Indiana University

NATIONAL CELL REPOSITORY FOR ALZHEIMER'S DISEASE

THE IU/JAX ALZHEIMER'S DISEASE PRECISION MODELS CENTER

EARLY ONSET AD CONSORTIUM - THE LEAD STUDY (LEADS)

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND - INSTITUTIONAL SHARE: INDIANA UNIVERSITY - BLOOMINGTON

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND: INDIANA UNIVERSITY-PURDUE UNIVERSITY INDIANAPOLIS

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND- INDIANA UNIVERSITY

ENZYMATIC SUBSTRATES FOR HTS: IUSM ALZHEIMER'S DISEASE DRUG DISCOVERY CENTER

THE AUTHORIZED AGENT IS REQEUSTED TO AMEND ORIGINAL MAARD NUMBER -615-MAARD-615-0003-3-70030 TO PROVIDE $6,500,000.00 TO INITIATE HIV/AIDS ACTIVITIES

EAST AFRICA IEDEA REGIONAL CONSORTIUM

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND: INDIANA UNIVERSITY-PURDUE UNIVERSITY INDIANAPOLIS

TRANSFORMING CLINICAL PRACTICES INITIATIVE - PTN

INDIANA UNIVERSITY MELVIN AND BREN SIMON CANCER CENTER SUPPORT GRANT

CENTER ON GENETIC DETERMINANTS OF ALCOHOL INGESTION AND RESPONSES TO ALCOHOL

CATEGORY I: JETSTREAM 2: ACCELERATING SCIENCE AND ENGINEERING ON-DEMAND

INDIANA UNIVERSITY OF PENNSYLVANIA- INSTITUTIONAL PORTION OF THE HEERF

INDIANA CLINICAL AND TRANSLATIONAL SCIENCES INSTITUTE

INDIANA ALZHEIMER DISEASE CENTER

CARES ACT: HIGHER EDUCATION EMERGENCY RELIEF FUND - INDIANA UNIVERSITY OF PENNSYLVANIA 00327700

INDIANA CLINICAL AND TRANSLATIONAL SCIENCES INSTITUTE

MORPHOGENESIS AND GROWTH OF THE VENTRICULAR WALL IN DEVELOPMENT AND DISEASE

THEORETICAL AND EXPERIMENTAL STUDIES OF ELEMENTARY PARTICLE PHYSICS

INDIANA CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE (UL1)

DEVELOPMENTAL AND HYPERACTIVE RAS TUMOR SPORE

OSTEOCYTE REGULATION OF BONE/MUSCLE WITH AGE

VALUE-BASED MEDICAL STUDENT EDUCATION TRAINING PROGRAM

THE INDIANA UNIVERSITY-OHIO STATE UNIVERSITY MATERNAL AND PEDIATRIC PRECISION IN THERAPEUTICS DATA, MODEL, KNOWLEDGE, AND RESEARCH COORDINATION CENTER (IU-OSU MPRINT DMKRCC) - PROJECT SUMMARY/ABSTRACT EARLY-ONSET, OR PRETERM, PREECLAMPSIA OCCURS IN ONLY 0.5% OF PREGNANCIES, BUT IT IS ASSOCIATED WITH A HIGH RISK OF LONG- TERM MATERNAL COMPLICATIONS, AS WELL AS HIGH FETAL MORBIDITY AND MORTALITY. BIOMARKERS ASSOCIATED WITH EARLY-ONSET PREECLAMPSIA ARE NEEDED TO IDENTIFY WOMEN AT RISK OF DEVELOPING EARLY-ONSET PREECLAMPSIA, GUIDE TREATMENT OPTIONS, AND SUPPORT DEVELOPMENT OF NEW THERAPEUTIC APPROACHES TO PREVENT AND TREAT THE DISEASE. ADDITIONALLY, IT IS IMPORTANT TO UNDERSTAND THE LONG-TERM CONSEQUENCES OF PRETERM PREECLAMPSIA IN BOTH THE MOTHER AND CHILD. HOWEVER, DUE TO THE LOW INCIDENCE OF EARLY-ONSET PREECLAMPSIA, IT IS DIFFICULT TO OBTAIN DATA AND NECESSARY BIOSPECIMENS FROM A SUFFICIENT NUMBER OF WOMEN THROUGH A SINGLE CENTER OR STUDY. WHETHER COLLECTED AS A PROSPECTIVE BIOBANKING ENDEAVOR OR LEFTOVER RESIDUAL SAMPLES FROM CLINICAL STUDIES, NUMEROUS BIOSPECIMENS FROM MATERNAL AND PEDIATRIC PATIENTS RESIDE WITHIN STORAGE FACILITIES ACROSS THE WORLD. THESE UNTAPPED BIOSAMPLES AND THEIR ASSOCIATED DATA HAVE THE POTENTIAL TO GREATLY ENHANCE MATERNAL AND PEDIATRIC THERAPEUTICS RESEARCH, ESPECIALLY FOR RARE CONDITIONS AND DISEASES SUCH AS EARLY-ONSET PREECLAMPSIA. HOWEVER, THERE IS NO SINGLE RESOURCE TO IDENTIFY SOURCES OF MATERNAL AND PEDIATRIC BIOSPECIMENS, SO OFTEN TRANSLATIONAL RESEARCHERS SEEKING SUCH SAMPLES MAY NOT BE AWARE OF THEIR EXISTENCE. THIS PROPOSAL WILL CHARACTERIZE THE LANDSCAPE OF AVAILABLE MATERNAL AND PEDIATRIC BIOSPECIMENS AND SURVEY INVESTIGATORS TO UNDERSTAND THE NEEDS OF THE TRANSLATIONAL RESEARCH COMMUNITY. WE WILL DEVELOP THE COLLABORATIVE ONLINE PERINATAL & PEDIATRIC REPOSITORY (COPPER), A USER-FRIENDLY PLATFORM TO FACILITATE IDENTIFICATION OF BIOBANKS AND NETWORKS WITH RESIDUAL BIOSPECIMENS AVAILABLE TO SUPPORT MATERNAL AND PEDIATRIC PRECISION THERAPY RESEARCH. THROUGH SURVEYS AND WORKING GROUP DISCUSSIONS, WE WILL SEEK TO UNDERSTAND THE EVOLUTION OF REGULATIONS RELATING TO FUTURE USE OF BIOSPECIMENS AND PROPOSE STRATEGIES TO ENHANCE THE ABILITY TO LINK LONG-TERM PEDIATRIC OUTCOMES TO SAMPLES COLLECTED DURING THE PERINATAL PERIOD. AT THE END OF THIS PROJECT, WE WILL DEVELOP A CENTRALIZED RESOURCE PROVIDING INFORMATION ON BIOREPOSITORIES WHICH COULD SUPPORT MATERNAL AND PEDIATRIC TRANSLATIONAL RESEARCH AND PRECISION THERAPEUTICS, DEVELOP PROPOSALS TO ENHANCE THE ABILITY TO LINK MATERNAL AND CHILD DATA AND SPECIMENS, AND IDENTIFY BIOSPECIMENS AND ASSOCIATED CLINICAL DATA TO SUPPORT FUTURE WORK TO DEVELOP BIOMARKERS AND THERAPEUTIC APPROACHES TO PREVENT AND TREAT EARLY-ONSET PREECLAMPSIA.

NINDS BIOMARKER REPOSITORY

INDIANA CLINICAL AND TRANSLATIONAL SCIENCES INSTITUTE - PROJECT SUMMARY/ABSTRACT THE INDIANA CLINICAL AND TRANSLATIONAL SCIENCES INSTITUTE (INDIANA CTSI) WAS CREATED IN 2008 AS A STATEWIDE PARTNERSHIP TO ACCELERATE CLINICAL AND TRANSLATIONAL RESEARCH BY THE THREE RESEARCH UNIVERSITIES, INDIANA, PURDUE AND NOTRE DAME, WITH PARTNER HEALTH CARE SYSTEMS AND PROVIDERS, COMMUNITY AND PATIENT STAKEHOLDERS, LOCAL FOUNDATIONS, CORPORATE AND GOVERNMENT PARTNERS. THE MISSION OF THE INDIANA CTSI IS TO BRING TOGETHER INDIANA'S BRIGHTEST MINDS TO SOLVE THE MOST PRESSING HEALTH CHALLENGES BY SERVING AS THE STATEWIDE CATALYST FOR CLINICAL AND TRANSLATIONAL RESEARCH AND IMPROVE HUMAN HEALTH ACROSS INDIANA, THE NATION AND BEYOND. THE INDIANA CTSI FOSTERS A COLLABORATIVE RESEARCH ENVIRONMENT, PROVIDES RESOURCES AND SERVICES TO CONDUCT THE HIGHEST-QUALITY CLINICAL AND TRANSLATIONAL RESEARCH, OFFERS EDUCATION AND TRAINING PROGRAMS TO BUILD A ROBUST TRANSLATIONAL WORKFORCE, ENGAGES OUR COMMUNITY AS A PARTNER AT ALL LEVELS, IDENTIFIES AND REMOVES BARRIERS TO RESEARCH THROUGH TRANSLATIONAL SCIENCE APPROACHES, AND FUNCTIONS AS AN EXEMPLARY MEMBER OF THE NATIONAL CTSA NETWORK. THE CTSI PLANS TO ACCOMPLISH ITS MISSION THROUGH FIVE SPECIFIC AIMS: AIM 1. ACCELERATE TRAINING AND RESEARCH OPPORTUNITIES ACROSS THE STATE TO CREATE A DIVERSE AND TRUSTED TRANSLATIONAL RESEARCH WORKFORCE THAT DEMONSTRATES RESPECT, RESPONSIBILITY, AND CULTURAL HUMILITY THROUGH EFFECTIVE COMMUNICATION, TEAM SCIENCE AND AUTHENTIC STAKEHOLDER ENGAGEMENT. AIM 2. ENRICH AND INTEGRATE OUR NETWORK OF PATIENT, HEALTH CARE, CORPORATE, COMMUNITY, AND GOVERNMENT AGENCY PARTNERS TO BETTER ENGAGE AND EMPOWER UNDERSERVED POPULATIONS ACROSS INDIANA, FOCUSING ON REGIONS AND GROUPS WITH POOREST HEALTH OUTCOMES. AIM 3. ENHANCE ACCESS TO I-CTSI PROGRAMS AND SERVICES TO FACILITATE AND EXPEDITE IMPACTFUL CLINICAL AND TRANSLATIONAL RESEARCH THAT IS INNOVATIVE, INCLUSIVE, COLLABORATIVE, AND ETHICAL, AND EFFECTIVELY DISSEMINATES AND IMPLEMENTS EVIDENCE-BASED INTERVENTIONS ACROSS THE STATE. AIM 4. IDENTIFY BARRIERS, CREATE SOLUTIONS, AND DISSEMINATE NOVEL APPROACHES FOR BEST PRACTICES OF CLINICAL AND TRANSLATIONAL SCIENCE THROUGH COMMUNITY AND STAKEHOLDER ENGAGEMENT, PILOT FUNDING, AND A TRUSTWORTHY AND INTEGRATED TRANSLATIONAL RESEARCH ECOSYSTEM. AIM 5. LEVERAGE OUR STATEWIDE INFORMATICS PLATFORM AND INNOVATIVE ANALYTIC CAPABILITIES TO HARMONIZE DISPARATE DATA SOURCES IN COLLABORATION WITH HEALTH SYSTEMS ACROSS THE STATE AND WITH DELIBERATE INCLUSION FROM DIVERSE POPULATIONS TO ADVANCE HEALTH EQUITY. IN 2030, AT THE END OF THIS SEVEN- YEAR RENEWAL FUNDING PERIOD, WE ENVISION THE I-CTSI WILL TRANSFORM OUR STATEWIDE RESEARCH ECOSYSTEM WITH DELIBERATE ATTENTION TO DIVERSITY AND INCLUSION IN OUR PARTNERSHIPS, WORKFORCE DEVELOPMENT AND RESEARCH ENGAGEMENT. WE WILL ACCELERATE INNOVATION AND RAPIDLY IMPLEMENT EVIDENCE INTO PRACTICE IN ORDER TO ADVANCE HEALTH EQUITY.

CENTER FOR ADVANCED RENAL MICROSCOPIC ANALYSIS

INITIATIVE TO REDUCE AVOIDABLE HOSPITALIZATIONS AMONG NURSING FACILITY RESIDENTS - PAYMENT REFORM

DATA COORDINATING CENTER FOR THE ALCOHOLIC HEPATITIS RESEARCH NETWORK

INDIANA ALZHEIMER'S DISEASE RESEARCH CENTER - PROJECT SUMMARY – IADRC OVERALL THE INDIANA ALZHEIMER’S DISEASE RESEARCH CENTER (IADRC) WAS ESTABLISHED IN 1991 TO BRING INVESTIGATORS AND INSTITUTIONAL RESOURCES AT THE INDIANA UNIVERSITY SCHOOL OF MEDICINE (IUSM) TOGETHER TO ADDRESS THE FUNDAMENTAL CAUSES AND TREATMENT OF ALZHEIMER’S DISEASE (AD) AND RELATED DEMENTIAS (ADRD). DESPITE MANY IMPORTANT GAINS, THE NEED FOR TARGETED RESEARCH IS GREATER THAN EVER, WITH AN ESTIMATED 5.8 MILLION PEOPLE IN THE U.S. SUFFERING FROM AD/ADRD. UNFORTUNATELY, WE DO NOT YET KNOW HOW TO PREVENT AD OR HAVE AN APPROVED DISEASE MODIFYING INTERVENTION. BOTH ARE CRITICAL TO STEM THE GROWTH IN DEMENTIA PREVALENCE. THE OVERARCHING GOAL OF THE IADRC GOING FORWARD IS TO SUPPORT THE GOAL OF THE NAPA TO PREVENT AND EFFECTIVELY TREAT AD BY 2025, THROUGH INNOVATIVE RESEARCH ON ETIOLOGY, EARLY DETECTION, AND THERAPEUTICS. BIOMARKER STUDIES INDICATE THAT PROCESSES LEADING TO AD BEGIN AT LEAST 20 YEARS PRIOR TO DEMENTIA, SUGGESTING THAT SUCCESSFUL INTERVENTIONS MUST BE IMPLEMENTED EARLY. THIS PRESENTS A POTENTIAL OPPORTUNITY FOR EARLY INTERVENTION, BUT THE FIELD IS CHALLENGED BY CRITICAL BARRIERS DECREASING THE PROSPECTS OF TIMELY SUCCESS. THE IADRC HAS IDENTIFIED THE BARRIERS AS: A) THE CURRENT UNDERSTANDING OF ETIOLOGY AND PATHOPHYSIOLOGY IS FRAGMENTED AND INCOMPLETE; B) SENSITIVE, SPECIFIC, AND COST-EFFECTIVE METHODS FOR EARLY DETECTION ARE NOT AVAILABLE; C) THERAPEUTIC DEVELOPMENT IS HAMPERED BY THE HETEROGENEITY AND COMPLEXITY OF ADRD; D) SHORTAGE OF DATA AND TRANSLATIONAL SCIENTISTS; AND, E) INADEQUATE DIVERSITY AT ALL LEVELS. THE IADRC SPECIFIC AIMS ENTAIL INNOVATION TO OVERCOME THESE BARRIERS AND ACCELERATE RESEARCH TOWARD PREVENTION AND EFFECTIVE TREATMENT: 1) SUPPORT, ENHANCE, AND EXPAND INNOVATIVE RESEARCH ON ADRD TARGETING CAUSES, DIAGNOSIS, TREATMENT, AND PREVENTION; 2) PROVIDE CRITICAL RESEARCH RESOURCES AND INFRASTRUCTURE TO SUPPORT EXISTING STUDIES AND ENABLE NEW INNOVATIVE RESEARCH, UTILIZING A WELL-CHARACTERIZED LONGITUDINAL CLINICAL COHORT, WITH PRIORITIZATION OF DIVERSE POPULATIONS INCLUDING UNDERREPRESENTED GROUPS (URG) AND THOSE IN PRECLINICAL AND EARLY SYMPTOMATIC PHASES, INCLUDING SUBJECTIVE COGNITIVE DECLINE AND MILD COGNITIVE IMPAIRMENT, WHICH WILL HELP TO ADVANCE THE IDENTIFICATION OF EASILY ACCESSIBLE BIOMARKERS FOR EARLY DETECTION; 3) IDENTIFY AND PRIORITIZE NOVEL THERAPEUTIC TARGETS FROM HIGH-THROUGHPUT APPROACHES WITH RAPID TRANSLATION TO PROOF- OF-CONCEPT STUDIES USING GENETIC AND OTHER ENRICHMENT STRATEGIES FOR BETTER BIOLOGICAL TARGETING AND REDUCTION OF PHENOTYPIC AND BIOLOGICAL HETEROGENEITY FOR MORE EFFICIENT AND COST-EFFECTIVE CLINICAL TRIALS; 4) INCREASE THE NUMBER OF INVESTIGATORS WITH DEEP EXPERTISE IN ADVANCED DATA SCIENCES TO BRIDGE CELLULAR/MOLECULAR PROCESSES OF NEURODEGENERATION AND CLINICAL PHENOTYPES, AS WELL AS CLINICAL AND TRANSLATIONAL RESEARCHERS WHO CAN MOVE THERAPEUTIC APPROACHES FROM MODEL SYSTEMS TO CLINICAL TRIALS; 5) PROVIDE EDUCATIONAL AND TRAINING OPPORTUNITIES RELATED TO DEMENTIA FOR A BROAD ARRAY OF LEARNERS, WITH SPECIAL EMPHASIS ON INCREASING PARTICIPATION FROM URG IN ADRD RELATED RESEARCH AND HEALTHCARE SPECIALTIES. THE IADRC IS WELL-POSITIONED TO HELP ACHIEVE THE NIA/NAPA GOALS THROUGH SUSTAINED AND IMPACTFUL CONTRIBUTIONS TOWARDS PREVENTION AND TREATMENT OF AD/ADRD.

THE NCAA-DOD GRAND ALLIANCE: CONCUSSION ASSESSMENT, RESEARCH, AND EDUCATION (CARE) CONSORTIUM

HIGH PERFORMANCE COMPUTING SYSTEM ACQUISITION: JETSTREAM - A SELF-PROVISIONED, SCALABLE SCIENCE AND ENGINEERING CLOUD ENVIRONMENT

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND: INDIANA UNIVERSITY - SOUTH BEND

INDIANA DIABETES RESEARCH CENTER

INITIATIVE TO REDUCE AVOIDABLE HOSPITALIZATIONS AMONG NURSING FACILITY RESIDENTS

ADMINISTRATIVE MODIFICATION

VALUE-BASED MEDICAL STUDENT EDUCATION TRAINING PROGRAM

TOWARD SAFER GENE THERAPY FOR HEMOPHILIA A - PROJECT SUMMARY ABSTRACT GENE THERAPY FOR THE X-LINKED BLEEDING DISORDER HEMOPHILIA HOLDS MUCH PROMISE TO ACCOMPLISH A LASTING CURE. FOUR CLINICAL TRIALS UTILIZING ADENO-ASSOCIATED VIRAL (AAV) GENE TRANSFER TO THE LIVERS OF MALES WITH SEVERE HEMOPHILIA ARE CURRENTLY BEING INVESTIGATED IN MULTIPLE PHASE III CLINICAL TRIALS. HEMOPHILIA A (DEFICIENCY IN FACTOR VIII, FVIII), THE MORE COMMON FORM OF THE DISEASE (~80% OF PATIENTS), HAS TRADITIONALLY BEEN MORE DIFFICULT TO TREAT BY GENE THERAPY BECAUSE FVIII IS A LARGE MOLECULE AND NOT EFFICIENTLY EXPRESSED AND SECRETED. NONETHELESS, INITIAL RESULTS DEMONSTRATED COMPLETE CORRECTION OF THE DISEASE. HOWEVER, FVIII LEVELS DECLINED SUBSTANTIALLY OVER TIME, RAISING WORRYING QUESTIONS ABOUT DURABILITY, AND PATIENTS ALSO EXPERIENCED PROLONGED MILD HEPATOTOXICITY DESPITE STEROID DRUG TREATMENT DURING THE FIRST YEAR OF GENE THERAPY. MULTIPLE RECENT OBSERVATIONS RAISE SERIOUS QUESTIONS ABOUT THE SAFETY OF HEPATIC GENE THERAPY FOR HEMOPHILIA A. THESE URGENTLY NEED TO BE ADDRESSED SO THAT THIS PROMISING APPROACH CAN BE SAFELY APPLIED TO PATIENTS AND TO ACHIEVE SUSTAINED CORRECTION. FOR INSTANCE, THE REASONS FOR HEPATOTOXICITY AND FOR THE DECLINE IN FVIII EXPRESSION ARE UNCLEAR, HIGHLIGHTING CRITICAL GAPS IN OUR KNOWLEDGE OF THE INTERACTIONS BETWEEN THE VECTOR AND HEPATOCYTES AND BETWEEN THE FVIII EXPRESSION AND HEPATOCYTES, AS WELL AS THE ROLE OF THE IMMUNE SYSTEM IN LONG-TERM OUTCOME. THERE IS ALSO RENEWED CONCERN ABOUT INSERTIONAL MUTAGENESIS. WE WILL ADDRESS THESE BASIC AND MECHANISTIC QUESTIONS RELATED TO THE BIOLOGY OF AAV AND FVIII. THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT MULTIPLE INTERCONNECTED FEATURES OF AAV AND FVIII BIOLOGY LIMIT DURABILITY OF THERAPEUTIC EXPRESSION AND POSE SERIOUS SAFETY CONCERNS. FURTHER, WE POSTULATE THAT UNRAVELING THESE MECHANISMS WILL ALLOW FOR DESIGN OF VECTORS AND PROTOCOLS THAT MINIMIZE THESE PROBLEMS, THUS RESULTING IN LASTING THERAPY AND ENHANCED SAFETY. THE PROGRAM COMBINES EXPERTISE IN FVIII BIOLOGY, CELLULAR STRESS RESPONSES, IMMUNOLOGY, AND AAV VECTOR BIOLOGY AND IS STRUCTURED INTO 3 SCIENTIFIC PROJECTS, AN ADMINISTRATIVE CORE AND 2 SCIENTIFIC CORES. PROJECT 1 (KAUFMAN) SEEKS TO OVERCOME FVIII PROTEIN MISFOLDING AND CELL TOXICITY. PROJECT 2 (XIAO) WILL UNCOVER THE MECHANISMS THAT LEAD TO FORMATION OF SUBGENOMIC AAV VECTOR PARTICLES THAT FORM DURING VECTOR PRODUCTION THROUGH NUCLEASE AND RECOMBINATION ACTIVITIES. PROJECT 3 (HERZOG) WILL DEFINE THE MECHANISMS OF INNATE AND ADAPTIVE IMMUNE RESPONSES TO AAV-FVIII GENE TRANSFER. THE OBJECTIVES OF THE THREE PROJECTS WILL BE SUPPORTED BY AN ADMINISTRATIVE CORE (CORE A), A CORE THAT PROVIDES HUMAN HEPATOCYTES FOR IN VITRO AND IN VIVO STUDIES (CORE B), AND A CORE THAT PERFORMS DEVELOPMENT AND MOLECULAR ANALYSIS OF AAV VECTORS (CORE C). OVERALL, THIS PROJECT APPLIES THE EXPERTISE OF THE INDIVIDUAL INVESTIGATORS TOWARDS ADDRESSING MAJOR UNANSWERED QUESTIONS IN FVIII BIOLOGY, GENE THERAPY FOR HEMOPHILIA, LIVER-DIRECTED GENE TRANSFER, AND MOLECULAR AND IMMUNOBIOLOGY OF AAV VECTORS.

PERSONALIZED SMALL MOLECULE THERAPY FOR SEVERE ASTHMA AND CYSTIC FIBROSIS.

CENTRAL & FORWARD TRACKING WITH WIRE CHAMBERS.

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND: INDIANA UNIVERSITY - SOUTHEAST

SCIENTIFIC INNOVATION FOR PERSONALIZED SEVERE ASTHMA MANAGEMENT - PROJECT SUMMARY/ABSTRACT OUR OVERALL GOAL IS TO CHARACTERIZE THE CELL BIOLOGY AND PHYSIOLOGY OF RECENTLY IDENTIFIED MECHANISMS UNDERLYING SEVERE ASTHMA. SEVERE ASTHMA IS A DISABLING OBSTRUCTIVE LUNG DISEASE THAT ACCOUNTS FOR THE MAJORITY OF THE MORBIDITY AND MORTALITY ASSOCIATED WITH ASTHMA; IT ACCOUNTS FOR ANNUAL HEALTHCARE COSTS IN EXCESS OF $10 BILLION IN THE UNITED STATES ALONE. SEVERE ASTHMA HAS BEEN A PARTICULAR FOCUS OF OUR THERAPEUTIC DEVELOPMENT EFFORTS. WE HAVE DISCOVERED AND STUDIED THREE NOVEL MECHANISMS RELEVANT TO SEVERE ASTHMA. THESE INCLUDE THE ROLE IN SEVERE ASTHMA OF: 1) SS2 ADRENERGIC RECEPTOR REGULATION BY S-NITROSYLATION; 2) AIRWAY ACIDIFICATION; AND 3) ANDROGEN SIGNALING. EACH OF THESE THREE MECHANISMS HAS THE POTENTIAL TO BE TREATED WITH NOVEL, PERSONALIZED THERAPIES THAT WILL BE STUDIED IN A COMPLEMENTARY FASHION IN THE THIRD AIM OF EACH PROJECT. THREE SYNERGISTIC PROPOSED PROJECTS ARE PROPOSED: PROJECT 1, S-NITROSYLATION SIGNALING IN SEVERE ASTHMA; PROJECT 2, AIRWAY PH REGULATION IN SEVERE ASTHMA; AND PROJECT 3, ANDROGEN SIGNALING IN SEVERE ASTHMA. NOTE THAT A SUBSTANTIAL AMOUNT OF THE SCIENCE, AND MOST OF THE PROPOSED CORES, ARE CURRENTLY INCORPORATED IN AN NHLBI –SPONSORED TRANSLATIONAL P01 AT OUR TWO INSTITUTIONS, INDIANA UNIVERSITY AND CASE WESTERN RESERVE UNIVERSITY. HOWEVER, THE NHLBI IS NOT PLANNING TO RENEW ITS TRANSLATIONAL P01 INITIATIVE. WHAT THIS MEANS FOR THE CURRENT PROPOSAL, HOWEVER, IS THAT THE SCIENTIFIC INTERFACE, AS WELL AS THE CORES, ARE CURRENTLY OPERATIONAL; AND THEY ARE NOT DUPLICATED AT EITHER INSTITUTION. WE PROPOSE TO CONTINUE THESE CORE FUNCTIONS IN THE CURRENT PROPOSAL. THE THREE PROJECTS HAVE SCIENTIFIC SYNERGY. FOR EXAMPLE, DETRIMENTAL DENITROSYLATION (PROJECT 1) IS REVERSED BOTH BY AIRWAY ALKALINIZATION (PROJECT 2) AND BY AIRWAY EPITHELIAL ANDROGEN TREATMENT (PROJECT 3). INTERLEUKIN 17, WHICH DECREASES AIRWAY EPITHELIAL S- NITROSOTHIOL SIGNALING (PROJECT 1) IS INHIBITED BY AIRWAY ALKALINIZATION (PROJECT 2) AND ANDROGEN RECEPTOR SIGNALING (PROJECT 3). INTERLEUKIN 4 GENE EXPRESSION APPEARS TO BE INHIBITED BOTH BY HUMAN AIRWAY ALKALINIZATION (PROJECT 2) AND BY ANDROGEN RECEPTOR SIGNALING (PROJECT 3). THESE AND RELATED INTERACTIONS WILL BE STUDIED IN DETAIL. THE PROGRAM ALSO HAS ROBUST OPERATIONAL SYNERGY. EACH PROJECT WILL MAKE USE OF EACH CORE. IN PARTICULAR, EACH WILL USE DATA AND SPECIMENS FROM THE RESEARCH BRONCHOSCOPY AND BIOSPECIMENS CORE AND FROM THE SEVERE ASTHMA CLINICAL TRIALS CORE; EACH WILL USE CELLS FROM THE PRIMARY HUMAN AIRWAY CELL CULTURE CORE; EACH WILL RELY HEAVILY ON THE PULMONARY BIOSTATISTICS CORE FOR DATA ANALYSIS; AND ALL PROJECTS AND CORES WILL BE COORDINATED BY AN ADMINISTRATIVE CORE. NOTE THAT THE ADMINISTRATIVE CORE WILL ALSO ASSIST ALL PROJECTS WITH DATA DISSEMINATION, WITH SPEAKERS AND WITH ADVISORY BOARDS. NONE OF THE THREE PROJECTS WOULD BE ABLE TO SUPPORT THESE CORE FUNCTIONALITIES AS AN INDEPENDENT R01. AT THE CONCLUSION OF THIS PROGRAM, WE ANTICIPATE HAVING USED OUR BASIC SCIENCE INNOVATIONS TO DEVELOP AT LEAST THREE NOVEL APPROACHES TO MANAGING SEVERE ASTHMA.

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND: INDIANA UNIVERSITY - SOUTH BEND

BLOOMINGTON DROSOPHILA STOCK CENTER AT INDIANA UNIVERSITY

KBASE2: KOREAN BRAIN AGING STUDY, LONGITUDINAL ENDOPHENOTYPES AND SYSTEMS BIOLOGY - PROJECT SUMMARY/ABSTRACT THE KOREAN BRAIN AGING STUDY FOR THE EARLY DIAGNOSIS AND PREDICTION OF AD (KBASE) IS A COMPREHENSIVE PROSPECTIVE COHORT STUDY LAUNCHED AT SEOUL NATIONAL UNIVERSITY (SNU) IN 2014 USING A SIMILAR DESIGN AND METHODS AS THE NORTH AMERICAN ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (ADNI). THE KBASE COHORT CONSISTS OF WELL-CHARACTERIZED PARTICIPANTS INCLUDING COGNITIVELY NORMAL (CN) CONTROLS WITH A WIDE AGE RANGE (20 TO 90 YEARS), MILD COGNITIVE IMPAIRMENT (MCI) AND AD DEMENTIA (AD). A UNIQUE ASPECT OF KBASE IS THE SYSTEMATIC LONGITUDINAL COLLECTION OF COMPREHENSIVE CLINICAL, COGNITIVE AND LIFESTYLE DATA, MULTIMODAL NEUROIMAGING (MRI/MRA, DTI, RSFMRI, AMYLOID, TAU AND FDG PET), AND BIO-SPECIMENS IN KOREA FOR THE FIRST FIVE YEARS (“KBASE1”). SOME KBASE DATA HAVE BEEN ANALYZED AND REPORTED BUT MUCH OF THE EXTENSIVE KBASE DATA SET AND SAMPLES AWAIT COMPREHENSIVE ANALYSIS. THE PROPOSED PROJECT (“KBASE2”) REPRESENTS A COLLABORATION BETWEEN THE NIA ALZHEIMER’S DISEASE SEQUENCING PROJECT (ADSP) AND PARTNERS, INDIANA UNIVERSITY (ADNI GENETICS CORE, INDIANA NIA-DESIGNATED ADRC, AND IU NETWORK SCIENCE INSTITUTE), THE KBASE TEAM AT SNU IN KOREA, UNIVERSITY OF SOUTHERN CALIFORNIA (USC), AND THE UNIVERSITY OF PENNSYLVANIA. OVER 1000 WHOLE GENOME SEQUENCES (WGS) OF KOREAN PARTICIPANTS WILL BE CONTRIBUTED TO THE ADSP, AND THE EXTENSIVE ADSP MULTI-ETHNIC DATA SET WILL BE ANALYZED. WGS DATA WILL BE HARMONIZED BY THE NIA GENETICS AND GENOMICS CENTER FOR AD (GCAD) AND SHARED VIA THE NIA GENETICS OF AD DATA STORAGE SITE (NIAGADS). THE LABORATORY OF NEUROIMAGING (LONI) AT USC WILL SUPPORT SHARING OF MRI AND PET AND RELATED ENDOPHENOTYPES, AS IT DOES FOR ADNI. KBASE2 WILL CONTINUE LONGITUDINAL DATA AND SAMPLE COLLECTION AND PROVIDE HIGH THROUGHPUT WGS AND RNA-SEQ AS WELL AS DATA HARMONIZATION AND SHARING (AIM 1), PERFORM INTENSIVE BRAIN NETWORK-BASED ANALYSES OF LONGITUDINAL AMYLOID, TAU, NEURODEGENERATION AND VASCULAR (A/T/N/V) IMAGING BIOMARKERS IN RELATION TO CLINICAL DATA (AIM 2), EMPLOY INTEGRATIVE SYSTEMS BIOLOGY AND FUNCTIONAL GENOMICS METHODS TO ANALYZE MULTI-OMICS DATA FOR ASSOCIATION WITH A/T/N/V BIOMARKERS FOR AD, AND PROVIDE NEW INSIGHT INTO AD BIOMARKER-RELATED DYSREGULATED GENE MODULES AND PATHWAYS (AIM 3). THE OVERARCHING CONCEPTS DRIVING THIS MULTIDISCIPLINARY INTERNATIONAL COLLABORATIVE PROJECT ARE THAT 1) DEVELOPMENT OF PRECISION MEDICINE FOR AD AND RELATED DISORDERS (ADRD) REQUIRES SYSTEMATIC MULTI-MODAL BIOMARKER COLLECTION IN DIVERSE COHORTS DURING EARLY AT-RISK STAGES OF DISEASE TO IDENTIFY ROBUST DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC TARGETS AND 2) SOPHISTICATED ANALYTIC STRATEGIES THAT ADDRESS THE COMPLEXITY OF MULTI- LAYER MULTIMODAL DATA AND HETEROGENEOUS AND DIVERSE PARTICIPANT COHORTS ARE ESSENTIAL. WE HYPOTHESIZE THAT INTEGRATIVE LONGITUDINAL ANALYSIS OF GENETIC AND -OMICS NETWORKS WITH STRUCTURAL AND FUNCTIONAL BRAIN NETWORKS WILL YIELD NEW DIAGNOSTIC AND TREATMENT-RELEVANT INSIGHTS RELATED TO A/T/N/V AND OTHER AGING RELATED PATHWAYS. RESULTS OF THIS COLLABORATION AND DATA SHARING WILL FACILITATE TRANSLATION OF ADSP FINDINGS FOR THERAPEUTIC DEVELOPMENT IN SUPPORT OF THE NATIONAL ALZHEIMER'S PROJECT ACT GOAL OF PREVENTION AND TREATMENT OF AD BY 2025.

GENETIC SUSCEPTIBILITY AND BIOMARKERS OF PLATINUM-RELATED TOXICITIES

PATHOGENESIS OF COGNITIVE/NEUROLOGIC DEFICITS IN CENTRAL NERVOUS SYSTEM MALARIA

CENTER OF EXCELLENCE FOR INDIVIDUALIZATION OF THERAPY FOR BREAST CANCER

FUTUREGRID: AN EXPERIMENTAL, HIGH-PERFORMANCE GRID TEST-BED

PULMONARY HYPERTENSION BREAKTHROUGH INITIATIVE

CUMULATIVE AND PERSISTENT INTERMEDIATE EFFECTS OF CONCUSSION AND HEAD IMPACT EXPOSURE IN CARE CONSORTIUM MILITARY SERVICE ACADEMY MEMBERS AND NCAA AT

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND: INDIANA UNIVERSITY - NORTHWEST

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND: INDIANA UNIVERSITY - SOUTHEAST

DESEGREGATION ASSISTANCE CENTERS

IMPLEMENTING GENOMIC MEDICINE THROUGH PRAGMATIC TRIALS IN DIVERSE AND UNDERSERVED POPULATIONS ACROSS INDIANA.

HEMATOPOIETIC STEM AND PROGENITOR CELL REGULATION FOR ENHANCED CLINICAL EFFICACY

CAVOPULMONARY ASSIST TO REVERSE THE FONTAN

COMPARATIVE GENOMICS OF PHENOTYPIC VARIATION IN THE COMPOSITAE

INDIANA PINCETON TENNESSEE ASTROBIOLOGY INSTITUTE DETECTION OF BIOSUSTAINABLE ENERGY AND NUTRIENT

AREA HEALTH EDUCATION CENTERS POINT OF SERVICE MAINTENANCE AND ENHANCEMENT

DROSOPHILA GENOMICS RESOURCE CENTER

GENETICS AND TREATMENT OF HEART FAILURE IN THE YOUNG

PARTNERSHIP FOR HIGHER EDUCATION REFORM AIMS TO SUPPORT THREE VIETNAM NATIONAL UNIVERSITIES.

INDIANA PROSPECT

RENOVATION OF THE WELLS RESEARCH CENTER FOR A PEDIATRIC PHENOTYPING CORE

ENERGETICS, DISPARITIES, & LIFESPAN: A UNIFIED HYPOTHESIS

UNDERSTANDING QCD IN THE LIGHT MESON SECTOR (WITH EMPHASIS ON MAPPING GLUONIC EXCITATIONS)...

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND: INDIANA UNIVERSITY - KOKOMO

TRAINING GRANT ON GENETIC ASPECTS OF ALCOHOLISM

THE INDIANA FIRST RESPONDER 3D INDOOR TRACKING CHALLENGE

LRP5 SIGNALING IN BONE MECHANO-RESPONSIVENESS

ANCILLARY STUDIES OF NAFLD AND NASH IN HIV INFECTED ADULTS

CICI: CENTER OF EXCELLENCE: CENTER FOR TRUSTWORTHY SCIENTIFIC CYBERINFRASTRUCTURE

DEVELOPMENT OF PHARMACOTHERAPIES FOR THE TREATMENT OF HYDROCEPHALUS AND ASSOCIATED SEQUELAE

TRANSLATIONAL RESEARCH AND EVOLVING ALCOHOLIC HEPATITIS TREATMENT (TREAT-IU)

TH17 AUTOIMMUNITY TO TYPE V COLLAGEN IN HEART AND LUNG TRANSPLANT

PROKARYOTIC GENOMIC INSTABILITY

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND: INDIANA UNIVERSITY - NORTHWEST

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

DISSEMINATION OF THE AGING BRAIN CARE PROGRAM

OPTICAL IMAGING OF PHOTORECEPTOR FUNCTION AND STRUCTURE

INTERDISCIPLINARY LEADERSHIP EDUCATION

THE ROLE OF PU.1 IN T HELPER 2 FUNCTION

INTRA-ARTICULAR INJECTION OF AMOBARBITAL TO PREVENT POSTTRAUMATIC OSTEOARTHRITIS IN PATIENTS SUSTAINING SEVERE ANKLE TRAUMA

OVERCOMING BARRIERS TO RETINAL GANGLION CELL REPLACEMENT IN EXPERIMENTAL GLAUCOMA - PROJECT SUMMARY / ABSTRACT RETINAL GANGLION CELLS (RGCS) ARE THE OUTPUT NEURONS OF THE RETINA RESPONSIBLE FOR TRANSMITTING INFORMATION ABOUT THE VISUAL WORLD FROM THE EYE TO THE BRAIN. THUS, RGC DAMAGE AND LOSS, A CHARACTERISTIC OF MANY DISORDERS OF THE VISUAL SYSTEM, HAS THE DIRECT CONSEQUENCE OF VISION IMPAIRMENT, OR BLINDNESS WHEN RGC LOSS IS MORE SEVERE. OUR TRANSLATION-ENABLING APPROACH BUILDS ON A VERY WELL-ESTABLISHED, THOROUGHLY CHARACTERIZED AND VALIDATED EXPERIMENTAL GLAUCOMA (EG) MODEL. THIS AFFORDS OUR STUDY THE DISTINCT ADVANTAGE OF CONDUCTING EACH OF THE PROPOSED HYPOTHESIS-DRIVEN EXPERIMENTS WITHIN THE FRAMEWORK OF A RELIABLE MODEL OF RGC DEGENERATION THAT CLOSELY RECAPITULATES THE ANATOMICAL CHANGES AND PATHOPHYSIOLOGICAL PROCESSES OBSERVED IN HUMAN GLAUCOMA. MOREOVER, OUR PRELIMINARY RESULTS ESTABLISH THE FEASIBILITY OF OUR APPROACH, DEMONSTRATING THAT WE HAVE ALREADY ACHIEVED SUCCESSFUL TRANSPLANTATION OF HUMAN INDUCED PLURIPOTENT STEM CELL (IPSC)-DERIVED RGCS INTO THE EG RETINA, WHILE ALSO CHARACTERIZING MAJOR BARRIERS THAT REQUIRE TARGETED SOLUTIONS. HENCE, WE PROPOSE TO EMPLOY A SERIES OF MANIPULATIONS TO BOTH DONOR RGCS AND THE RECIPIENT EG RETINA IN ORDER TO OVERCOME THE EXISTING BARRIERS TO RGC REPLACEMENT AND THUS MAKE A GIANT LEAP FORWARD TOWARD REALIZATION OF THE AUDACIOUS GOAL TO RESTORE VISION IN PERSONS BLINDED BY GLAUCOMA OR OTHER OPTIC NEUROPATHIES. EACH OF OUR AIMS IS SOUNDLY BASED ON EXISTING KNOWLEDGE OF THE RELEVANT BIOLOGY AND WILL LEAD TO MEANINGFUL ENHANCEMENT OF DONOR RGC SURVIVAL, INTEGRATION, AND FUNCTION IN THE GLAUCOMATOUS EG RETINA. WE WILL UTILIZE RIGOROUS QUANTITATIVE ELECTROPHYSIOLOGICAL AND ANATOMICAL ASSESSMENTS FOR TESTING THE HYPOTHESIS AT THE CORE OF EACH AIM. AIM 1 WILL TARGET NEUROINFLAMMATION TO IMPROVE THE LONG-TERM SURVIVAL OF TRANSPLANTED RGCS. WE WILL CREATE HYPOIMMUNOGENIC IPSCS AND MANIPULATE THE HOST RETINAL ENVIRONMENT USING SYSTEMIC IMMUNOSUPPRESSIVE AGENTS OR INHIBITION OF MICROGLIAL ACTIVATION. AIM 2 WILL AUGMENT DONOR CELL SURVIVAL AND INTEGRATION THROUGH MODULATION OF CELLULAR AGE, WITH HOST RETINAL GLIA EXPERIMENTALLY INDUCED TO AN IMMATURE STATE THROUGH CELLULAR REJUVENATION. AIM 3 WILL ENHANCE THE CONNECTIVITY AND AXON OUTGROWTH OF DONOR RGCS IN THE RETINA. DONOR RGCS WILL BE EDITED TO EXPRESS HM3DQ DREADD RECEPTORS FOR CHEMOGENETIC STIMULATION AND MTOR ACTIVATORS. THROMBOSPONDIN WILL BE OVEREXPRESSED IN HOST RETINAL ASTROCYTES AND DONOR RGCS, LEVERAGING ASTROCYTE-DERIVED FACTORS THAT PROMOTE AXONAL OUTGROWTH AND SYNAPTOGENESIS. TOGETHER, THESE AIMS WILL GENERATE A WEALTH OF KNOWLEDGE AND RESOURCES FOR THE SCIENTIFIC COMMUNITY AND BRING US SIGNIFICANTLY CLOSER TO THE REALITY OF VISION RESTORATION THROUGH RGC REPLACEMENT.

TRAINING PROGRAM IN INTEGRATIVE DEVELOPMENTAL PROCESS

LONG TERM EFFECTS OF ACUTE RENAL FAILURE

CENTER FOR THE INVESTIGATION OF FACTOR VIII INHIBITORS AND GLYCOSYLATION

CLINICAL RESEARCH ON NON-ALCOHOLIC STEATOHEPATITIS

INDIANA CORE CENTER FOR CLINICAL RESEARCH IN MUSCULOSKELETAL HEALTH

MECHANISMS OF PROKARYOTIC EVOLUTION

ACCOMMODATION AND DEFOCUS IN THE INFANT VISUAL SYSTEM

ENHANCING IMMUNE REGULATION IN GENE THERAPY FOR HEMOPHILIA

MODELING INNER EAR DIFFERENTIATION WITH PLURIPOTENT STEM CELLS

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND: INDIANA UNIVERSITY - KOKOMO

HOW INSULIN BINDS TO THE INSULIN RECEPTOR

THE NH EXPLANATORY TRIALS NETWORK: SUPPORTING TRANSFORMATION BY ENHANCING PARTNERSHIPS (THE NEXT STEPS). - THE PROPOSED PROJECT, NEXT STEPS (NURSING HOME EXPLANATORY CLINICAL TRIALS: SUPPORTING TRANSFORMATION BY ENHANCING PARTNERSHIPS) NETWORK, CREATES A NATIONAL INFRASTRUCTURE THAT WILL ADDRESS SYSTEMIC BARRIERS TO CONDUCTING RESEARCH IN NURSING HOMES (NHS). NHS CARE FOR PEOPLE WITH SERIOUS, COMPLEX MEDICAL ILLNESSES AND ARE A CRITICAL SITE OF CARE FOR PEOPLE WITH ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD). THE PROPOSED INFRASTRUCTURE IS NEEDED TO IDENTIFY AND OVERCOME THE MULTIPLE CHALLENGES TO CONDUCTING RESEARCH IN THIS SETTING OF CARE, WHICH INCLUDE NAVIGATING REGULATORY AND RECRUITMENT CHALLENGES FOR PEOPLE WITH ADRD. THE NEXT STEPS NETWORK AIMS TO PROVIDE INTEGRATED SUPPORT FOR INVESTIGATORS TO CONDUCT EQUITABLE, EXPLANATORY TRIALS IN NURSING HOMES. NEXT STEPS WILL CREATE A COLLABORATIVE COMMUNITY OF NH LEADERS, STAFF, RESIDENTS AND CARE PARTNERS, CLINICIANS, AND RESEARCHERS TO IDENTIFY RESEARCH PRIORITIES FOR THE FIELD AND DEVELOP ACTION PLANS TO ADDRESS THEM. THIS WILL BE ACCOMPLISHED VIA PROJECT CORES INCLUDING CENTRAL COORDINATION; RECRUITMENT AND RETENTION; METHODS, MEASURES, AND DATA; AND PROJECTS AND TRAINING. CONSENSUS-BASED BEST PRACTICES FOR NH CLINICAL TRIALS WILL BE USED TO CREATE TOOLKITS AND RESEARCH GUIDANCE AND FOSTER COLLABORATIONS. A PILOT PROJECTS PROGRAM AND RESEARCH MENTORSHIP WILL CREATE INCREASED NATIONAL CAPACITY TO CONDUCT NH CLINICAL TRIALS. A KEY COMPONENT OF THIS PROJECT IS THE BI-DIRECTIONAL COLLABORATION WITH THE LONG-TERM CARE DATA COOPERATIVE (LTCDC), WHICH HAS CREATED INTEGRATED DATASETS FOR HUNDREDS OF THOUSANDS OF NURSING HOME RESIDENTS. THE NEXT STEPS NETWORK REAL WORLD DATA SCHOLARS AND PILOT GRANT AWARDEES WILL UTILIZE THE LTCDC FOR PROPOSED PROJECTS. THE DEVELOPMENT OF EXPERIENTIAL LEARNING MODELS WILL PROVIDE EMBEDDED OPPORTUNITIES FOR COLLABORATION AND LEARNING FOR RESEARCHERS IN THE NURSING HOME SETTING. RESEARCH AND INDUSTRY/ADVOCACY ADVISORY PANELS AND PARTNER WORKGROUPS WILL REPRESENT KEY VIEWPOINTS IN NURSING HOME CARE AND INFORM ALL ASPECTS OF THE PROJECT. THE PROJECT TEAM WILL FOCUS ON DISSEMINATING BEST PRACTICES, PILOT PROJECT FINDINGS AND HOSTING ANNUAL MEETINGS, PRESENTING AT NATIONAL CONFERENCES AND CONVENING REGIONAL PARTNER MEETINGS TO ENSURE EFFECTIVE DISSEMINATION OF KEY FINDINGS. THE NEXT STEPS NETWORK WILL ENABLE RESEARCHERS FROM DIFFERENT DISCIPLINES TO COLLABORATE, WITH A GOAL OF INCREASING THE NUMBER AND QUALITY OF CLINICAL TRIALS CONDUCTED IN NHS, INCLUDING THOSE THAT FOCUS ON PREVENTION, MEDICAL THERAPEUTICS, BEHAVIORAL, HEALTH SERVICES INTERVENTIONS, AND THE CARE OF SPECIAL POPULATIONS INCLUDING PEOPLE WITH ADRD. NEXT STEPS WILL CREATE STRONG LINKAGES BETWEEN RESEARCHERS, INDUSTRY, AND OTHER CRUCIAL PARTIES, FOSTERING EVIDENCE-BASED INNOVATIONS ON KEY PRIORITIES TO OPTIMIZE RESIDENT CARE AND QUALITY OF LIFE FOR THOSE LIVING, SUPPORTING LOVED ONES, AND WORKING IN NHS.

IRNC: AMI: NETSAGE - AN OPEN, PRIVACY-AWARE, NETWORK MEASUREMENT, ANALYSIS, AND VISUALIZATION SERVICE

CICI: CCOE: TRUSTED CI: ADVANCING TRUSTWORTHY SCIENCE

THIS AGREEMENT PROVIDES ASSISTANCE TO THE TRUSTEES OF INDIANA UNIVERSITY TO IMPLEMENT ITS PROJECT TO SUPPORT THE GREAT LAKES RESTORATION INITIATIVE (GLRI) TO PROTECT AND RESTORE THE CHEMICAL, PHYSICAL AND BIOLOGICAL INTEGRITY OF THE GREAT LAKES BASIN ECOSYSTEM. SPECIFICALLY, THE RECIPIENT WILL OPERATE THE INTEGRATED ATMOSPHERIC DEPOSITION NETWORK (IADN), MONITORING ATMOSPHERIC LOADINGS OF TOXIC ORGANIC COMPOUNDS TO THE GREAT LAKES FROM SIX SITES ON THE SHORES OF THE GREAT LAKES.

THIS PROJECT SUPPORTS THE GREAT LAKES RESTORATION INITIATIVE (GLRI) AND THE GREAT LAKES WATER QUALITY AGREEMENT, PURSUANT TO PUBLIC LAW 113-76. THE I

INDIANA UNIVERSITY (IU) CLINICAL CENTER FOR CHRONIC PANCREATITIS CLINICAL RESEARCH NETWORK

AREA HEALTH EDUCATION CENTERS POINT OF SERVICE MAINTENANCE AND ENHANCEMENT

IU CLINICAL CENTER: DRUG INDUCED LIVER INJURY NETWORK

BILIARY ATRESIA CHOLESTATIC LIVER DISEASES AND CYSTIC FIBROSIS: INDIANA UNIVERS

ACADEMIC-COMMUNITY EPINET (AC-EPINET): MITIGATING BARRIERS TO CARE

ADVANCING THE EPIDEMIOLOGY AND MANAGEMENT OF POST-COVID-19 CONDITIONS THROUGH SURVEILLANCE AND RESEARCH - INDIVIDUALS INFECTED WITH THE SARS-COV-2 VIRUS (WHICH CAUSES COVID-19) CAN EXPERIENCE PERSISTENT SYMPTOMS MANY MONTHS AFTER ACUTE INFECTION. THESE LINGERING SYMPTOMS ARE REFERRED TO AS POST-COVID CONDITIONS (PCCS), ALSO KNOWN AS “LONG COVID” OR POST-ACUTE SEQUALAE. PRECISE, POPULATION-BASED ESTIMATES OF THE INCIDENCE AND PREVALENCE OF PCCS USING RELIABLE METHODS ARE UNKNOWN. THE PURPOSE OF THIS PROJECT IS TO ENHANCE SURVEILLANCE OF PCCS IN ORDER TO BETTER ESTIMATE THE INCIDENCE AND PREVALENCE OF PCCS AS WELL AS MEASURE THE BURDEN AND OUTCOMES ON POPULATIONS IMPACTED BY PCCS. USING INTEGRATED ELECTRONIC HEALTH RECORDS OF INDIVIDUALS WHO HAVE TESTED POSITIVE FOR SARS-COV-2, INDIANA UNIVERSITY (IU) AND THE REGENSTRIEF INSTITUTE, IN COLLABORATION WITH LOCAL CLINICAL AND PUBLIC HEALTH PARTNERS AS WELL AS THE CDC AND PCC COORDINATING CENTER, WILL DEVELOP A COMPREHENSIVE, STATEWIDE SURVEILLANCE SYSTEM FOR PCCS. FIRST, WE WILL DEFINE, EXTRACT, AND VALIDATE A RETROSPECTIVE, POPULATION-LEVEL COHORT OF DIVERSE INDIVIDUALS WITH SARS-COV-2 INFECTION. THE COHORT WILL EXPAND OVER TIME, ENABLING MEASUREMENT OF INCIDENCE AND PREVALENCE OF PCCS LONGITUDINALLY. SECOND, WE WILL RECRUIT THREE AGE-BASED COHORTS (<12 YEARS, 12-17 YEARS, 18+ YEARS) TO PROSPECTIVELY TRACK INDIVIDUALS WITH RECENT SARS-COV-2 INFECTION TO MEASURE THE BURDEN AND OUTCOMES FOR INDIVIDUALS WITH PCCS. OUR MULTI-PRONGED SURVEILLANCE APPROACH WILL ENABLE MEASUREMENT OF THE CLINICAL SPECTRUM, PROGRESSION, INCIDENCE, AND PREVALENCE OF PCCS IN DIVERSE POPULATIONS. OUR WORK WILL LEVERAGE THE ROBUST HEALTH INFORMATION INFRASTRUCTURE IN INDIANA THAT INCLUDES DATA EXCHANGED BETWEEN CLINICAL AND PUBLIC HEALTH PARTNERS. IT WILL FURTHER SUPPORT THE TRAINING OF JUNIOR SCIENTISTS WHO WILL BE PART OF A FUTURE PUBLIC HEALTH WORKFORCE WITH SKILLS IN PUBLIC HEALTH INFORMATICS AS WELL AS DATA SCIENCE.

EXPERIMENTAL NUCLEAR PHYSICS AND FUNDAMENTAL INTERACTIONS AT INDIANA UNIVERSITY

ALLIANCE TO DISSEMINATE ADDICTION PREVENTION AND TREATMENT (ADAPT): A STATEWIDE LEARNING HEALTH SYSTEM TO REDUCE SUBSTANCE USE AMONG JUSTICE-INVOLVED YOUTH IN RURAL COMMUNITIES.

GENOMICS OF PULMONARY VASCULAR DISEASE

USING COMPLEX VIDEO STIMULI TO ELUCIDATE ATYPICAL BRAIN FUNCTIONING IN ASD

INDIANA CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE (UL1)

EXPERIMENTAL NUCLEAR PHYSICS AND FUNDAMENTAL INTERACTIONS AT INDIANA UNIVERSITY

STUDIES IN NUCLEAR PHYSICS AND FUNDAMENTAL INTERACTIONS AT INDIANA UNIVERSITY

POST DPP FOLLOWUP STUDY

IRNC:PRONET: TRANSPAC3 - ASIA-US HIGH PERFORMANCE INTERNATIONAL NETWORKING

REGULATION OF PHI AND FLUID FLUX IN CORNEAL ENDOTHELIUM

NATIONAL GENE VECTOR BIOREPOSITORY AND COORDINATING CENTER AT INDIANA UNIVERSITY

INTERPLAY OF TRANSITION METAL HOMEOSTASIS AND REACTIVE SULFUR SPECIES IN BACTERIAL PATHOGENS

HOST ADAPTATION OF THE LYME DISEASE SPIROCHETE

CLINICAL PHARMACOLOGY TRAINING GRANT

TRANSFORMING INDIANA UNIVERSITY NORTHWEST FOR OPPORTUNITIES IN STEM (TRIUNFOS)

ORPHANED & SEPARATED CHILDREN'S ASSESSMENT RELATED TO THEIR HEALTH & WELL-BEING

SMOOTH MUSCLE MECHANISMS IN DYNAMIC AIRWAY PROPERTIES

CIF21 DIBBS: MIDDLEWARE AND HIGH PERFORMANCE ANALYTICS LIBRARIES FOR SCALABLE DATA SCIENCE

IRNC: PRONET: ACE - AMERICA CONNECTS TO EUROPE

IMMUNOLOGY OF FACTOR IX GENE TRANSFER TO LIVER

NOVEL ROLE OF REF-1 IN PANCREATIC CANCER ETIOLOGY AND PROGRESSION

IRNC-BACKBONE- TRANSPAC4 - PRAGMATIC APPLICATION-DRIVEN INTERNATIONAL NETWORKING

INDIANA MEDICAL SCIENTIST/ENGINEER TRAINING PROGRAM

BASIC/CORE AREA HEALTH EDUCATION CENTER

CICI: CSRC: RESEARCH SECURITY OPERATIONS CENTER (RESEARCHSOC)

BASIC SCIENCE STUDIES ON GENE THERAPY OF BLOOD DISEASES

MECHANISM OF RNA SYNTHESIS AND 5'-CAPPING BY DENGUE VIRUS NS5 POLYMERASE

HIGH ENERGY EXPERIMENTAL AND THEORETICAL PARTICLE PHYSICS

INFLATION REDUCTION ACT THE URBAN GREEN INFRASTRUCTURE RESILIENCE COHORT FOR INDIANAS DISADVANTAGED COMMUNITIES

THIS ASSISTANCE WILL PROVIDE CONTINUED IMPLEMENTATION OF THE INTEGRATED ATMOSPHERIC DEPOSITION NETWORK (IADN) AS MANDATED BY ANNEX 15 OF THE GREAT LA

MOLECULAR AND GENETIC STUDIES OF NMNAT2 IN NEUROPROTECTION

THEORETICAL STUDIES IN NUCLEAR AND HADRONIC PHYSICS

DEVELOPING A MRI-GUIDED DISEASE-MODIFYING THERAPY FOR POST INFARCTION CHRONIC HEART FAILURE

INDIANA STEM LSAMP

DIGITAL DETECTION OF DEMENTIA STUDIES (D CUBED STUDIES).

MUSCLE PROGENITOR CELL-BASED IMPLANTS FOR DYNAMIC LARYNGEAL MUSCLE RECONSTRUCTION

GROWTH FACTORS IN THE DEVELOPMENT AND PHYSIOLOGY OF GENICULATE TASTE NEURONS

IMPROVING PATIENT-CENTERED OUTCOMES RESEARCH IN PEDIATRIC SUBSPECIALITIES

MEMORY CIRCUITRY IN MCI AND EARLY ALZHEIMER'S DISEASE

IRNC: CORE IMPROVEMENT: TRANSPAC5: MULTILATERAL PARTNERSHIPS TO ACCELERATE INTERNATIONAL RESEARCH AND EXPERIMENTATION

IRNC: CORE IMPROVEMENT: NETWORK FOR EUROPEAN, AMERICAN, AFRICAN, AND ARCTIC RESEARCH (NEA3R)

IMMUNOLOGY AND INFECTIOUS DISEASES

THE EAST AFRICA CONSORTIUM FOR HPV AND CERVICAL CANCER IN WOMEN LIVING WITH HIV/AIDS

IBCST - COMPETITIVE RENEWAL OF MSM: MULTISCALE STUDIES OF SEGMENTATION IN VERTERB

INSTITUTIONAL CAREER DEVELOPMENT CORE

POXVIRUS MODULATION OF IMMUNE RESPONSES

INTERDISCIPLINARY LEADERSHIP EDUCATION

ROLE OF SPHINGOLIPID PATHWAYS IN THE PATHOBIOLOGY OF PAH

EFFECT OF VIRAL CAPSID STABILITY AND FLEXIBILITY ON VIRAL PATHOGENESIS

MANY-BODY NUCLEAR DYNAMICS

CENTER FOR TRUSTWORTHY SCIENTIFIC CYBERINFRASTRUCTURE

ANAPLEROTIC REPROGRAMMING OF ENDOTHELIAL CELLS IN PULMONARY HYPERTENSION.

CD28-MEDIATED REGULATION OF MULTIPLE MYELOMA CELL PROLIFERATION AND SURVIVAL

STUDIES IN NUCLEAR PHYSICS AND FUNDAMENTAL INTERACTIONS AT INDIANA UNIVERSITY -NEW INFORMATION ON THE BEHAVIOR OF PROTONS AND NEUTRONS, THE BUILDING BLOCKS OF THE ATOMIC NUCLEI, CAN ADVANCE PHYSICS AND CLARIFY THE INTERPRETATION OF ASTRONOMICAL OBSERVATIONS. THE PIS WILL CONDUCT A FOCUSED SET OF PRECISION MEASUREMENTS INVOLVING PROTONS AND NEUTRONS TO PROBE THE POORLY-UNDERSTOOD INTERNAL DYNAMICS INSIDE THE PROTON, SEARCH FOR NEW FORCES OF NATURE, AND QUANTIFY SOME OF THE KEY NUCLEAR REACTION RATES WHICH TEST THE PREDICTIONS OF THE BIG BANG THEORY OF THE UNIVERSE. THESE RESEARCH ACTIVITIES DEVELOP NEW TECHNOLOGIES AND EDUCATE THE NEXT GENERATION OF SKILLED PHD SCIENTISTS FOR JOBS IN RESEARCH AND TEACHING UNIVERSITIES, INDUSTRY AND NATIONAL LABS, AND MEDICAL AND COMPUTER TECHNOLOGY. THE PIS STUDY THE POORLY-UNDERSTOOD DYNAMICS OF HOW THE PROTON'S SPIN ANGULAR MOMENTUM IS BUILT FROM QUARKS AND GLUONS AND THEIR ORBITAL MOTION AND HOW THE QUARKS AND GLUONS `FRAGMENT? INTO THE PARTICLES THAT ARE OBSERVED IN DETECTORS. THE PIS MEASURE THE SIZE OF CONSTRUCTIVE INTERFERENCE IN NEUTRINO SCATTERING FROM PROTONS AND NEUTRONS IN THE NUCLEUS TO TEST THE STANDARD MODEL OF PARTICLES AND TO CALIBRATE SUPERNOVA NEUTRINO DETECTORS. THE PIS MEASURE DIFFERENT TYPES OF SPIN-DEPENDENT NEUTRON INTERACTIONS WITH MATTER, SOME WHICH CAN ONLY BE CAUSED BY NEW TYPES OF FORCES, AND MEASURE THE RATES OF CERTAIN NUCLEAR REACTIONS WHICH ARE KNOWN TO BE IMPORTANT TO UNDERSTAND THE DYNAMICS OF THE EARLY UNIVERSE. 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.

NETWORK PROPERTIES OF CIRCADIAN CLOCK MODULATION AND ENTRAINMENT

EMBEDDING PHARMACOGENOTYPING IN AN INTEGRATED HEALTH SYSTEM FOR THE UNDERSERVED

SPEECH PERCEPTION AND SPOKEN WORD RECOGNITION

STUDIES IN NUCLEAR PHYSICS AND FUNDAMENTAL INTERACTIONS AT INDIANA UNIVERSITY

R&D, SCIENCE AND ENGINEERING, IN THE AREA OF SOCIAL SCIENCES, NOT ELSEWHERE CLASSIFIED

GENETIC ANALYSIS OF MECHANISMS OF CHLAMYDIAL IMMUNE EVASION

INDIANA UNIVERSITY BLOOMINGTON (IUB) CENTER FOR CANNABIS, CANNABINOIDS, AND ADDICTION (C3A) - ABSTRACT WE ARE PROPOSING TO ESTABLISH THE IU BLOOMINGTON CENTER FOR CANNABIS, CANNABINOID, AND ADDICTION (IUB-C3A) AS A NIDA CORE CENTER FOR EXCELLENCE TO SERVE ADDICTION RESEARCHERS BOTH IN THE CENTRAL MIDWEST AND ACROSS THE NATION. THIS CENTER WILL OFFER CORE SERVICES TO FURTHER OUR UNDERSTANDING OF FUNDAMENTAL BRAIN PROCESSES LEADING TO OR FOLLOWING THE USE OF ADDICTIVE DRUGS, PARTICULARLY CANNABIS. THE IUB-C3A WILL CONSIST OF TWO SERVICE CORES, A PILOT PROJECT CORE, AND AN ADMINISTRATIVE CORE. THE ADMINISTRATIVE CORE WILL PROVIDE A WELL- DEFINED STRUCTURE FOR EFFICIENT CENTER MANAGEMENT, FOR PUBLIC OUTREACH, FOR ORGANIZING THE CENTER’S COURSES, AS WELL AS FOR PRESERVING AND MAKING EASILY ACCESSIBLE THE DATA GENERATED BY THE CENTER’S SCIENTISTS. THE BIOACTIVE LIPID MEDIATORS CORE (BLMC) WILL PROVIDE ANALYTICAL SERVICE FOR DETECTING CANNABINOIDS AND OTHER BIOACTIVE LIPID MEDIATORS IN BIOLOGICAL SAMPLES AND RUN A SUMMER COURSE DIRECTED TOWARDS UNDERSERVED MINORITY COLLEGE STUDENTS INTERESTED IN STEM CAREERS. THE MULTISCALE IMAGING CORE (MSIC) WILL OFFER SERVICES AND TRAINING ACROSS A RANGE OF LIGHT MICROSCOPIC IMAGING MODALITIES. THE MULTIPHOTON RESOURCE OF THE MSIC WILL INCLUDE TRAINING AND ACCESS TO LONGITUDINAL IN VIVO IMAGING OF CALCIUM AND OTHER SENSORS (E.G., NEUROMODULATORS SUCH AS ENDOCANNABINOIDS, DOPAMINE, AND SEROTONIN) FROM VERY YOUNG AGES AS WELL AS LONG-RANGE PATHWAY TRACING IN “CLEARED” BRAIN SPECIMENS. THE STORM/CONFOCAL RESOURCE OF THE MSIC WILL OFFER USERS THE OPPORTUNITY TO PERFORM CORRELATIVE STRUCTURE/FUNCTION STUDIES FROM THE MACRO- TO NANOSCALE LEVEL AND WILL ALSO OFFER COURSES ON THESE TECHNIQUES. BOTH CORES WILL EMPHASIZE INNOVATION AND INTEGRATION OF THEIR RESPECTIVE TECHNIQUES, AS OUTLINED IN THE PROPOSAL. THE PILOT PROJECT CORE WILL SOLICIT PILOT PROJECTS FROM C3A AFFILIATES AND INVESTIGATORS OUTSIDE OF THE DRUG ABUSE FIELD AND MENTOR THEM THROUGH THE PROCESS OF OBTAINING DATA AND NIDA SUPPORT FOR THEIR RESEARCH IDEAS. THE PIS FOR THE IUB-C3A HAVE A LONG HISTORY OF PRODUCTIVE COLLABORATIONS, INCLUDING PUBLISHING MORE THAN SIXTY PAPERS TOGETHER AND HOLDING SEVERAL MPI NIH GRANTS. THE IUB-C3A IS CONCEPTUALIZED AS A RESOURCE THAT WILL OFFER OPPORTUNITIES FOR OTHER ADDICTION INVESTIGATORS ACROSS THE CENTRAL MIDWEST (SOUTHERN ILLINOIS, INDIANA, KENTUCKY, OHIO, AND WEST VIRGINIA), A REGION STRONGLY AFFECTED BY DRUG ADDICTION, AND ACROSS THE NATION. THE IUB-C3A AIMS TO INCREASE DIVERSITY IN ADDICTION RESEARCH THROUGH A COMBINATION OF SUMMER EXPERIENCES AND PILOT PROJECT PROGRAMS TARGETED TO UNDER-REPRESENTED POPULATIONS IN NEUROSCIENCE AND ADDICTION. A CORE GOAL OF THESE PROGRAMS IS TO BRING TALENTED INDIVIDUALS INTO THE FIELD OF ADDICTION RESEARCH. WE ANTICIPATE THAT THEY WILL APPLY CREATIVE DIRECTIONS, RIGOROUS EXPERIMENTAL APPROACHES, AND NOVEL WAYS OF THINKING TO A MAJOR PUBLIC HEALTH PROBLEM. THE STRONG SUPPORT OF INDIANA UNIVERSITY TO THIS ENDEAVOR IS EVIDENT BY GENEROUS MATCHING FUNDS FOR BOTH EQUIPMENT PURCHASES AND OUR DIVERSITY PROGRAMS. ALL OF THESE FACTORS PREDICT THAT THE IUB-C3A WILL BECOME A REGIONAL AND NATIONAL RESOURCE FOR BETTER UNDERSTANDING AND DEVELOPING TREATMENTS FOR ADDICTIVE DISORDERS AND THEIR CONSEQUENCES.

OPTIMIZATION OF SHIP1 INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE - PROJECT SUMMARY/ABSTRACT ALZHEIMER'S DISEASE (AD) IS A FATAL NEURODEGENERATIVE CONDITION CHARACTERIZED BY COGNITIVE DECLINE, Β- AMYLOID (AΒ) PLAQUES, AND TAU-CONTAINING NEUROFIBRILLARY TANGLES (NFTS). RECENT HUMAN GENETIC EVIDENCE SUPPORTS AN IMPORTANT ROLE FOR MICROGLIA IN THE ETIOLOGY OF AD. MICROGLIA ARE THE RESIDENT IMMUNE CELLS IN THE BRAIN AND PLAY IMPORTANT ROLES IN MAINTAINING NEURONAL HEALTH AND PROPER IMMUNOMODULATION OF NEIGHBORING GLIAL CELLS. MICROGLIA CLEAR NEUROTOXINS, AΒ OLIGOMERS, AND AΒ PLAQUES, AND THEREBY MITIGATE AN INFLAMMATORY MICROENVIRONMENT THAT IS TOXIC TO NEURONS. LOWER EXPRESSION OF TREM2, A CELL SURFACE MICROGLIAL IMMUNE RECEPTOR, AND HYPOMORPHIC VARIANTS (E.G. R47H), ARE CORRELATED WITH AN INCREASED RISK OF DEVELOPING OF AD. CONVERSELY, ENHANCED SIGNALING DOWNSTREAM FROM TREM2 VIA THE HYPERMORPHIC P522R VARIANT OF PLCΓ2 REDUCES RISK FOR AD. THIS HUMAN GENETIC EVIDENCE SUGGESTS THAT MICROGLIA THAT ARE MORE SENSITIVE TO TREM2- MEDIATED SIGNALING PROTECT AGAINST NEURODEGENERATION. SRC HOMOLOGY 2 DOMAIN CONTAINING INOSITOL POLYPHOSPHATE 5-PHOSPHATASE 1 (SHIP1) IS A MEMBER OF THE INOSITOL POLYPHOSPHATE-5-PHOSPHATASE (INPP5) FAMILY OF PHOSPHATIDYLINOSITOL PHOSPHATASES. INPP5D, THE GENE THAT ENCODES SHIP1, HAS ALSO BEEN IDENTIFIED AS A RISK GENE FOR AD. SHIP1, PLAYS A KEY ROLE REGULATING PATHWAYS DOWNSTREAM FROM IMMUNE RECEPTORS, INCLUDING TREM2 AND FCΓRIIB. SHIP1, BINDS IMMUNORECEPTOR TYROSINE-BASED INHIBITION MOTIFS (ITIMS) WHERE IT COMPETES WITH KINASES AND MODULATES PHOSPHATIDYLINOSITOL-DEPENDENT SIGNALING. WE HYPOTHESIZE THAT INHIBITION OF SHIP1 WILL IMPROVE TREM2-MEDIATED MICROGLIAL RESPONSES TO NEUROTOXINS, AND PROMOTE AN OVERALL NEUROPROTECTIVE PHENOTYPE TO MICROGLIAL STATES , AND THEREBY SLOW COGNITIVE DECLINE. FURTHERMORE, SINCE RECENTLY APPROVED DISEASE MODIFYING ANTI-AΒ ANTIBODIES DEPEND IN PART ON FC RECEPTOR ACTIVATION OF MICROGLIA, SHIP1 INHIBITORS MAY ALSO BE COMBINED WITH ANTI-AΒ ANTIBODIES TO IMPROVE THEIR EFFICACY. TO TEST THIS HYPOTHESIS, WE WILL OPTIMIZE THE POTENCY AND DRUG-LIKE PROPERTIES OF SHIP1 INHIBITORS FROM IDENTIFIED CHEMICAL SCAFFOLDS (AIM 1). WE WILL IDENTIFY THE EFFECT OF SHIP1 INHIBITION ON MICROGLIAL STATES IN MOUSE BRAIN, DEFINE PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) RELATIONSHIPS, AND DETERMINE THE LEVEL AND DURATION OF SHIP1 INHIBITION REQUIRED FOR EFFICACY IN A MOUSE MODEL OF AD (AIM 2). WITH AN UNDERSTANDING OF THE TARGET ENGAGEMENT REQUIRED FOR EFFICACY, SHIP1 INHIBITORS WITH SUFFICIENT HUMAN POTENCY AND DRUG-LIKE PROPERTIES WILL BE USED TO DEVELOP TARGET ENGAGEMENT AND TRANSLATIONAL BIOMARKER ASSAYS FOR HUMAN STUDIES (AIM 3). COLLECTIVELY, THESE STUDIES WILL SUPPORT THE TRANSLATION OF NEW MOLECULAR ENTITIES INTO THE CLINIC THAT WILL REDUCE NEUROINFLAMMATION AND AMYLOID BURDEN AND IMPROVE COGNITION, THUS ADVANCING THE NIH/NIA MISSION TO DEVELOP NOVEL THERAPIES FOR AD.

PROKARYOTIC GENE REGULATION BY LIGHT AND OXYGEN

PHARMACOGENETICS RESEARCH NETWORK AND KNOWLEDGE BASE

PROXIMAL TUBULE ALBUMIN TRANSPORT IN DISEASE STATES

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND: INDIANA UNIVERSITY - EAST

CYTOKINE REGULATION OF SKIN BARRIER FUNCTION

LEVERAGING NEUROIMAGING BIOMARKERS TO UNDERSTAND THE ROLE OF SOCIAL NETWORKS IN ALZHEIMER'S DISEASE

DEVELOPMENTAL CONSEQUENCES OF BIRTH INTERVENTIONS

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.

METABOLIC STRESS RESPONSES AND EIF2 KINASE GCN2

ADAPTIVE OPTICS IMAGING OF HUMAN RETINAL VASCULAR STRUCTURE AND FUNCTION

INTEGRATED SPATIAL INTERROGATION OF CELLULAR AND MOLECULAR SIGNATURES OF HUMAN KIDNEY DISEASE - (PLEASE KEEP IN WORD, DO NOT PDF) ENTER THE TEXT HERE THAT IS THE NEW ABSTRACT INFORMATION FOR YOUR APPLICATION. THIS SECTION MUST BE NO LONGER THAN 30 LINES OF TEXT. ABSTRACT THERE IS A FUNDAMENTAL GAP IN UNDERSTANDING THE MECHANISMS THAT DETERMINE PROGRESSION IN HUMAN KIDNEY DISEASE. THE LONG-TERM GOAL IS TO CHARACTERIZE KEY CELLULAR AND MOLECULAR PATHWAYS REGULATING PROGRESSION OF ACUTE AND CHRONIC KIDNEY DISEASES (AKI AND CKD), TO IDENTIFY NOVEL MARKERS THAT ASSESS DISEASE PROGRESSION, AND TO DEVELOP SPECIFIC THERAPEUTIC INTERVENTIONS TARGETING THESE PATHWAYS. THERE IS OFTEN HETEROGENEITY IN THE PATTERN OF KIDNEY INJURY WHEREBY VARIOUS CELL TYPES AND CELL STATES ARE DIFFERENTIALLY DISTRIBUTED ACROSS FOCAL REGIONS OF A BIOPSY SPECIMEN. IMMUNE CELL SUB-POPULATIONS ARE OBSERVED IN THESE INJURY REGIONS, SUGGESTING ROBUST CROSS-TALK BETWEEN INFILTRATING IMMUNE CELLS AND THE RESIDENT RENAL EPITHELIAL, ENDOTHELIAL, AND STROMAL CELLS. FURTHER, THESE REGIONAL MOLECULAR DISEASE PHENOTYPES OFTEN ARE NOT FULLY APPRECIATED ON STANDARD HISTOPATHOLOGIC ASSESSMENT. THEREFORE, THERE IS A CRITICAL NEED TO EXPAND OUR EFFORTS TO COMPREHENSIVELY LOCALIZE CELL TYPES AND CELL STATES IN THE KIDNEY, SUB-PHENOTYPE DISEASE, UNCOVER CELL-CELL INTERACTIONS, AND UNDERSTAND THE CELLULAR AND MOLECULAR PHENOTYPES UNDERLYING MORPHOLOGIC CHANGES IN THE KIDNEY. THE OVERARCHING HYPOTHESIS OF THIS PROPOSAL IS THAT MECHANISMS OF KIDNEY DISEASE CAN ONLY BE UNDERSTOOD WHEN THE DIVERSITY OF CELLULAR AND MOLECULAR PHENOTYPES ARE INTERPRETED IN THE SPATIAL CONTEXT OF THE INDIVIDUALS’ KIDNEY. THE CENTRAL HYPOTHESIS WILL BE TESTED USING AN INTEGRATED PIPELINE OF SPATIALLY RESOLVED IMAGING, TRANSCRIPTOMIC, AND PROTEOMIC TECHNOLOGIES THAT WILL CAPTURE THE FEATURES OF KIDNEY DISEASE AT THE CELL, REGIONAL, AND ORGAN LEVELS. THESE TECHNOLOGIES INCLUDE LARGE SCALE 3D MICROSCOPY AND TISSUE CYTOMETRY (3DTC), SPATIAL TRANSCRIPTOMICS (ST), AND CO-DETECTION BY INDEXING (CODEX) MULTIPLEXED IMMUNOFLUORESCENCE. TOGETHER, THIS ANALYTICAL PIPELINE WILL FACILITATE MAPPING OF INJURY DISTRIBUTION AND EFFECTIVELY LINK WITH OTHER KPMP TECHNOLOGIES THROUGH THE FOLLOWING AIMS: SPECIFIC AIM 1: DEPLOY A SUITE OF KPMP-APPROVED SPATIAL TECHNOLOGIES AS A SYNCHRONIZED ANALYTICAL PIPELINE TO DEFINE THE CELLULAR COMPONENTS AND MOLECULAR STRUCTURE OF EACH HUMAN KIDNEY BIOPSY. SPECIFIC AIM 2: INTEGRATE IMAGING, TRANSCRIPTOMIC, AND PROTEOMIC SIGNATURES FROM EACH BIOPSY SPECIMEN TO GENERATE A MULTI-COMPONENT SPATIAL MAP OF CELLULAR AND MOLECULAR PHENOTYPES. SPECIFIC AIM 3: INTEGRATE OUR ANALYTICAL PIPELINE ACROSS THE KPMP, LINKING OUR SPATIALLY-ANCHORED CELLULAR AND MOLECULAR PHENOTYPES TO OTHER KPMP TECHNOLOGIES, PATHOLOGY, AND CLINICAL FEATURES. THE PROPOSED RESEARCH IS SIGNIFICANT, BECAUSE IT IS THE NEXT STEP IN A CONTINUUM OF RESEARCH THAT IS EXPECTED TO IDENTIFY CRITICALLY NEEDED BIOMARKERS OF DISEASE PROGRESSION, OPTIMIZE PRECLINICAL STUDIES, AND DEVELOP SPECIFIC AND TARGETED THERAPEUTIC INTERVENTIONS IN THE VAST CLINICAL PROBLEM OF AKI AND CKD.

RESEARCH TRAINING PROGRAM IN DIABETES AND OBESITY

THE INDIANA TRAINING PROGRAM IN PUBLIC & POPULATION HEALTH INFORMATICS

MVNP, P62P392L AND IL-6 IN THE PATHOGENESIS OF PD

BEHAVIORAL DISINHIBITION IN EARLY-ONSET ALCOHOLISM

ROLE OF SKELETAL MUSCLE IN PULMONARY VASCULAR REMODELING

EXPERIMENTAL NUCLEAR PHYSICS AND FUNDAMENTAL INTERACTIONS AT INDIANA UNIVERSITY

COMPREHENSIVE TRAINING PROGRAM IN MUSCULOSKELETAL RESEARCH

NEW REGULATORY INTERACTIONS AND CIRCUITS THAT MEDIATE THE DYNAMICS, HOMEOSTASIS, AND STRESS RESPONSES OF PEPTIDOGLYCAN SYNTHESIS IN THE SUPERBUG STREPTOCOCCUS PNEUMONIAE

INDIANA PREGMED

URETHRAL MICROBIOME OF ADOLESCENT MALES

MOLECULAR AND CELLULAR FUNCTIONS OF ANO5 IN HEART

HIV, INFLAMMATION, AND ENDOTHELIAL DYSFUNCTION

MODULATION OF AIRWAY REACTIVITY BY CHRONIC MECHANICAL STRAIN

A DROSOPHILA MODEL FOR THE REGULATION OF AEROBIC GLYCOLYSIS

HPV E6 AND NFX1-123 IN DIFFERENTIATION, CELL REGULATION, AND CANCER

ADDICTION MEDICINE FELLOWSHIP

GLOBAL NETWORK FOR WOMEN'S AND CHILDREN'S HEALTH RESEARCH

EMPOWERING INFORMATICS DIVERSITY ENHANCED WORKFORCE