE BUT REQUIRE A 7 TO 14-DAY OPIOID-FREE INTERVAL BEFORE STARTING NALTREXONE, LEAVING AMPLE TIME TO RELAPSE. NON-OPIOID DETOXIFICATION WITH AN ALPHA-2 ADRENERGIC RECEPTOR AGONIST MAY SHORTEN THE TIME, AND LOFEXIDINE WAS RECENTLY APPROVED FOR THIS INDICATION. IT IS SAFER THAN CLONIDINE HOWEVER LIKE CLONIDINE, IT DOES NOT REDUCE THE SUBJECTIVE EFFECTS OF WITHDRAWAL AND PATIENTS DO NOT LIKE IT. A MEDICATION THAT BETTER TARGETS THESE SYMPTOMS MAY IMPROVE OUTCOMES AND INCREASE THE PROPORTION THAT TRANSITION TO XR-NTX. PREGABALIN MAY BE SUCH A MEDICATION. IT POTENTIATES THE ACTIVITY OF GLUTAMIC ACID DECARBOXYLASE, INHIBITS CALCIUM INFLUX AND RELEASE OF EXCITATORY NEUROTRANSMITTERS, RAISES GABA LEVELS, AND IS APPROVED FOR NEUROPATHIC PAIN, FIBROMYALGIA, ADJUNCTIVE THERAPY FOR ADULTS WITH PARTIAL ONSET SEIZURES AND IN EUROPE, FOR ANXIETY. IT WAS NOT CONTROLLED IN RUSSIA FOR SEVERAL YEARS BUT WAS PLACED ON THEIR EQUIVALENT OF OUR SCHEDULE V DUE TO REPORTS THAT OPIOID ADDICTED PERSONS WERE USING IT TO REDUCE WITHDRAWAL AND ABUSE. BASED ON THIS INFORMATION, KRUPITSKY AND COLLEAGUES RANDOMIZED 34 CONSENTING, HEROIN-ADDICTED INPATIENTS UNDER DOUBLE-BLIND CONDITIONS TO PREGABALIN OR CLONIDINE-BASED DETOXIFICATION PROTOCOLS. MORE PREGABALIN THAN CLONIDINE PATIENTS COMPLETED DETOXIFICATION (P = 0.01) AND PREGABALIN PATIENTS HAD BETTER RETENTION THAN CLONIDINE PATIENTS (P = 0.001) WITH NO DIFFERENCES IN ADVERSE EVENTS. HERE WE PROPOSE TO SEE IF PREGABALIN CAN BE COMBINED WITH LOFEXIDINE TO BETTER REDUCE THE SUBJECTIVE EFFECTS OF OPIOID WITHDRAWAL THAN LOFEXIDINE, AND INCREASE THE PROPORTION THAT TRANSITION TO XR-NTX. SUCH A DOSING COMBINATION COULD LOWER THE DETOXIFICATION HURDLE FOR PATIENTS WHO ARE INTERESTED IN ANTAGONIST TREATMENT OR WHO ARE IN SETTINGS WHERE IT IS UNAVAILABLE OR DIFFICULT TO ACCESS. THIS WORK WILL REQUIRE TWO PHASES, AND BOTH FIT INTO THE UG3/UH3 ANNOUNCEMENT. IN UG3 WE WILL STUDY PREGABALIN/LOFEXIDINE COMBINATIONS TO IDENTIFY ONE THAT REDUCES WITHDRAWAL-RELATED SUBJECTIVE EFFECTS WITHOUT GENERATING MORE SERIOUS ADVERSE EVENTS THAN LOFEXIDINE ALONE. IN UH3 WE WILL TEST THAT COMBINATION IN AN ADEQUATELY POWERED TRIAL TO DETERMINE IF IT INCREASES THE NUMBER OF PATIENTS THAT COMPLETE DETOXIFICATION AND TRANSITION TO XR-NTX. HYPOTHESES ARE THAT WE WILL IDENTIFY A DOSING COMBINATION THAT IS SAFE AND REDUCES OPIOID WITHDRAWAL TO A GREATER DEGREE THAN LOFEXIDINE ALONE, AND THAT THIS LOFEXIDINE/PREGABALIN COMBINATION WILL RESULT IN MORE PATIENTS COMPLETING DETOXIFICATION AND TRANSITIONING TO XR-NTX. THE ULTIMATE GOAL IS TO GENERATE DATA TO SUPPORT NEW OR MODIFIED INDICATIONS(S) AND/OR INCLUSION OF NEW RECOMMENDATIONS IN PRODUCT PRESCRIBING INFORMATION TO IMPROVE DETOXIFICATION OUTCOME AND INCREASE THE PROPORTION THAT TRANSITION TO XR-NTX

GRADUATE RESEARCH FELLOWSHIP PROGRAM

TRAINING IN CRITICAL CARE HEALTH POLICY RESEARCH

PROBING THE CARDIAC PGC-1 REGULATORY CASCADE

MECHANISM OF ANTI-CD45 INDUCED TRANSPLANTATION TOLERANCE

EXPANSION OF CARDIAC AND HEMATOPOIETIC PROGENITORS BY WNT AND NOTCH

UNIVERSITY OF PENNSYLVANIA PREVENTION RESEARCH CENTER

THE ORO-RESPIRATORY-GUT VIROME AXIS OVER SPACE AND TIME - OVERALL - ABSTRACT THE HUMAN VIROME IS VAST, DIFFERS AMONG HUMAN INDIVIDUALS, AND CHANGES OVER THE HUMAN LIFESPAN. WHILE THE VIROME INFLUENCES HUMAN HEALTH IN DIVERSE WAYS, TRUE UNDERSTANDING OF ITS IMPACT IS LIMITED BY INCOMPLETE CHARACTERIZATION OF THE HUMAN VIROME COMPOSITION. THE GOAL OF THE PENN VIROME CHARACTERIZATION CENTER (VCC), TITLED “THE ORO-RESPIRATORY-GUT VIROME AXIS OVER SPACE AND TIME”, IS TO DEFINE THE HUMAN VIROME AND ITS DYNAMICS IN PRIORITY BODY SITES IN GENERALLY HEALTHY INDIVIDUALS WITHOUT ACUTE ILLNESSES, REFLECTING TYPICAL US POPULATIONS ACROSS DIVERSE LIFESPAN AND COMMUNITY PARTICIPANTS. OUR PROGRAM WILL PROVIDE KEY INSIGHTS INTO VIROME COMPOSITION, RICHNESS AND COMPLEXITY, AND PRODUCE EXTENSIVE DATA AND METHODOLOGIES FOR FUTURE STUDIES OF DISEASE ASSOCIATIONS. WE WILL FOCUS ON KEY BODY SITES IDENTIFIED BY THE NIH HUMAN VIROME PROGRAM AS PRIORITY TARGETS, INCLUDING ORAL/DENTAL, GUT (FECAL), RESPIRATORY TRACT (UPPER AND LOWER) AND BLOOD. OUR COLLABORATIVE TEAM HAS PUBLISHED EXTENSIVELY ON THE MICROBIOME AND VIROME, AND IN THE COURSE OF THESE STUDIES ASSEMBLED UNIQUE COHORTS WITH BIOBANKED SPECIMEN REPOSITORIES SUITABLE FOR RAPID INITIATION OF THE PENN VCC PROGRAM. MOST OF OUR SAMPLING IS FROM AN URBAN SETTING IN THE MID-ATLANTIC REGION, SO THAT AFRICAN AMERICANS ARE PARTICULARLY WELL REPRESENTED. TO ACHIEVE OUR GOALS, THE PENN VCC WILL: (A) TAKE ADVANTAGE OF RICH IN HAND BIOBANKS OF HUMAN SAMPLES FOR RAPID EFFICIENT ANALYSIS, AND ENROLL AND PHENOTYPE NEW SUBJECTS TO OBTAIN LONGITUDINAL ORO-RESPIRATORY-GUT-BLOOD SPECIMENS, FROM EXISTING COHORTS OF HEALTHY CHILDREN, ADOLESCENTS, ADULTS AND ELDERLY INDIVIDUALS; (B) COMPREHENSIVELY DESCRIBE AND QUANTIFY VIROME POPULATIONS FROM DISTINCT ORO-RESPIRATORY-GUT-BLOOD SITES, INCLUDING VIRUSES OF HUMANS, BACTERIA, AND HUMAN EUKARYOTIC COMMENSALS, AND IMPLEMENT METHODS FOR MOLECULAR IDENTIFICATION OF HOST CELLS FOR NOVEL VIRUSES AND CHARACTERIZATION OF VIRAL DNA MODIFICATION; (E) DEFINE THE COMMONALITIES AND DIFFERENCES OF VIROME COMMUNITIES ACROSS ORO-RESPIRATORY-GUT BIOGEOGRAPHY AND BLOOD OVER TIME WITHIN INDIVIDUALS AND BETWEEN AGE GROUPS; (F) PROTECT PARTICIPANTS, INVESTIGATORS, AND NIH BY ENSURING ADHERENCE TO ETHICAL NORMS AND REGULATORY REQUIREMENTS, WHILE CONDUCTING RIGOROUS LEGAL AND QUALITATIVE RESEARCH THAT ADDRESSES UNANSWERED QUESTIONS RAISED BY HUMAN VIROME RESEARCH THAT WILL INFORM FUTURE POLICY AND RESEARCH PRACTICE VIA OUR ETHICAL, LEGAL, AND SOCIAL IMPLICATIONS CORE; (G) ENSURE HARMONIZATION AND INTEGRATION WITH OTHER VCCS OF THE HUMAN VIROME PROGRAM, AND ESTABLISH OPEN SHARING OF DATA TO MAXIMIZE RESEARCH VALUE; (H) SUPPORT COLLABORATIVE RESEARCH AMONG HVP INVESTIGATORS USING SPECIMENS, DATA, AND NOVEL INSIGHTS GENERATED THROUGH THE VCC; AND (I) ENSURE REPRESENTATION OF TRADITIONALLY UNDER-STUDIED POPULATIONS AS RESEARCH PARTICIPANTS, AND ENHANCE DIVERSITY AND INCLUSION WITHIN THE VIROLOGY, MICROBIOME AND COMPUTATIONAL BIOLOGY RESEARCH COMMUNITIES.

PENN RESOURCE-BASED CENTER TO SUPPORT AND TRANSLATE SKIN DISEASESRESEARCH

COMPREHENSIVE BIOMARKER STUDY TO CAPITALIZE ON EXISTING GWAS IN 10K SOUTH ASIANS

PROGRAM TO CHARACTERIZE EVOLVING ENDOPHENOTYPES OF DEGENERATION AFTER TRAUMATIC BRAIN INJURY (PROCEED-TBI)

CANCER CLINICAL EPIDEMIOLOGY TRAINING GRANT

TRANSCRIPTION AND REPLICATION OF ONCOGENIC VIRUSES IN HYPOXIA - SUMMARY ONCOGENIC VIRUSES ARE MAJOR CONTRIBUTORS TO APPROXIMATELY 20% OF HUMAN CANCERS, WITH ABOUT 8 WELL-KNOWN VIRUSES DIRECTLY SHOWN TO BE CAUSATIVE AGENTS. OUR PROGRAM WILL FOCUS ON EXAMINING CELLULAR PROCESSES THAT ARE USURPED BY THESE VIRAL AGENTS TO DRIVE THE ONCOGENIC PHENOTYPE. THE TRANSCRIPTION AND REPLICATION OF ONCOGENIC VIRUSES IN THE HYPOXIC MICROENVIRONMENT HAS NOT BEEN EXTENSIVELY EXPLORED AND HERE WE WILL EXPLORE THE MECHANISMS CONTROLLED BY MERKEL CELL POLYOMA VIRUS (MCPYV), EPSTEIN BARR VIRUS (EBV) AND KAPOSI’S SARCOMA ASSOCIATED HERPESVIRUS (KSHV). MCPYV IS THE CAUSATIVE AGENT OF MERKEL CELL CARCINOMAS, EBV IS THE CAUSATIVE AGENT LINKED TO NASOPHARYNGEAL CARCINOMAS, BURKITT’S LYMPHOMAS, HODGKIN’S LYMPHOMAS, NON- HODGKIN’S LYMPHOMAS, POST-TRANSPLANT LYMPHOPROLIFERATIVE DISEASE IN HIV PATIENTS THAT ARE IMMUNOCOMPROMISED, AND KSHV IS THE CAUSATIVE AGENT FOR KAPOSI’S SARCOMA AND PLEURAL EFFUSION LYMPHOMAS AND IS ALSO ASSOCIATED WITH MULTI-CENTRIC CASTLEMAN’S DISEASE. THESE VIRAL AGENTS HAVE BEEN THE FOCUS OF DECADES OF STUDIES BUT THEIR FUNCTION HAS NOT BEEN EXAMINED EXTENSIVELY IN HYPOXIA. THE FOCUS OF THIS APPLICATION IS TO BRING TOGETHER FOUR PROMINENT GROUPS, LED BY INVESTIGATORS WITHIN THE UNIVERSITY OF PENNSYLVANIA COMMUNITY TO JOIN THEIR SCIENTIFIC EXPERTISE TO ADDRESS THE MECHANISM OF VIRAL-MEDIATED ONCOGENESIS. THE OVERALL GOAL WILL INVESTIGATE THE MECHANISM OF TRANSCRIPTION AND REPLICATION CONTROL BY VIRAL-ENCODED ANTIGENS AND THE METABOLIC CHANGES THAT ARE REQUIRED FOR THEIR FUNCTION IN HYPOXIA. THESE FUNDAMENTAL CELLULAR PROCESSES TARGETED IN HYPOXIA WILL PROVIDE NOVEL INFORMATION FOR SUCCESSFUL ESTABLISHMENT OF VIRAL INFECTION IN HYPOXIA. THE PROGRAM CONSISTS OF FOUR SCIENTIFIC PROJECTS, AN ADMINISTRATIVE CORE, A VIRUS, VECTOR AND CELL CULTURE CORE AND A NEXT GENERATION SEQUENCING CORE. THE SCIENTIFIC PROJECTS ARE: 1. KSHV REPROGRAMS TRANSCRIPTION AND REPLICATION IN HYPOXIA; 2. KSHV INDUCES TUMORIGENESIS BY HARNESSING DIFFERENTIATION IN HYPOXIA; 3. SKIN HYPOXIA, MCPYV INFECTION AND MCC TUMORIGENESIS; AND 4. REGULATION OF EBV LATENCY AND ONCOGENESIS BY OXYGEN METABOLISM. THE SUCCESS OF THESE PROJECTS WILL ESTABLISH A COMPREHENSIVE MECHANISTIC VIEW OF ONCOGENIC VIRAL INFECTION AND PATHOGENESIS IN HYPOXIA, AND PROVIDE NEW CLUES FOR THE DEVELOPMENT OF STRATEGIES TO PREVENT AND TREAT THE ASSOCIATED CANCERS IN HIV PATIENTS. IN ADDITION, THE ACCUMULATION OF NEW INFORMATION ON THE BIOLOGY OF THESE VIRUSES WILL BE CRITICAL FOR INSIGHTS INTO THEIR MECHANISM OF ONCOGENESIS AND SO REDUCE THE BURDEN OF DISEASE IN HIV INFECTED, TRANSPLANTS AND OTHER IMMUNOCOMPROMISED PATIENTS.

PENN VISION CLINICAL SCIENTIST PROGRAM

TRANSLATIONAL GENE THERAPY FOR RHODOPSIN AUTOSOMAL DOMINANT RETINITIS PIGMENTOSA

TRAINING IN HIV PATHOGENESIS

CANCER CENTER RESEARCH TRAINING PROGRAM

REFERRAL CENTER-ANIMAL MODELS OF HUMAN GENETIC DISEASE

SISGR - BI-CONTINUOUS MULTI-COMPONENT NANOCRYSTAL SUPERLATTICES FOR SOLAR ENERGY CONVERSION

A TRIAL OF TRANSPLANTING HEPATITIS C-VIREMIC KIDNEYS INTO HEPATITIS C-NEGATIVE KIDNEY RECIPIENTS (THINKER-NEXT) - PROJECT SUMMARY/ABSTRACT KIDNEY TRANSPLANT EXTENDS LIFE, IMPROVES QUALITY OF LIFE, AND REDUCES HEALTHCARE COSTS. UNFORTUNATELY, THE WAITING LIST EXCEEDS 94,000 PEOPLE WHILE ONLY APPROXIMATELY 14,000 DECEASED DONOR KIDNEY TRANSPLANTS (DDKT) OCCUR ANNUALLY AND MANY PATIENTS WAIT >5 YEARS FOR A DDKT. FOR THE ELDERLY AND SOME OTHER PATIENT GROUPS, IT IS COMMON TO DIE WAITING. YET, NEARLY 600 KIDNEYS FROM DONORS INFECTED HEPATITIS C VIRUS (HCV) WERE DISCARDED IN 2018 (50.1% OF THE TOTAL NUMBER OF KIDNEYS FROM HCV-VIREMIC DONORS); HUNDREDS MORE KIDNEYS ARE NEVER PROCURED BECAUSE OF THE PERCEPTION THAT NO CENTER WILL ACCEPT THEM. EARLY SUCCESSES OF PILOT CLINICAL TRIALS AND SINGLE-CENTER SERIES OF TRANSPLANTING KIDNEYS FROM HCV-VIREMIC DONORS HAVE DEMONSTRATED THE POTENTIAL FOR THIS PRACTICE TO INCREASE THE NUMBER OF LIFESAVING KIDNEY TRANSPLANTS BY MORE THAN 1,000 KIDNEY TRANSPLANTS EACH YEAR. HOWEVER, THE DOMINANT SYSTEM FOR ASSESSING KIDNEY QUALITY ALSO APPLIES A LOWER QUALITY SCORE TO ANY KIDNEY FROM AN HCV-VIREMIC DONOR, THEREBY PROMOTING ORGAN DISCARD. ALSO, EARLY EXPERIENCES FROM UNCONTROLLED STUDIES WITHOUT WELL-MATCHED COMPARATOR GROUPS HAS LED TO REPORTS OF UNEXPECTED COMPLICATIONS AND/OR HIGHER THAN ANTICIPATED RATES OF TREATMENT FAILURES THAT UNDERSCORE THE NEED FOR A FORMAL MULTI-CENTER CLINICAL TRIAL. RECENT REPORTS HAVE HIGHLIGHTED A SERIES OF POST-TRANSPLANT COMPLICATIONS THAT NECESSITATE EVALUATION IN A LARGE MULTI-CENTER TRIAL, FOR EXAMPLE: A) FIBROSING CHOLESTATIC HCV IN SEVERAL HCV-NEGATIVE RECIPIENTS OF AN HCV-VIREMIC DONOR; B) INCREASED INCIDENCE OF CMV VIREMIA IN RECIPIENTS OF HCV-VIREMIC KIDNEYS; AND C) MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS. WHILE THESE COMPLICATIONS ARE RARE, THEY UNDERSCORE THE VIEW FROM TRANSPLANT LEADERS, INCLUDING THE AMERICAN SOCIETY OF TRANSPLANTATION, THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES, AND THE INFECTIOUS DISEASE SOCIETY OF AMERICA THAT THIS PRACTICE IS CONSIDERED `EXPERIMENTAL' AND IS BEST PERFORMED UNDER IRB-APPROVED PROTOCOLS WITH RIGOROUS INFORMED CONSENT AND ASSURANCES OF ACCESS TO HCV TREATMENT. FURTHERMORE, DESPITE INCREASED TRANSPLANTATION OF KIDNEYS FROM HCV- VIREMIC DONORS INTO HCV-NEGATIVE PATIENTS, THERE REMAIN PERSISTENT KNOWLEDGE GAPS THAT NEED TO BE ADDRESSED FOR THIS PRACTICE TO BE ACCEPTED AS ROUTINE CLINICAL CARE FROM THE PERSPECTIVE OF PATIENTS, PROVIDERS, AND PAYERS. THIS MULTI-CENTER TRIAL SEEKS TO PROVIDE SIGNIFICANT KNOWLEDGE GAPS THAT REMAIN BY ADDRESSING THESE SPECIFIC AIMS: A) ESTIMATE HCV CURE RATES IN HCV-NEGATIVE RECIPIENTS OF HCV-VIREMIC KIDNEYS WITH A NARROW CONFIDENCE INTERVAL; B) DETERMINE WHETHER CONSENTING TO RECEIVING AN HCV-VIREMIC KIDNEY IMPROVES SURVIVAL; C) EVALUATE 1- YEAR RENAL FUNCTION OF HCV-VIREMIC KIDNEYS COMPARED TO MATCHED COMPARATORS; D) ASSESS WHETHER HCV- NEGATIVE RECIPIENTS OF HCV-VIREMIC KIDNEYS HAVE INCREASED RISKS OF CMV INFECTION; AND E) DETERMINE IF THE PREVALENCE OF CHRONIC KIDNEY DISEASE PATHOLOGY IS SIMILAR IN HCV-VIREMIC VS HCV-NEGATIVE KIDNEY DONORS. THE OVERARCHING GOAL IS TO DETERMINE IF KIDNEYS FROM HCV-VIREMIC DONORS CAN SAFELY BE TRANSPLANTED INTO HCV- NEGATIVE PATIENTS WITH END-STAGE RENAL DISEASE.

IMMUNOLOGICAL STRATEGIES TO MODULATE SIV REBOUND FOLLOWING ART INTERRUPTION

ENGINEERING A HUMAN BRAIN ORGANOID-BASED PLATFORM TO STUDY NEUROTROPIC VIRUSES

TRAINING PROGRAM IN CELL AND MOLECULAR BIOLOGY

STATISTICAL ATLASES OF BRAIN TUMOR MRI:DO IMAGING PHENOTYPES PREDICT PROGRESSION?

ROLE OF THE NOTCH PATHWAY IN KIDNEY INJURY

CELLULAR AND MOLECULAR BIOLOGY OF LUNG SURFACTANT

MECHANISMS UNDERLYING HETEROGENEITY OF COGNITIVE OUTCOMES IN SYNUCLEINOPATHY - OVERALL ABSTRACT/SUMMARY THE MISSION OF THIS PENN PO1 CENTER ON “MECHANISMS UNDERLYING HETEROGENEITY OF COGNITIVE OUTCOME IN SYNUCLEINOPATHY” IS TO UNDERSTAND WHY THE SAME UNDERLYING CORE PATHOLOGY – INCLUSIONS OF ALPHA-SYNUCLEIN (ASYN) – VARIES SO WIDELY IN THE PACE AND PATTERN OF SPREAD WITHIN THE BRAIN, RESULTING IN DRAMATICALLY DIVERGENT CLINICAL TRAJECTORIES. THE LEWY BODY DISORDERS (LBD) – NAMELY, DEMENTIA WITH LEWY BODIES (DLB), PARKINSON’S DISEASE (PD), AND ALZHEIMER’S DISEASE WITH LEWY BODIES (LBD+AD) – SHARE THE CORE FEATURE OF NEURONAL ASYN INCLUSIONS. HOWEVER, PATIENTS MANIFEST VERY DIFFERENTLY FROM ONE ANOTHER, WITH DIFFERENCES IN COGNITION PLAYING A VITAL ROLE WITH RESPECT TO PATIENT QUALITY OF LIFE AND COST TO THE HEALTHCARE SYSTEM. BECAUSE THE LBD AFFECT SO MANY, WITH NO FDA-APPROVED DISEASE-MODIFYING THERAPIES, THEY CONSTITUTE ONE OF THE MOST IMPORTANT ALZHEIMER’S DISEASE RELATED DEMENTIAS (ADRD) AFFECTING THE WORLD TODAY. THIS PO1 CENTER HYPOTHESIZES THAT SEVERAL KEY FEATURES PLAY FUNDAMENTAL ROLES IN DETERMINING WHETHER A GIVEN LBD INDIVIDUAL MIGHT DEVELOP DEMENTIA FROM THE OUTSET, AFTER A FEW YEARS, AFTER MANY DECADES, OR NOT AT ALL. THESE FEATURES ARE: (1) THE INTERPLAY OF ASYN WITH - AMYLOID PLAQUES AND TAU NEUROFIBRILLARY TANGLES, (2) THE CONFORMATION OF ASYN, (3) HOST GENOMICS AND PROTEOMICS, AND (4) THE LOCUS/ENTRY POINT OF EARLY PATHOLOGY. WE TEST THIS HYPOTHESIS IN FOUR SYNERGISTIC RESEARCH PROJECTS. PROJECT I INVESTIGATES THE ROLE OF CONCOMITANT -AMYLOID AND TAU PATHOLOGY IN GOVERNING PATTERNS OF ASYN SPREAD IN HUMAN POSTMORTEM BRAIN. PROJECT II CHARACTERIZES HUMAN BRAIN-DERIVED ASYN STRAINS WITH CRYO-ET AND CELL BIOLOGICAL TECHNIQUES. PROJECT III LEVERAGES GENOMIC AND BIOMARKER DATA TO DERIVE CANDIDATE MOLECULAR PLAYERS, THEN MANIPULATES THESE GENES/PROTEINS IN NEURONS TO UNDERSTAND THEIR ROLE IN THE UPTAKE OF FIBRILLAR ASYN, DEVELOPMENT OF ASYN PATHOLOGY, AND CELL-TO-CELL TRANSMISSION OF ASYN PATHOLOGY. PROJECT IV EXTENDS OUR INVESTIGATIONS OF HOST FACTORS TO MOUSE MODELS, TESTING THE ROLE OF GENETIC BACKGROUND, ROUTE OF ASYN EXPOSURE, AND TYPE OF ASYN STRAIN IN MODULATING IN VIVO PATHOLOGICAL ASYN SPREAD. ALL FOUR RESEARCH PROJECTS FOCUS ON MECHANISMS, GROUNDED IN HUMAN DATA, AND THEY ARE SUPPORTED BY FOUR CORES THAT (1) SERVE ADMINISTRATIVE FUNCTIONS, (2) RECRUIT CLINICAL PATIENTS, (3) PROVIDE BIOSAMPLE RESOURCES TO RESEARCH PROJECTS AND TO EXTERNAL INVESTIGATORS, AND (4) MANAGE DATA FOR RESEARCH PROJECTS AND SHARING TO EXTERNAL INVESTIGATORS. THUS, THE PENN PO1 CENTER SEEKS TO DISCOVER AND DEVELOP NEW THERAPEUTIC STRATEGIES TO DELAY OR PREVENT DEMENTIA IN THE LBD.

CONTROL OF VIRAL PATHOGENESIS BY REGULATION OF 2-5A LEVELS

NUCLEAR HORMONE RECEPTORS IN ADIPOCYTE DIFFERENTIATION

LARGE-AREA 3D OPTICAL METAMATERIALS WITH TUNABILITY AND LOW LOSS

NEW PHASE CHANGE MATERIALS FOR PHOTONICS: FROM IN-SILICO DESIGN TO NOVEL DEVICE CONCEPTS

DYNAMIC FIBROUS SCAFFOLDS FOR ENGINEERING DENSE CONNECTIVE TISSUES

CLINICAL PHARMACOEPIDEMIOLOGY TRAINING GRANT

SPREADING TAU PATHOLOGY IN NON-AMNESTIC ALZHEIMER'S DISEASE

CUREGN-PENN PCC