The Medical College Of Wisconsin Inc

A DATA RESOURCE FOR ANALYZING BLOOD AND MARROW TRANSPLANTS

BLOOD AND MARROW TRANSPLANT CLINICAL TRIALS NETWORK DATA COORDINATING CENTER

CLINICAL AND TRANSLATIONAL SCIENCE AWARD

BLOOD & MARROW TRANSPLANT CLINICAL TRIALS NETWORK DATA COORDINATING CENTER

RAT GENOME DATABASE

PPG-GENETIC AND SIGNALING MECHANISMS IN THE CENTRAL REGULATION OF BLOOD PRESSURE

BMT CLINICAL RESEARCH NETWORK DATA COORDINATING CENTER

CENTER FOR AIDS INTERVENTION RESEARCH-CORE SUPPORT

RENAL MECHANISMS IN BLOOD PRESSURE CONTROL

GENETIC & PHYSIOLOGICAL BASIS OF SALT-INDUCED HYPERTENSION

ANESTHETIC-INDUCED CARDIAC PRECONDITIONING

DISSEMINATION AND COORDINATING CENTER FOR THE SCGE CONSORTIUM

NATIONAL BIOMEDICAL EPR CENTER

CLINCAL AND TRANSLATIONAL SCIENCE AWARD

MECHANISMS OF UPPER GUT AND AIRWAY INTERACTION - PROGRAM PROJECT

MOLECULAR MECHANISMS OF CALCIFICATION: ROLES AND OPPORTUNITIES IN DISEASES OF AGING - OVERALL SUMMARY MOLECULAR MECHANISMS OF CALCIFICATION: ROLES AND OPPORTUNITIES IN DISEASES OF AGING. ECTOPIC CALCIFICATION IS A HALLMARK OF MAJOR DISEASES OF AGING, INCLUDING AGE-RELATED MACULAR DEGENERATION (AMD) AND ALZHEIMER'S DISEASE (AD), DISORDERS THAT EACH REPRESENT THE LEADING CAUSES OF CENTRAL VISION LOSS AND DEMENTIA AMONG THE AGING POPULATION WORLDWIDE, AND ARE CURRENTLY INCURABLE. THERE IS AN URGENT NEED TO UNDERSTAND DISEASE MECHANISMS TO ENABLE THE DEVELOPMENT OF EFFECTIVE TREATMENTS. THE OVERALL GOAL OF THIS PROGRAM PROJECT IS TO ELUCIDATE THE BIOLOGICAL MECHANISMS OF ECTOPIC CALCIFICATION AND ITS ROLE IN THE ONSET AND ETIOLOGY OF DISEASES OF AGING, WITH PARTICULAR FOCUS ON AGE-RELATED MACULAR DEGENERATION (AMD) AND ALZHEIMER’S DISEASE (AD). THE MAJOR COMPONENTS OF THE ECTOPIC CALCIFICATIONS IN AMD AND AD ARE PROTEINS, LIPIDS AND MINERALIZED CALCIUM PHOSPHATE, ESPECIALLY IN THE FORM OF HYDROXYAPATITE (HAP) AND WHITLOCKITE (WHT), BUT THE ROLES OF THESE COMPONENTS IN THE CALCIFICATION PROCESS AND DISEASE PROGRESSION ARE NOT KNOWN. FOUR PROJECTS, AN ADMINISTRATIVE CORE AND A TECHNICAL CORE, WILL SYNERGIZE TO INVESTIGATE ECTOPIC CALCIFICATION AT THE MOLECULAR, CELLULAR AND ORGANISMAL LEVELS, AND BUILD A COMPREHENSIVE VIEW OF THE KEY MOLECULES AND PATHWAYS RESPONSIBLE FOR THIS AGING-RELATED PHENOMENON. THERE ARE THREE OVERALL GOALS: (1) ELUCIDATE THE MOLECULAR MECHANISMS OF ECTOPIC CALCIFICATION; (2) DEVELOP DIAGNOSTIC SENSORS FOR ECTOPIC CALCIFICATION; AND (3) DISSECT INTRA- AND EXTRA-CELLULAR FACTORS OF ECTOPIC CALCIFICATION. THE PRIMARY ROLE OF ADMINISTRATIVE CORE WILL BE TO FACILITATE INTERACTIONS AMONG THE INVESTIGATORS TO GENERATE A COMPREHENSIVE VIEW OF CALCIFICATION THAT COULD NOT BE ACHIEVED BY INDIVIDUAL LABORATORIES WORKING ALONE.

CURRENTLY, WISCONSIN DOES NOT HAVE A COMPREHENSIVE APPROACH TO VIOLENCE AS A PUBLIC HEALTH ISSUE. AS A CRITICAL STEP TOWARD THIS GOAL, THE MEDICAL COLLEGE OF WISCONSINS (MCW) COMPREHENSIVE INJURY CENTER (CIC) WAS AWARDED FUNDING TO CREATE THE WISCONSIN COMMUNITY SAFETY FUND (WCSF) PROGRAM IN 2022 TO SERVE AS AN INTERMEDIARY ADMINISTERING RESOURCES TO SUPPORT LOCAL, COMMUNITY-SPECIFIC, AND EVIDENCE-INFORMED PUBLIC HEALTH STRATEGIES TO ADDRESS VIOLENCE FOR PRIORITY GROUPS THAT ARE DISPROPORTIONATELY IMPACTED. COLLECTIVELY, THE CIC TEAM IS SUPPORTING IMPLEMENTATION OF COMMUNITY VIOLENCE INTERVENTION (CVI) STRATEGIES AT THE LOCAL LEVEL IN MULTIPLE COUNTIES ACROSS WISCONSIN AND IS PARTNERING WITH COALITIONS, AGENCIES, AND COORDINATING BODIES TO INFORM THE DEVELOPMENT OF A COMPREHENSIVE STATEWIDE APPROACH TO COMMUNITY SAFETY USING A HEALTH EQUITY LENS. FOR THIS INITIATIVE, THE MCW CIC WILL UTILIZE THIS FUNDING TO ENHANCE AND EXPAND UPON THE INITIAL WORK OF THE WCSF. THIS FUNDING WILL PROVIDE UP TO FIVE SUBAWARDS TO COMMUNITY-BASED ORGANIZATIONS (CBOS) TO SUPPORT LOCAL CVI IMPLEMENTATION AS PART OF THE GROWING ECOSYSTEM OF LOCAL COMMUNITY-BASED VIOLENCE INTERVENTION AND PREVENTION INITIATIVES (CVIPI). THE SUBRECIPIENTS WILL RECEIVE INTENSIVE TRAINING AND TECHNICAL ASSISTANCE IN PROVIDING TRANSFORMATIONAL SERVICES AND COMMUNITY ENGAGEMENT FOCUSED ON RISK AND PROTECTIVE FACTORS FOR THOSE MOST VULNERABLE TO AND IMPACTED BY COMMUNITY VIOLENCE.

PURPOSE: THE CARESCAN MOBILE SCREENING CENTER OF EXCELLENCE PROJECT, LED BY THE MEDICAL COLLEGE OF WISCONSIN (MCW), WILL BRING EFFECTIVE TECHNOLOGIES TO WIDE MARKETS WHILE ALSO IMPROVING HEALTH. CARESCAN PIONEERS A FIRST-OF-ITS-KIND COMMUNITY-DRIVEN MOBILE CANCER SCREENING FLEET TO DELIVER CARE DIRECTLY TO 107,585 RESIDENTS IN WISCONSIN?S DISTRESSED COMMUNITIES. THROUGH A VIRTUAL TOOLKIT, CARESCAN ALSO GUIDES PROTOCOL DEVELOPMENT AND PROVIDES UNIQUE INSIGHTS FOR CLINICAL PATHWAY DEPLOYMENT. THIS PROJECT WILL INTEGRATE ADVANCED SCREENING WITH DISPARATE HEALTHCARE NETWORKS, IMPROVE HEALTH DATA QUALITY, CONNECT COMPANIES WITH A COMPREHENSIVE PRODUCT EVALUATION TOOLKIT, AND DEFINE A NEW HEALTHCARE SEGMENT WHICH CAN EMPLOY 15,000 NEW WORKERS NATIONALLY. CARESCAN IS AN ESSENTIAL CATALYST FOR THE FUTURE OF PERSONALIZED MEDICINE ? STREAMLINING ROBUST, EFFICIENT VALIDATION AND DEPLOYMENT OF NEW SCREENING AND THERAPIES ACROSS WISCONSIN AND THE NATION. ACTIVITIES TO BE PERFORMED: BUILD A TRUSTED COMMUNITY-CASED SCREENING NETWORK PILOT CARESCAN AS A SCALABLE MOBILE SCREENING MODEL FOR WIDESPREAD AND EFFICIENT IMAGING SOLUTIONS PILOT A CLEAN PATHWAY TO PRODUCT REALIZATION FOR INNOVATORS THROUGH A STUDY BUILD A SCREENING CENTER OF EXCELLENCE MODEL WITH SHAREABLE BEST PRACTICES. EXPECTED OUTCOMES: ESTABLISH COMMUNITY ADVISORY BOARD AND COMMUNITY-BASED PARTNERS LAUNCH TELEHEALTH NEXUSMD MIA PLATFORM TO EXPANDED AND CUSTOMIZED TELERADIOLOGISTS LAUNCH CARECOMPANION APPS DEPLOY CARESCAN FLEET OF VANS TO COMMUNITY DESIGN MARKETING AND OUTREACH STRATEGIES TO REGISTER 30,000 PARTICIPANTS IN CARECOMPANION APPS BUILD A SCREENING CENTER OF EXCELLENCE AND DEPLOY MARKETING STRATEGY INTENDED BENEFICIARIES: WISCONSIN?S COMMUNITIES; ESTABLISHED AND START-UP PRODUCT DEVELOPMENT COMPANIES; AND COMMUNITIES NATIONALLY AND GLOBALLY. SUBRECIPIENT ACTIVITIES: UNIVERSITY OF WISCONSIN-MADISON: THE DEPARTMENT OF RADIOLOGY AT THE UNIVERSITY OF WISCONSIN WILL SUPPORT DEVELOPMENT AND IMPLEMENTATION OF THE CARESCAN MOBILE IMAGING PLATFORM. THEIR INVOLVEMENT WILL INCLUDE SCIENTIFIC TECHNICAL PROJECT LEADERS AND APPLICATIONS SUPPORT TEAMS UTILIZING EXPERTISE IN IMAGING TO ADVISE ON THE DEPLOYMENT, PROTOCOL CONFIGURATION, AND INTEGRATION OF CARESCAN IMAGING MODALITIES AND ASSOCIATED TELEHEALTH SOLUTIONS. RADIOLOGIST COLLABORATORS WILL CONSULT ON PROTOCOL REFINEMENTS TO ENSURE OPTIMAL AND EFFICIENT DIAGNOSTIC PERFORMANCE. MILWAUKEE SCHOOL OF ENGINEERING (MSOE): WORKING WITH APP DEVELOPERS AND MARKETING EXPERTS, MSOE FACULTY AND STUDENTS WILL BE CRITICAL TO DEVELOPING TWO APPS WITH PERSONALIZED VIDEO MESSAGES, CONVERSATIONAL AI, AND A NOVEL CHAT INTERFACE THAT TRANSLATES MEDICAL RESULTS INTO PLAIN LANGUAGE TO TRANSPARENTLY AUGMENT COMMUNITY MEMBER CONNECTIONS WITH HUMAN CARE COORDINATORS.

IMMUNO-ONCOLOGY TRANSLATION NETWORK (IOTN): CELLULAR IMMUNOTHERAPY DATA RESOURCE (CIDR)

NOCICEPTIVE MECHANISMS UNDERLYING SICKLE CELL PAIN

GENE TARGETED RAT RESOURCE FOR THE STUDY OF COMPLEX DISEASE

MEMBRANE PROTEIN EFFECTORS OF PATHOGEN INTERACTIONS WITH HOST

TRANSLATIONAL COORDINATION AND DISSEMINATION CENTER FOR THE SCGE CONSORTIUM - PROJECT SUMMARY THE GOAL OF THE NIH COMMON FUND’S SOMATIC CELL GENOME EDITING (SCGE) PROGRAM IS TO TAKE ADVANCES IN TECHNOLOGIES AIMED AT GENOME EDITING AND DELIVERY SYSTEM APPROACHES TO CORRECT DISEASE-CAUSING MUTATIONS DEVELOPED IN PHASE I AND TRANSLATE THESE EFFORTS INTO THE CLINIC DURING PHASE II. THE SCGE TRANSLATIONAL COORDINATION AND DISSEMINATION CENTER (TCDC) AT THE MEDICAL COLLEGE OF WISCONSIN (MCW) WILL CONTINUE THE EFFORTS OF THE PHASE I SCGE DISSEMINATION AND COORDINATING CENTER ACTING AS THE HUB TO SUPPORT THE THREE LAB AND CLINICAL TRIALS-BASED INITIATIVES IN A COORDINATED EFFORT TO FACILITATE THE DISSEMINATION OF PROTOCOLS, BEST PRACTICES, SCGE RESULTS, AND DEVELOP A NETWORK OF COLLABORATION. THE SCGE TCDC AT MCW BRINGS A TEAM OF EXPERIENCED INVESTIGATORS, PLATFORMS FOR EFFECTIVE COMMUNICATION AND TRACKING OF DELIVERABLES AND MILESTONES AND DEMONSTRATED SUCCESS IN STRATEGIC COLLABORATIONS WITHIN THE CONSORTIUM. THE OVERALL GOAL FOR THE SCGE TCDC IS TO SUPPORT THE SCGE CONSORTIUM AND WORK COOPERATIVELY WITH ALL INITIATIVES, PROJECTS, AND MEMBERS TO FACILITATE THE OBJECTIVES OF THE ENTIRE SCGE CONSORTIUM. TO ACCOMPLISH THIS, THE MCW TCDC WILL 1) BUILD UPON AND EXTEND THE CURRENT COMMUNICATION PLATFORMS TO FACILITATE COMMUNICATION AMONG PARTICIPANTS, 2) DEVELOP THE INFRASTRUCTURE TO COLLECT, DIGEST, ANNOTATE, INTEGRATE, AND DISTRIBUTE DATA AND RESOURCES GENERATED WITHIN THE SCGE CONSORTIUM, AND 3) CREATE A ROBUST PLATFORM FOR COLLABORATION WITHIN THE SCGE CONSORTIUM AND WITH OUTSIDE PARTNERS. THE MCW TCDC WILL CREATE THE INFRASTRUCTURE TO DEVELOP POLICIES, TRACK PROGRESS WITHIN THE CONSORTIUM, COMMUNICATE WITHIN AND BEYOND THE CONSORTIUM, DEVELOP OUTREACH AND EDUCATIONAL ACTIVITIES TO SUPPORT THE PROCESS OF MOVING PRE-CLINICAL STUDIES THROUGH THE REGULATORY PROCESS, INTO CLINICAL TRIALS, AND EVENTUALLY TO THE PATIENT. TO DISSEMINATE DATA AND RESOURCES DEVELOPED WITHIN THE SCGE CONSORTIUM, THE SCGE PLATFORM WILL BE ASSEMBLED TO STORE, QUERY, VISUALIZE, AND ANALYZE THE OUTCOMES OF THE SCGE INITIATIVES. THE MCW TCDC TEAM WILL FACILITATE THE ADMINISTRATIVE AND MANAGEMENT ACTIVITIES TO SUPPORT THE OVERALL SUCCESS OF THE PROGRAM.

A PHASE I CLINICAL TRIAL TESTING FEASIBILITY OF HEMATOPOIETIC STEM CELL GENE THERAPY USING PLATELET FACTOR VIII TO SAFELY IMPROVE HEMOSTASIS FOR SEVERE HEMOPHILIA A WITH INHIBITORY ANTIBODIES

INDUCTION OF CARDIOVASCULAR CELLS FROM HESCS BY EMBRYONIC CUES

CLINCAL AND TRANSLATIONAL SCIENCE AWARD

ASSESSING PHOTORECEPTOR STRUCTURE AND FUNCTION IN NORMAL AND DISEASED RETINA

BLOOD PRESSURE -- DETERMINANTS & CONTROLLERS

POST-IRRADIATION INTERVENTION TO MITIGATE AND TREAT NON*

STRUCTURAL ANALYSIS OF THE MANNOSE 6-PHOSPHATE RECEPTORS

INTESTINAL BACTERIAL METAGENOME IN PEDIATRIC NAFLD

HEAD AND SPINE INJURY PREVENTION AND MITIGATION, AND QUANTIFIED INJURY CRITERIA

HYBRID RAT DIVERSITY PROGRAM

PEDIATRIC MEASUREMENT CENTER OF EXCELLENCE (PMCOE)

MECHANISTIC CHARACTERIZATION OF GENES FOR HYPERTENSION AND RENAL DISEASE.

NEUROPHYSIOLOGIC & AUTONOMIC CHARACTERIZATION OF INTERSTITIAL CYSTITIS/PAINFUL BL

DEVELOPING CONE-DOMINANT RETINAL DISEASE MODELS AS A RESOURCE FOR TRANSLATIONAL VISION RESEARCH

PLATELET-DERIVED FVIII GENE THERAPY OF HEMOPHILIA A

RYAN WHITE TITLE IV WOMEN, INFANTS, CHILDREN, YOUTH AND AFFECTED FAMILY MEMBERS AIDS HEALTHCARE

BIOMECHANICAL MECHANISM OF BETA-CELL DESTRUCTION

COMPREHENSIVE STUDY OF ACUTE EFFECTS AND RECOVERY AFTER CONCUSSION

FUNCTIONAL GWAS FOR LVH USING IPS-DERIVED CARDIOMYOCYTES: THE HYPERGEN CIPS STUD

VACCINES AGAINST BOTULISM

RYAN WHITE TITLE IV WOMEN, INFANTS, CHILDREN, YOUTH AND AFFECTED FAMILY MEMBERS AIDS HEALTHCARE

ALZHEIMER'S DISEASE CONNECTOME PROJECT

MECHANISMS OF VIRAL-INDUCED BETA-CELL DAMAGE

PREVENTION OF HIV INFECTION IN HIGH-RISK SOCIAL NETWORKS OF AFRICAN AMERICAN MSM

SELECTIVE UPTAKE AND HYDROLYSIS OF CHOLESTERYL ESTER BY SR-BI

MECHANISTIC AND THERAPEUTIC ROLE OF THE CD137-CD137L AXIS IN TYPE 1 DIABETES

PAIN MECHANISMS IN FABRY DISEASE

THE ROLE OF ZINC FINGER GENES IN PANCREATIC CELL GROWTH

PPARG-DEPENDENT MECHANISMS CONTROL ENDOTHELIAL-SMOOTH MUSCLE COORDINATION, ARTERIAL PRESSURE, VASOMOTOR FUNCTION AND ARTERIAL STIFFNESS

TRP CHANNELS IN REGULATION OF VASCULAR TONE

CORE GRANT FOR VISION RESEARCH

ROLE OF INTERLEUKIN 23 IN GASTROINTESTINAL GVHD

RAPID POINT-OF-CARE DIAGNOSTIC FOR BIOTERRORISM "A" AGENTS AND PANDEMIC INFLUENZA

INTEGRATED PHYSIOLOGY TRAINING: MOLECULE TO ORGANISM

THE EPILEPSY CONNECTOME PROJECT

MCW NCTN LEAD ACADEMIC PARTICIPATING SITE

1/2A PHASE III RANDOMIZED TRIAL COMPARING UNRELATED DONOR BONE MARROW TRANSPLANTATION WITH IMMUNE SUPPRESSIVE THERAPY FOR NEWLY DIAGNOSED PEDIATRIC AND YOUNG ADULT PATIENTS WITH SEVERE APLASTIC ANEMIA - ABSTRACT ACQUIRED SEVERE APLASTIC ANEMIA (SAA) IS A RARE BONE MARROW FAILURE DISORDER WITH AN ANNUAL INCIDENCE OF 3-4 PER MILLION IN NORTH AMERICA (300-500 CASES < AGE 25 IN THE US YEARLY). THE LARGE MAJORITY OF CASES ARE CAUSED BY AUTOIMMUNE DESTRUCTION OF HEMATOPOIETIC STEM CELLS (HSCS); ACCORDINGLY THE DISEASE CAN BE TREATED AND OFTEN CURED BY EITHER IMMUNE SUPPRESSION THERAPY (IST) OR BONE MARROW TRANSPLANTATION (BMT). THE ATG/ CYCLOSPORINE (CSA) COMBINATION DEVELOPED IN THE 1990S IS THE PREFERRED IST APPROACH FOR NEWLY DIAGNOSED SAA PATIENTS AND HAS RESPONSE RATES OF 60-80%, WITH 5-YEAR SURVIVAL EXCEEDING 90%. BMT FROM AN HLA MATCHED SIBLING DONOR (MSD) IS THE STANDARD FOR INITIAL THERAPY FOR YOUNGER, NEWLY DIAGNOSED PATIENTS WITH LONG-TERM SURVIVAL RATES OF OVER 95% HOWEVER, ONLY 20% OF PATIENTS HAVE A SUITABLE SIBLING DONOR, CONSEQUENTLY, THE LARGE MAJORITY OF PATIENTS RECEIVE IST FOR INITIAL THERAPY. OUTCOMES OF MATCHED UNRELATED DONOR (MUD) BMT FOR SAA HAVE IMPROVED SIGNIFICANTLY OVER THE PAST DECADE, WITH STUDIES REPORTING SIMILAR OUTCOMES FOR BMT USING MUD COMPARED TO MSD. ALTHOUGH THESE DATA ARE PROVOCATIVE, MUD BMT CARRIES SIGNIFICANT RISKS, AND A STATE OF EQUIPOISE EXISTS BETWEEN THE TWO APPROACHES. TO ADDRESS THIS CHALLENGE, THE NORTH AMERICAN PEDIATRIC APLASTIC ANEMIA CONSORTIUM (NAPAAC), IN COLLABORATION WITH THE PEDIATRIC TRANSPLANTATION AND CELLULAR THERAPY CONSORTIUM (PTCTC) CONDUCTED AN NHLBI FUNDED PILOT TRIAL, WHICH HAS SHOWN THE FEASIBILITY AND SAFETY OF RANDOMIZING PATIENTS BETWEEN IST AND MUD BMT. IN THIS CLUSTER APPLICATION, THE RESOURCE FOR CLINICAL INVESTIGATION IN BMT (RCI BMT), THE PROSPECTIVE CLINICAL TRIAL ARM OF THE CENTER FOR INTERNATIONAL BLOOD AND MARROW TRANSPLANT RESEARCH (CIBMTR), WILL SERVE AS THE DATA COORDINATING CENTER (DCC) TO MANAGE THE DEFINITIVE PHASE III RANDOMIZED CONTROLLED TRIAL (RCT) IN COLLABORATION WITH THE CLINICAL COORDINATING CENTER (CCC) PARTNERSHIP OF NAPAAC AND PTCTC. OUR SPECIFIC AIMS ARE TO: 1) COMPARE THE PROPORTION OF SAA PATIENTS WITH IMMUNE SUPPRESSION FREE SURVIVAL WITH ADEQUATE COUNTS AT TWO YEARS FOR PATIENTS RANDOMIZED TO IST VERSUS BMT, INCLUDING TO UNDERSTAND THE IMPACT OF EITHER THERAPY ON FERTILITY, QUALITY OF LIFE AND BIOLOGICAL FACTORS, 2) SUPPORT AND MANAGE THE EFFICIENT IMPLEMENTATION, GOVERNANCE AND COMPLETION OF THIS RCT, AND 3) LEVERAGE EXISTING SYSTEMS AND EXPERTISE TO ENSURE ADHERENCE TO HIGH QUALITY DATA COLLECTION. THE PROPOSED DCC PROVIDES AN EFFICIENT AND EXPERIENCED INFRASTRUCTURE THAT LEVERAGES EXISTING RELATIONSHIPS AND A FRAMEWORK WHICH HAS SUCCESSFULLY DELIVERED CLINICAL TRIALS OVER 15 YEARS, INCLUDING A SEASONED STATISTICAL TEAM. THESE ASSETS WILL ENSURE THAT THIS TRIAL IS DESIGNED, ANALYZED AND CONDUCTED WITH THE UTMOST INTEGRITY AND EFFICIENCY AND THAT IT WILL MEET ITS GOAL OF ADVANCING KNOWLEDGE REGARDING THE BEST THERAPY FOR CHILDREN AND YOUNG ADULTS WITH SAA.

MEDICAL SCIENTIST TRAINING PROGRAM

QUANTITATIVE (PERFUSION AND DIFFUSION) MRI BIOMARKERS TO MEASURE GLIOMA RESPONSE

STRUCTURAL BIOLOGY OF MITOCHONDRIAL FISSION

FUNCTIONAL ARCHITECTURE OF IP3-EVOKED LOCAL CA2+ SIGNALS

INTERACTION BETWEEN LEPTIN AND ANGIOTENSIN IN THE PATHOGENESIS OF OBESITY-HYPERTENSION

FUNCTIONAL ANALYSIS OF DISTINCT NOCICEPTOR POPULATIONS

ADDRESSING KEY SOCIAL-STRUCTURAL RISK FACTORS FOR RACIAL DISPARITIES IN MATERNAL MORBIDITY IN SOUTHEASTERN WISCONSIN (ASCEND WI) - PROJECT SUMMARY/ABSTRACT: OVERALL COMPONENT THERE ARE SIGNIFICANT RACIAL AND ETHNIC DISPARITIES IN SEVERE MATERNAL MORBIDITY AND MORTALITY IN THE US. SOCIAL DETERMINANTS OF HEALTH AND SOCIAL RISK FACTORS HAVE A CENTRAL ROLE IN MATERNAL HEALTH DISPARITIES, WITH STRUCTURAL RACISM REINFORCING INEQUITABLE EXPOSURE TO SOCIAL RISK FACTORS IN INNER CITY ENVIRONMENTS. OUR TEAM PROVIDES HEALTHCARE SERVICES IN MILWAUKEE, WISCONSIN, ONE OF THE FIVE MOST SEGREGATED CITIES IN THE US. THE ADVERSE HEALTH EFFECTS ASSOCIATED WITH RESIDENTIAL SEGREGATION, CONCENTRATED POVERTY, AND NEIGHBORHOOD CONDITIONS RESULT IN PERPETUATED RACIAL DISPARITIES IN ALL HEALTH OUTCOMES IN SOUTHEASTERN WI, INCLUDING MATERNAL HEALTH OUTCOMES. IN THIS PROPOSAL, WE AIM TO ADDRESS KEY SOCIAL-STRUCTURAL RISK FACTORS FOR RACIAL DISPARITIES IN MATERNAL MORBIDITY IN SOUTHEASTERN WISCONSIN IDENTIFIED BY OUR RESEARCH COMMUNITY AND COMMUNITY PARTNERS. THESE RISK FACTORS INCLUDE HOUSING INSTABILITY, MEDICAL MISTRUST, AND FRAGMENTED ACCESS TO PREVENTATIVE CARE POSTPARTUM. WE PLAN TO ADDRESS THESE RISK FACTORS WITH THREE RESEARCH PROJECTS INVOLVING COMMUNITY STAKEHOLDERS IN HOUSING (RESEARCH PROJECT 1), COMMUNITY-BASED DOULAS (RESEARCH PROJECT 2), AND COMMUNITY HEALTH WORKERS AND POSTPARTUM TELEMONITORING (RESEARCH PROJECT 3). THE THREE PROJECTS WERE CONCEPTUALIZED AND DEVELOPED IN COLLABORATION WITH COMMUNITY PARTNERS WITH SYNERGY OF ADDRESSING MATERNAL HEALTH INEQUITIES THROUGHOUT THE CONTINUUM OF PRECONCEPTION, PREGNANCY, AND POSTPARTUM. THE MCW CENTER’S THEME IS ADDRESSING KEY SOCIAL-STRUCTURAL RISK FACTORS FOR RACIAL DISPARITIES IN MATERNAL MORBIDITY IN SOUTHEASTERN WISCONSIN - ASCEND WI. ASCEND WI HAS FOUR OVERARCHING AIMS: 1) PARTNER WITH COMMUNITY ORGANIZATIONS TO MITIGATE THE IMPACT OF SOCIAL-STRUCTURAL RISK FACTORS ON MATERNAL HEALTH, 2) DEVELOP AND EVALUATE INTERVENTIONS TO ADDRESS SOCIAL-STRUCTURAL RISK FACTORS FOR RACIAL DISPARITIES IN MATERNAL HEALTH, 3) DISSEMINATE FINDINGS TO RELEVANT STAKEHOLDERS AND POLICYMAKERS, AND 4) TRAIN A DIVERSE GROUP OF EARLY-STAGE SCIENTISTS IN MATERNAL HEALTH EQUITY RESEARCH. THE ASCEND WI TEAM UTILIZES INNOVATIVE APPROACHES, EQUITABLE COLLABORATIONS, AND SKILLED ACADEMIC AND COMMUNITY-BASED PARTNERS TO CREATE SUSTAINABLE CHANGE AND WILL WORK EFFECTIVELY TO ERADICATE MATERNAL HEALTH DISPARITIES IN SOUTHEASTERN WISCONSIN AND BEYOND.

MOLECULAR MECHANISMS OF CENTRAL C02 CHEMORECEPTION

DEVELOPMENT OF BIOMEDICAL EPR INSTRUMENTATION

NEUOROMOLECULAR MECHANISMS OF CHRONIC PELVIC PAIN IN NEONATALLY-INDUCED CYSTITIS

DISCOVERY AND FUNCTIONAL STUDIES OF GENES FOR T1D GWAS SUSCEPTIBILITY LOCI

ACELLULAR VACCINES AGAINST BACTERIAL PATHOGENS

GASTROSCHISIS OUTCOMES OF DELIVERY (GOOD) STUDY - GASTROSCHISIS IS THE MOST COMMON CONGENITAL ABDOMINAL WALL DEFECT IN WHICH THE INTESTINES HERNIATE OUTSIDE THE FETUS INTO THE AMNIOTIC FLUID. IT IS DIAGNOSED BY PRENATAL ULTRASOUND AFTER 14 WEEKS GESTATION. APPROXIMATELY 1 OUT OF EVERY 4000 BIRTHS IS AFFECTED BY GASTROSCHISIS, AND THE INCIDENCE IS INCREASING. SUBSETS OF PATIENTS HAVE COMPLICATED COURSES DUE TO DAMAGE OR LOSS OF INTESTINE. THIS MAY BE DUE TO EXPOSURE OF THE HERNIATED INTESTINES TO THE CAUSTIC EFFECTS OF AMNIOTIC FLUID OR THE NARROWING OF THE ABDOMINAL WALL DEFECT CONSTRICTING THE INTESTINAL BLOOD SUPPLY. ADDITIONALLY, GASTROSCHISIS PATIENTS HAVE AN INCREASED RISK OF DEVELOPING OLIGOHYDRAMNIOS (REDUCED AMNIOTIC FLUID VOLUME), FETAL GROWTH LAG AND STILLBIRTH. THE RISK OF FETAL DEMISE (STILLBIRTH) OR INTESTINAL DAMAGE LATE IN THE THIRD TRIMESTER HAS PROMPTED SOME PROVIDERS TO DELIVER GASTROSCHISIS PATIENTS EARLY. THIS MAY RESULT IN AN INCREASED RISK OF PREMATURITY-RELATED MORBIDITY. CURRENTLY, NO CONSENSUS EXISTS ABOUT THE IDEAL TIME TO DELIVER A BABY WITH GASTROSCHISIS AND NATIONALLY PRACTICE PATTERNS VARY WIDELY. IT IS UNCLEAR WHICH OFFERS THE FETUS A CHANCE AT A BETTER OUTCOME - EARLY DELIVERY TO MITIGATE RISK OF DEMISE AND INTESTINAL INJURY VERSUS DELIVERY CLOSER TO TERM. RETROSPECTIVE DATA PUBLISHED SHOW INCONSISTENT RESULTS WITH EARLY VERSUS LATER GESTATIONAL AGE DELIVERY IN GASTROSCHISIS. ONLY TWO RANDOMIZED, SINGLE INSTITUTION, PROSPECTIVE TRIALS WITH ELECTIVE PRETERM DELIVERY VERSUS AWAITING SPONTANEOUS LABOR HAVE BEEN ATTEMPTED. THE FIRST TRIAL INCLUDED 42 PATIENTS RENDERING THE STUDY LARGELY UNDERPOWERED. WHILE A TREND TOWARDS DECREASED LENGTH OF STAY AND EARLIER TIME TO FULL FEEDING IN THE EARLY DELIVERY GROUP WAS REPORTED, THE RESULTS DID NOT REACH STATISTICAL SIGNIFICANCE. THE SECOND TRIAL WAS STOPPED AFTER 21 PATIENTS WERE ENROLLED BECAUSE OF CONCERNS OF FUTILITY AND THE RATE OF SEPSIS IN THE 34 WEEK DELIVERY GROUP. A HIGHER RATE OF SEPSIS WAS NOT SEEN IN THE EARLY GROUP IN THE INITIAL TRIAL AND IN OTHER PUBLISHED PROSPECTIVE DATA. DUE TO THE PAUCITY OF HIGH-QUALITY EVIDENCE, DELIVERY TIMING FOR GASTROSCHISIS VARIES NATIONALLY BETWEEN 34 WEEKS GESTATIONAL AGE AND MONITORING UNTIL SPONTANEOUS DELIVERY, WHICH COULD BE UP TO 40 WEEKS. AS THE BEST EVIDENCE AVAILABLE DOES NOT ADEQUATELY ANSWER THE QUESTION OF OPTIMAL GESTATIONAL AGE OF DELIVERY, THE OBJECTIVE OF THIS COMPARATIVE EFFECTIVENESS STUDY IS TO INVESTIGATE THE HYPOTHESIS THAT DELIVERY AT 35 WEEKS IN STABLE PATIENTS WITH GASTROSCHISIS IS SUPERIOR TO OBSERVATION AND EXPECTANT MANAGEMENT WITH A GOAL OF DELIVERY AT 38 WEEKS. TO TEST THIS HYPOTHESIS, WE WILL COMPLETE A RANDOMIZED, PROSPECTIVE, MULTI-INSTITUTIONAL TRIAL. PATIENTS MAY BE ENROLLED IN THE STUDY ANY TIME PRIOR TO 33 WEEKS AND WILL BE RANDOMIZED AT 33 WEEKS TO EITHER DELIVERY AT 35 OR 38 WEEKS. THE PRIMARY COMPOSITE OUTCOME WILL INCLUDE INTRAUTERINE FETAL DEMISE, NEONATAL DEATH PRIOR TO DISCHARGE, RESPIRATORY MORBIDITY, GASTROINTESTINAL MORBIDITY, AND SEPSIS. MATERNAL, FETAL, AND NEONATAL SECONDARY OUTCOMES WILL ALSO BE INVESTIGATED. THIS STUDY HAS THE POTENTIAL TO FINALLY DETERMINE THE OPTIMAL TREATMENT FOR BABIES WITH GASTROSCHISIS AND THE MOTHERS WHO DELIVER THEM.

MECHANISMS OF INFLAMMATION IN SICKLE CELL DISEASE

HUMAN INJURY TOLERANCE TOWARD DEVELOPMENT AND VALIDATION OF A WARRIOR MANIKIN

INTEGRATIVE BIOLOGY OF CHILDHOOD KIDNEY DISEASE

LYSINE ACETYLATION IN N. GONORRHOEAE QUORUM SENSING AND BIOFILM FORMATION

TRAINING IN SIGNATURE TRANSDISCIPLINARY CARDIOVASCULAR SCIENCES

LIPID RAFTS IN EYE LENS: DISCRIMINATION BY PULSE EPR

DEFINING GENETIC PATHWAYS OF PLASMA-CELL NEOPLASIA

FMRI TECHNOLOGY AND ANALYSIS

MOLECULAR MECHANISMS OF AXENFELD-RIEGER SYNDROME

GENOME WIDE ASSOCIATION OF CORONARY ARTERY DISEASE AND RELATED RISK FACTORS

TYPE III EFFECTOR-COFACTOR DYNAMICS WITHIN THE CELLULAR ENVIRONMENT

A PRECISION MEDICINE BASIS FOR ESTROGEN THERAPY FOR ADVANCED BREAST CANCER

EXPERIMENTAL AND COMPUTATIONAL ANALYSIS OF MECHANISMS OF MITOCHONDRIAL-CELLULAR ROS CROSSTALK IN THE KIDNEY IN SALT-SENSITIVE HYPERTENSION - PROJECT SUMMARY SALT-SENSITIVE HYPERTENSION IS A SIGNIFICANT HEALTH PROBLEM WORLDWIDE AND THERE IS A NEED TO UNDERSTAND THE UNDERLYING MOLECULAR MECHANISMS TO ENABLE MORE EFFECTIVE TREATMENTS. THE PROPOSED STUDIES ARE BASED ON A STRONG SCIENTIFIC FOUNDATION WITH EXPERIMENTS PERFORMED IN OUR LABORATORIES IN DAHL SALT-SENSITIVE (SS) RATS WHICH MIMIC THE HUMAN CONDITION OF THE DISEASE. WE HAVE DEMONSTRATED THAT THIS FORM OF HYPERTENSION IS ASSOCIATED WITH EXCESS RENAL AND VASCULAR REACTIVE OXYGEN SPECIES (ROS) PRODUCTION AND REDUCED ABILITY TO EXCRETE NA+. EXCESS REABSORPTION OCCURS IN THE RENAL MEDULLARY THICK ASCENDING LIMB (MTAL) LEADING TO GREATER REABSORPTION OF FILTERED NA+. MOST RELEVANT TO THIS GRANT, SS RATS EXHIBIT A REDUCED ABILITY TO GENERATE ATP THROUGH MITOCHONDRIAL RESPIRATION IN THE MTAL, THE TUBULAR SEGMENT THAT IS RESPONSIBLE FOR REABSORPTION OF NEARLY 25% OF THE FILTERED NA+ OF THE KIDNEY. IN THIS REGION OF THE KIDNEY, THERE EXISTS HIGH LEVELS OF OXIDATIVE STRESS (EXCESS ROS PRODUCTION) EMANATING FROM BOTH THE MITOCHONDRIA AND CELL MEMBRANE NADPH OXIDASES (NOX2 AND NOX4). TWO OF THE MAJOR GAPS THAT REMAIN IN THIS FIELD ARE FIRST A LACK OF MECHANISTIC STUDIES OF CELLULAR/MITOCHONDRIAL METABOLISM, AND SECOND, AN ABSENCE OF APPROACHES TO QUANTITATIVELY EVALUATE THE INTERDEPENDENCE OF THE COMPLEX CELLULAR PROCESSES. WE HYPOTHESIZE THAT A HIGH SALT DIET WHICH INCREASES THE DELIVERY OF NA+ TO THE MTAL OF SS RATS RESULTS IN EXCESS NA+ REABSORPTION AND AN INCREASE OF MTAL CYTOSOLIC [NA+] WHICH STIMULATES MITOCHONDRIAL ATP SYNTHESIS AND ROS PRODUCTION WHICH IN TURN STIMULATES MEMBRANE NOXS (ROS-ROS CROSSTALK AND VICIOUS CYCLE) LEADING TO UNCOUPLING OF MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION (OXPHOS) AND TISSUE INJURY. AIM 1 WILL UTILIZE INTACT MICRODISSECTED MTAL TO TEST THE HYPOTHESIS IN SS RATS THAT HIGH SALT DIET INCREASES CYTOSOLIC [NA+] THEREBY STIMULATING MITOCHONDRIAL ROS PRODUCTION WHICH IN TURN ENHANCES GREATER UPTAKE OF NA+ INTO THE CELL AND THOUGH ROS-ROS CROSSTALK OF MITOCHONDRIA AND MEMBRANE NOX2 AND NOX4 WHICH AMPLIFIES TOTAL INTRACELLULAR ROS PRODUCTION LEADING TO OXPHOS UNCOUPLING. CONTRIBUTION OF MEMBRANE NOXS AND MITOCHONDRIAL ROS INTERACTIONS WILL BE DETERMINED USING NOVEL GENETICALLY ENGINEERED KNOCKOUT STRAINS SSNOX4KO AND SSP67/NOX4DKO RATS. AIM 2 WILL DETERMINE THE PROGRESSION OF THE POSTULATED BIOENERGETIC EVENTS IN ISOLATED MITOCHONDRIA OF THE KIDNEY (BOTH OUTER MEDULLA AND CORTEX) OF HIGH SALT FED SS RATS. PROGRESSIVE ALTERATIONS OF MITOCHONDRIAL BIOENERGETICS AND ROS PRODUCTION WILL BE DETERMINED AT FOUR TIME POINTS DURING THE THREE WEEKS OF HIGH SALT FEEDING. AIM 3 WILL UTILIZE THE MEASURED DATA-DRIVEN COMPUTATIONAL MODELING TO PROVIDE A QUANTITATIVE, INTEGRATED, AND MECHANISTIC FRAMEWORK THAT CAN PREDICT THE COMPLEX RELATIONSHIPS EXISTING BETWEEN CELLULAR OXYGEN UTILIZATION, ENERGY PRODUCTION, AND OXIDATIVE STRESS IN THE KIDNEY DURING THE DEVELOPMENT OF SALT-SENSITIVE HYPERTENSION.

INVESTIGATING THE ROLE OF THE MICROBIOME AND INFLAMMATION IN ACUTE AND CHRONIC PAIN IN PATIENTS WITH SICKLE CELL DISEASE

INJURY RESEARCH CENTER AT THE MEDICAL COLLEGE OF WISCONSIN

MECHANISMS REGULATING CEREBRAL BLOOD FLOW

NATIONAL RESEARCH SERVICE AWARD

THE ROLES OF LYME SPIROCHETE ADHESINS IN HEMATOGENOUS DISSEMINATION - UPON TRANSMISSION BY A VECTOR TICK BITE, LYME DISEASE SPIROCHETES, PRIMARILY B. BURGDORFERI (BB) IN THE US, ESTABLISH A LOCAL SKIN INFECTION, THEN DISSEMINATE TO MULTIPLE TISSUES. CHRONIC INFECTION BY BB IS OFTEN ASSOCIATED WITH ARTHRITIS. OUR LABORATORIES HAVE IDENTIFIED AND/OR CHARACTERIZED MANY BB CELL- OR EXTRACELLULAR MATRIX (ECM)- BINDING ADHESINS USING MULTIPLE APPROACHES, OVERCOMING THE CHALLENGES OF DEFINING THEIR ROLES IN BB BIOLOGY. OUR APPROACHES INCLUDE ANALYSES OF BIOCHEMICAL ACTIVITIES AND GENERATION OF TARGETED MUTANTS SELECTIVELY DEFECTIVE FOR A SINGLE ADHESIVE ACTIVITY AND ANALYSIS OF THE MUTANTS IN MULTIPLE MURINE INFECTION MODELS. TO GAIN DETAILED MECHANISTIC INSIGHT INTO INTERACTIONS THAT MAY OCCUR DURING BB DISSEMINATION IN VIVO, FOLLOWING INTRAVENOUS INOCULATION WE USED INTRAVITAL MICROSCOPY TO CHARACTERIZE VASCULAR ATTACHMENT AND TRANSMIGRATION IN SKIN AND JOINT-PROXIMAL TISSUE. THESE STUDIES REVEALED THAT ADHESINS BBK32 AND VLSE ACCOUNT FOR VIRTUALLY ALL OF THE TRANSIENT BB-ENDOTHELIUM BINDING OCCURRING MINUTES AFTER INOCULATION, TERMED “MEETING” INTERACTIONS. A DISTINCT SET OF ADHESINS, DBPB/A, OSPC, AND P66, MEDIATE CONTACTS REQUIRED FOR INVASION INTO EXTRAVASCULAR JOINT SPACE AFTER 24 HOURS (HR), TERMED “TRANSMIGRATING” INTERACTIONS. USING ISOGENIC STRAIN SETS THAT HAVE ACQUIRED OR LOST SPECIFIC ADHESIVE ACTIVITIES IN MULTIPLE SHORT-TERM AND LONG-TERM INFECTION MODELS WE SHOWED ROLES FOR FIVE OF THE SIX MEETING OR TRANSMIGRATING ADHESINS IN SHORT-TERM TISSUE LOCALIZATION AND/OR LONG-TERM COLONIZATION IN OTHER MURINE INFECTION MODELS. WHILE TRANSMIGRATING ADHESINS DO NOT PROMOTE “MEETING” INTERACTIONS, OUR DISCOVERY OF ENHANCED ADHESIVE CAPACITY OF THE ENDOTHELIUM AS INFECTION PROGRESSES HAS HELPED CLARIFY WHY DIFFERENT ADHESINS HAVE ROLES AT DIFFERENT STAGES OF INFECTION. WITHIN HR, “ENDOTHELIAL ACTIVATION” PERMITS BBK32- AND VLSE-INDEPENDENT (“GREETING”) INTERACTIONS. AFTER ~24 HR “ENDOTHELIAL POTENTIATION” OCCURS, REFLECTED BY THE ABILITY OF THE JOINT VASCULATURE TO SUPPORT BB TRANSMIGRATION. ALTHOUGH BOTH OSPC AND P66 FUNCTION AS TRANSMIGRATING ADHESINS, ONLY P66, AN INTEGRIN-BINDING ADHESIN THAT ALTERS TRANSCRIPTION IN CULTURED ENDOTHELIAL CELLS, IS ALSO POTENTIATING, I.E., REQUIRED TO PROMOTE THE RAPID TRANSMIGRATION OF A SECOND BB STRAIN. ACTIVATION IS MIMICKED BY EXOGENOUS TREATMENT OF MICE WITH SEVERAL CYTOKINES PRODUCED BY INFECTED MICE, BUT POTENTIATION IS SEEN ONLY WITH TNF-A, MCP-1 OR IL-10. THESE FINDINGS REVEAL PREVIOUSLY UNRECOGNIZED STEPS THAT ARE CRITICAL FOR BB SPREAD AND PROVIDE A MEANS TO DISTINGUISH ROLES FOR EACH ADHESIN IN DISTINCT INFECTION STAGES: MEETING, GREETING, POTENTIATING, TRANSMIGRATING AND COLONIZING. IN AIM 1 WE WILL IDENTIFY KNOWN ADHESINS THAT FACILITATE GREETING INTERACTIONS; TO BETTER PRIORITIZE OUR ADHESIN LIST, WE PROPOSE A GENOME-WIDE SCREEN THAT MAY ALSO IDENTIFY NOVEL ADHESINS. IN AIM 2 WE WILL CLARIFY THE ROLES OF KNOWN (AND, IF APPLICABLE, NOVEL) ADHESINS IN ENDOTHELIAL POTENTIATION AND TRANSMIGRATION. OUR USE OF RIGOROUS GENETIC ANALYSES IN INFECTION MODELS FROM VISUALIZATION OF KEY INTERACTIONS IN VIVO TO QUANTITATIVE ANALYSIS OF BB AT DIFFERENT STAGES OF INFECTION WILL RESULT IN DETAILED UNDERSTANDING OF A CRITICAL FACET OF BB BIOLOGY: DISSEMINATION.

RYAN WHITE TITLE IV PROGRAM

CLINICAL AND TRANSLATIONAL SCIENCE AWARD

INCREASING PREP USE IN HIGH-RISK SOCIAL NETWORKS OF AFRICAN AMERICAN MSM IN UNDERSERVED LOW-UPTAKE CITIES

CHIMC: SAVE LIVES-IMMUNIZE

MEN MOVING FORWARD: A LIFESTYLE INTERVENTION FOR AFRICAN AMERICAN PROSTATE CANCER SURVIVORS

RESEARCH TRAINING PROGRAM IN VISION SCIENCE

PRESURGICAL APPLICATIONS OF FUNCTIONAL MRI IN EPILEPSY

STOPPING TYROSINE KINASE INHIBITORS IN CML PATIENTS (STOP-TKIS)

INTEGRATIVE ANALYSIS OF VERTEBRATE RETINAL LAMINATION

MECHANISTIC STUDIES OF PHOSPHODIESTERASE INHIBITORS IN COCAINE ADDICTION

IDENTIFICATION OF TARGETS OF THE ANTIPARASITIC DRUG PRAZIQUANTEL

FUNCTIONAL ANALYSES OF BORRELIA BURGDORFERI ADHESINS

REGULATING CEREBRAL MICROCIRCULATION BY ASTROCYTES

MOLECULAR MECHANISMS OF G PROTEIN-COUPLED RECEPTOR BIASED SIGNALING

VISUAL CELL PIGMENT CELL INTERFACE AND DISC TURNOVER

A SELF-ORGANIZING EMBRYOID MODEL OF PERI-IMPLANTATION HUMAN DEVELOPMENT

TARGETED, HIGHLY SENSITIVE, NON-INVASIVE CARDIAC TRANSPLANT REJECTION MONITORING

IMPACT OF HCMV PROTEINS ON VIRAL REPLICATION AND CELLULAR SIGNALING PATHWAYS

DETERMINING THE ACCURACY OF SELF- AND PARTNER ANAL EXAMS FOR DETECTING ANAL ABNORMALITIES.

EVERY DAY COUNTS: A LIFESTYLE PROGRAM FOR WOMEN METASTATIC BREAST CANCER - THE COMMUNITY OF WOMEN WITH METASTATIC BREAST CANCER (MBC) IS GROWING DUE TO GREATER DISEASE INCIDENCE AND TREATMENT ADVANCES, WITH OVER 30% OF WOMEN NOW SURVIVING OVER 5 YEARS (VS. JUST 4% IN 2000). MANAGING SYMPTOMS TO MAINTAIN THE HIGHEST QUALITY OF LIFE (QOL) IS THE MAJOR GOAL OF CARE IN THE METASTATIC SETTING. THUS, RESEARCH THAT ADDRESSES QOL, PROGNOSIS AND SURVIVORSHIP IN THIS BURGEONING AND UNDERSERVED SURVIVOR GROUP IS CRITICALLY NEEDED. BC TREATMENT IS ASSOCIATED WITH ADVERSE BODY COMPOSITION CHANGES, SPECIFICALLY GAINS IN ADIPOSE TISSUE AND REDUCTIONS IN STRENGTH AND LEAN MASS (LM). EXCESS ADIPOSITY CONTRIBUTES TO INFLAMMATION AND INSULIN-RESISTANCE, WHICH ARE THEORIZED TO PROMOTE TUMOR PROGRESSION AND LOSS OF LM. LOW LEVELS OF LM ARE ASSOCIATED WITH CHEMOTHERAPY TOXICITY, INCREASED SYMPTOM BURDEN AND COMPROMISED SURVIVAL IN WOMEN WITH MBC. LIFESTYLE INTERVENTIONS WITH EARLY STAGE BC SURVIVORS RESULT IN REDUCED SYMPTOMS, IMPROVED BIOMARKERS OF BC PROGNOSIS AND ENHANCED QUALITY OF LIFE (QOL). TO DATE, WOMEN WITH MBC HAVE BEEN LARGELY EXCLUDED FROM THESE TRIALS. OUR PILOT WORK IN WOMEN WITH MBC DEMONSTRATES THEY ARE INTERESTED, CAPABLE, ADHERENT AND BENEFIT FROM PARTICIPATION IN A LIFESTYLE INTERVENTION. OUR RESULTS SHOW CLINICALLY MEANINGFUL IMPROVEMENTS IN QOL, INCREASED PHYSICAL ACTIVITY AND STRENGTH. WE ALSO FIND IMPROVED TRENDS IN BIOMARKERS OF PROGNOSIS, AS WELL AS MITOCHONDRIAL FUNCTION FOR WOMEN IN THE IMMEDIATE INTERVENTION VS. CONTROL GROUP. FURTHER, OUR WORK SHOWS THAT INFLAMMATION-ASSOCIATED MICRORNAS ARE DIFFERENTIALLY EXPRESSED FOLLOWING PARTICIPATION IN OUR PILOT TRIAL, PROVIDING HIGHLY NOVEL POTENTIAL TARGETS TO EXPLAIN MECHANISMS BY WHICH LIFESTYLE INTERVENTIONS IMPROVE QOL FOR THESE WOMEN. WE PROPOSE A RANDOMIZED ATTTENTION CONTROL TRIAL IN WOMEN WITH MBC (N=176) TO TEST THE IMMEDIATE AND SUSTAINED EFFECTS OF “EVERY DAY COUNTS,” A 16-WEEK LIFESTYLE INTERVENTION BASED ON CURRENT LIFESTYLE RECOMMENDATIONS FOR CANCER SURVIVORS. THIS TRIAL IS ADEQUATELY POWERED TO EXAMINE CHANGES IN: 1) QOL - THE PRIMARY DETERMINANT OF CARE IN THE METASTATIC SETTING AND (2) BODY COMPOSITION, SERUM BIOMARKERS OF PROGNOSIS/SURVIVAL, AND PERTINENT PATIENT REPORTED OUTCOMES. WE WILL ALSO EXPLORE MITOCHONDRIAL FUNCTION AND NOVEL MICRORNA SIGNATURES ASSOCIATED WITH INFLAMMATORY BIOMARKERS AND MITOCHONDRIAL FUNCTION. EVERY DAY COUNTS INCORPORATES CRITICAL FEEDBACK AND EXPERIENCES FROM OUR PILOT STUDY WITH WOMEN WITH MBC. OUR ROBUST, MULTIDISCIPLINARY STUDY TEAM APPLIES AN INNOVATIVE, HIGHLY INTEGRATED PHYSIOLOGIC MODEL TO EXAMINE THE MECHANISTIC EFFECTS OF THE INTERVENTION ON DECIDEDLY RELEVANT OUTCOMES OF INTEREST. THE PRESENT STUDY CHALLENGES CURRENT CLINICAL ASSUMPTIONS REGARDING THE PRESUMED INEFFECTIVENESS OF LIFESTYLE BEHAVIORS IN THE METASTATIC SETTING, PROVIDING EVIDENCE THAT MAY INFORM A PARADIGM SHIFT EXPANDING THE APPLICATION AND RELEVANCE OF THE NUTRITION AND PHYSICAL ACTIVITY GUIDELINES TO WOMEN WITH MBC. IMPORTANTLY, THIS STUDY WILL PROVIDE CLINICIANS WITH UPDATED EVIDENCE AND STRATEGIES TO HELP MAKE EVERY DAY COUNT FOR WOMEN WITH MBC REPRESENTING HIGH IMPACT FOR A CURRENTLY UNDERSERVED GROUP OF SURVIVORS.

STRUCTURAL BASIS FOR CHEMOKINE FUNCTION

MECHANISMS OF MORBIDITY AFTER CORRECTING AORTIC COARCTATIONS OF VARYING SEVERITY

HIGH RISK CRACK USE SETTINGS AND HIV IN EL SALVADOR

GENETIC MAPPING OF BREAST CANCER RISK IN THE TUMOR MICROENVIRONMENT

BIOCHEMICAL MECHANISMS OF BETA CELL PROTECTION THROUGH BROMODOMAIN INHIBITION

COMPARISON OF SUPPORTIVE HOUSING MODELS FOR HIV+ AND AT-RISK CHRONICALLY HOMELESS

MIDWEST BASIC AND TRANSLATIONAL RESEARCH CENTER

THE MIDWEST CHILD PATIENT REPORTED OUTCOMES (M-CPROS) CONSORTIUM

CHARACTERIZATION AND GENETICS OF KI TOXICITY IN IPSC-DERIVED CARDIOMYOCYTES

CONCEPT REPRESENTATION IN THE HUMAN BRAIN

MULTI-COHORT VALIDATION OF MACHINE LEARNING RADIOGENOMIC MODELS (ML-RGX) TO PREDICT LATE TOXICITY IN PROSTATE CANCER - PROJECT SUMMARY RADIOTHERAPY IS A CORNERSTONE OF TREATMENT FOR PROSTATE CANCER, BUT RADIATION-RELATED GENITOURINARY (GU) AND GASTROINTESTINAL (GI) TOXICITIES CAN NEGATIVELY IMPACT QUALITY OF LIFE AMONG SURVIVORS. RADIOTHERAPY CAN DAMAGE THE BLADDER AND RECTUM LEADING TO GROSS BLEEDING, INFLAMMATION, PAIN, FIBROSIS, AND WHEN SEVERE, LIFE- THREATENING COMPLICATIONS. UP TO 20% OF MEN TREATED WITH RADIOTHERAPY FOR PROSTATE CANCER DEVELOP MILD TO MODERATE LATE GU AND/OR GI TOXICITIES THAT ARE OFTEN PERMANENT AND NEGATIVELY IMPACT QUALITY OF LIFE; UP TO 5% DEVELOP SEVERE OR LIFE-THREATENING EFFECTS REQUIRING MEDICAL OR SURGICAL INTERVENTION. RADIATION EXPOSURE DRIVES RISK OF LATE TOXICITY, BUT GENETIC PREDISPOSITION IS A SIGNIFICANT CONTRIBUTOR AND CAN EXPLAIN WHY SOME PATIENTS DEVELOP TOXICITY WHILE OTHERS NO NOT DESPITE IDENTICAL TREATMENT PLANS. OUR PRIOR WORK SHOWS THAT LATE GU AND GI TOXICITIES ARE POLYGENIC IN ETIOLOGY, WITH RISK MODIFIED BY THE COMBINED EFFECTS OF MANY LOW-PENETRANCE SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS), RAISING THE ATTRACTIVE POSSIBILITY OF USING A POLYGENIC RISK SCORE TO IDENTIFY SUSCEPTIBLE PATIENTS PRIOR TO STARTING RADIOTHERAPY. TOWARDS THIS GOAL, WE DEVELOPED A NOVEL MACHINE LEARNING APPROACH TO COMBINE INFORMATION FROM MANY RISK SNPS AND DOSE-VOLUME PARAMETERS INTO A RADIOGENOMIC (ML- RGX) RISK SCORE. OUR PRELIMINARY DATA SHOWS THAT THIS MODELLING APPROACH OUT-PERFORMS EXISTING METHODS AND SHOWS PROMISE FOR USE IN THE CLINIC. THE PROPOSED PROJECT WILL APPLY THIS METHOD TO A LARGE TRAINING DATASET FROM THE NCI-SUPPORTED INTERNATIONAL RADIOGENOMICS CONSORTIUM TO BUILD ML-RGX MODELS OF GU AND GI TOXICITY THAT WILL THEN BE EXTERNALLY VALIDATED USING DATA AND BIOSPECIMENS FROM TWO LARGE PHASE III RADIOTHERAPY TRIALS COMPLETED THROUGH THE NRG ONCOLOGY COOPERATIVE GROUP. BIOINFORMATIC APPROACHES WILL BE APPLIED TO PRIORITIZE SNPS FOR INCLUSION IN THE MODELLING AND TO UNCOVER BIOLOGIC PATHWAYS UNDERLYING GENETIC PREDISPOSITION TO NORMAL TISSUE INJURY. THE STUDY HAS THREE AIMS: (1) TO TRAIN ML-RGX MODELS FOR EACH OF RADIATION-INDUCED GU AND GI TOXICITY AND DEFINE A THRESHOLD FOR LOW AND HIGH RISK; (2) TO VALIDATE ML-RGX MODELS IN TWO INDEPENDENT DATASETS FROM NRG ONCOLOGY COOPERATIVE GROUP TRIALS; AND (3) TO ASSESS FEASIBILITY AND IMPACT OF ML-RGX MODELS ON TREATMENT PLANNING WORKFLOW IN A RADIATION ONCOLOGY CLINIC. THIS WORK WILL BRING PERSONALIZED MEDICINE TO THE FIELD OF RADIATION ONCOLOGY AND IMPROVE PROSTATE CANCER CARE. OUR INNOVATIVE MODELLING APPROACHES WILL ALSO UNCOVER IMPORTANT MOLECULAR PATHWAYS THAT COULD BE TARGETED WITH INTERVENTIONS TO PREVENT AND/OR MITIGATE TOXICITIES.

EFFECTS OF HEAD IMPACT EXPOSURE DURING CONTACT SPORT ON MIDDLE SCHOOL AND HIGH SCHOOL ATHLETES

MICRORNAS AND ANESTHETIC-INDUCED DEVELOPMENTAL NEUROTOXICITY

DEVELOPMENT OF LISINOPRIL FOR POST-EXPOSURE MITIGATION OF LATE EFFECTS FROM A RAD

MECHANISM OF RADIATION INDUCED ENDOVASCULAR INJURY AND MITIGATION VIA THE NOTCH-DLL4 PATHWAY

ROLE OF NEURONAL NOS & SUPEROXIDE IN NEURODEGENERATION

PROSTATE CANCER RADIO-PATHOMICS FOR DIFFERENTIATING CLINICALLY SIGNIFICANT DISEASE - ABSTRACT PROSTATE CANCER IS THE MOST COMMONLY DIAGNOSED NON-CUTANEOUS CANCER, AFFECTING ONE IN SEVEN MEN. EVEN WHEN TREATED WITH A RADICAL PROSTATECTOMY, HISTORICALLY ABOUT 20% OF PATIENTS EXHIBIT TUMOR RECURRENCE. THIS PROPOSAL WILL FOCUS ON THE INTEGRATION OF TWO SEPARATE, COMPLIMENTARY DATASETS TO BETTER DIFFERENTIATE HIGH RISK PATIENTS: MULTI-PARAMETRIC MAGNETIC RESONANCE IMAGING (MP-MRI) AND WHOLE-MOUNT POST-SURGICAL PROSTATE PATHOLOGY SAMPLES. WE WILL DEVELOP RADIO-PATHOMIC ALGORITHMS CAPABLE OF PREDICTING UNDERLYING PATHOMIC FEATURES FROM NON-INVASIVE IMAGING IN ORDER TO DIFFERENTIATE PROSTATE CANCER WITH HIGH METASTATIC POTENTIAL. OUR OVERARCHING HYPOTHESIS IS THAT MICROSCOPIC, HETEROGENEOUS PATHOMIC FEATURES OF PROSTATE CANCER ARE RELIABLY DETECTABLE AND QUANTIFIABLE WITH MACROSCOPIC QUANTITATIVE MP-MRI. NON-INVASIVELY MAPPING THESE FEATURES WILL PROVIDE A CLINICALLY USEFUL TOOL FOR DIFFERENTIATING AGGRESSIVE FROM INDOLENT PROSTATE CANCER, AND FOR POTENTIALLY TARGETING WITH RADIATION. THIS PROPOSAL INCLUDES TWO SPECIFIC AIMS IN RESPONSE TO THE GOALS OUTLINED IN PAR-19-264. SPECIFIC TO THE FUNDING OPPORTUNITY ANNOUNCEMENT: AIM 1 WILL DEVELOP RADIO-PATHOMIC APPROACHES FOR DEFINING IMAGING- BASED BIOMARKERS CAPABLE OF DISTINGUISHING AGGRESSIVE FROM INDOLENT PROSTATE CANCER. THIS WILL BE DONE AT THE MICROSCOPIC LEVEL IN AIM 1.1 WITH HISTOLOGY, AND THEN AT THE MACROSCOPIC LEVEL IN AIM 1.2 WITH MP-MRI. AIM 1.3 WILL TEST THE RESILIENCE OF THE RADIO-PATHOMIC ALGORITHM BY INTENTIONALLY PERTURBING THE SYSTEM AND ALGORITHMS. COMBINING THE RAD-PATH DATASETS WITH CLINICAL VARIABLES IN AIM 1.4 WILL LOOK TO IMPROVE SENSITIVITY AND SPECIFICITY FOR EARLY DETECTION AND DIFFERENTIAL DIAGNOSIS, BY CORRELATING OUR RADIO-PATHOMIC MAPS WITH OTHER OMICS. ADDITIONALLY, INCLUDED IN AIM 1, ARE EXTENSIVE VALIDATION EXPERIMENTS MEANT TO FURTHER ESTABLISH THE ROBUSTNESS OF THE RADIO-PATHOMIC ALGORITHM. IN AIM 2, THIS PROJECT WILL TRANSLATE THE RADIO-PATHOMIC ALGORITHMS TO THE CLINIC. THIS WILL INCLUDE IN AIM 2.1 ADAPTING OUR ALGORITHMS TO TWO CLINICAL MR IMAGING SYSTEMS (GE AND SIEMENS), AND IN AIM 2.2 DEVELOPING A RADIO-PATHOMIC DRIVEN MRI PROTOCOL FOR SERIAL IMAGING ON A COMBINED MR-LINAC SYSTEM, ONE OF ONLY TWO OPERATIONAL IN THE US. COMPLETION OF THIS PROJECT WILL PROVIDE A POWERFUL SET OF QUANTITATIVE IMAGING TOOLS TO CLINICIANS FOR IMPROVED DIFFERENTIATION OF HIGH-RISK PROSTATE CANCER AND FOR MEASURING RESPONSE TO PROSTATE CANCER THERAPY.

IMPROVING PATIENT CLASSIFICATION AND OUTCOME MEASUREMENT IN TRAUMATIC BRAIN INJURY (TBI)

GENETIC DETERMINANTS OF GENE EXPRESSION PHENOTYPES IN AGGRESSIVE PROSTATE CANCER

DKK1-ENDOTHELIAL PROGENITOR CELL TREATMENT FOR THE MITIGATION OF HEMATOPOIETIC RADIATION INJURY

IMPACT OF L. PLANTARUM 299V SUPPLEMENTATION ON ENDOTHELIAL FUNCTION AND SYSTEMIC INFLAMMATION

MECHANISMS OF MEK/ERK GROWTH ARREST SIGNALING

ENDOTHELIAL FUNCTION IN HUMAN DIABETES: ROLE OF MITOCHONDRIAL FISSION PROTEINS

REGULAR HIV TESTING AND HIV PREVENTION AMONG AT-RISK LATINO MEN IN THE HEARTLAND

ANALYSIS OF GLAUCOMA GENE INTERACTIONS

SULFOTYROSINE-GUIDED DISCOVERY OF SMALL MOLECULE CHEMOKINE INHIBITORS

ROLE OF BETA-ARRESTINS IN G PROTEIN-COUPLED RECEPTOR SORTING AND SIGNALING

COMPUTER MODELING OF SURGICAL OUTCOMES FOR NASAL AIRWAY OBSTRUCTION

CLINICAL AND TRANSLATIONAL SCIENCE AWARD

MOBILE DECISION SUPPORT SYSTEM FOR NURSE MANAGEMENT OF NEUROMODULATION THERAPY

THE EFFECT OF EMERGENCY DEPARTMENT AND AFTER-EMERGENCY DEPARTMENT ANALGESIC TREATMENT ON PEDIATRIC LONG BONE FRACTURE OUTCOMES

MRI CONTRAST AGENT METHODS OF ASSESSING TUMOR ANGIOGENESIS

BRIDGING COMMUNITY-BASED CONTINENCE PROMOTION AND PRIMARY CARE - PROJECT SUMMARY/ABSTRACT URINARY INCONTINENCE AFFECTS MORE THAN 18 MILLION U.S. WOMEN AND IS ASSOCIATED WITH HEALTHCARE COSTS IN EXCESS OF $18 BILLION ANNUALLY, WITH INCREASING PREVALENCE AS OUR POPULATION AGES. INCONTINENCE LIMITS QUALITY OF LIFE AND INCREASES THE RISK OF DEPRESSION, FALLS, AND INSTITUTIONALIZATION. EFFECTIVE NON-SURGICAL SOLUTIONS EXIST, BUT ONLY HALF OF WOMEN WITH INCONTINENCE DISCUSS THEIR SYMPTOMS WITH A HEALTHCARE PROVIDER. PRIMARY CARE PROVIDERS RECOGNIZE THE IMPORTANCE OF DIAGNOSING AND TREATING INCONTINENCE BUT REMAIN OVERBURDENED BY INCREASING AND OVERWHELMING COMPETING PRIORITIES, AND THUS INCONTINENCE REMAINS UNDERDIAGNOSED AND UNDERTREATED. WE WILL TEST TWO IMPLEMENTATION STRATEGIES TO HELP PRIMARY CARE CLINICS INCORPORATE SCREENING AND TREATMENT OF URINARY INCONTINENCE: ASK (SCREEN); ADVISE (EDUCATE THAT INCONTINENCE IS COMMON AND TREATABLE); AND ASSIST (OFFER EVIDENCE-BASED TREATMENT), CALLED UI-ASSIST. RECOGNIZING THAT EFFECTIVE PARTNERSHIPS BETWEEN PRIMARY CARE AND PUBLIC HEALTH AGENCIES IMPROVE HEALTH AND DECREASE BURDEN WHEN IMPLEMENTED SUCCESSFULLY, WE HYPOTHESIZE THAT AN IMPLEMENTATION STRATEGY THAT SUPPLEMENTS STREAMLINED PRACTICE FACILITATION WITH PARTNERSHIP BUILDING (ENGAGING COMMUNITY RESOURCES, BUILDING COALITIONS, PROVIDING ONGOING CONSULTATION, AND CREATING AN ONLINE LEARNING COMMUNITY) WILL OVERCOME KNOWN BARRIERS TO INTERVENTION IMPLEMENTATION, RESULTING IN BROADER REACH AND ULTIMATELY LARGER IMPACT. WE HAVE ENGAGED PARTNERS AT THE LOCAL, STATE, AND NATIONAL LEVELS WHOSE MISSIONS ALIGN WITH THE PROPOSED WORK AND SUPPORTING PRIMARY CARE TO IMPROVE TREATMENT OF URINARY INCONTINENCE, INCREASING LIKELIHOOD OF SUSTAINABILITY AND SUBSEQUENT SCALE. WE WILL COMPARE THE IMPACT OF STREAMLINED PRACTICE FACILITATION VERSUS STREAMLINED PRACTICE FACILITATION WITH PARTNERSHIP BUILDING. GUIDED BY GLASGOW’S REACH, EFFECTIVENESS, ADOPTION, IMPLEMENTATION, AND MAINTENANCE (RE-AIM) FRAMEWORK, WE WILL TEST OUR HYPOTHESIS THROUGH A TYPE 3 HYBRID CLUSTER RANDOMIZED TRIAL OF 50 PRIMARY CARE PRACTICES. WE WILL USE A DIFFERENCE-IN-DIFFERENCES ANALYSES THAT COMPARES THE PROPORTION OF PATIENTS WHO ARE (A) SCREENED AND (B) OFFERED TREATMENT FOR INCONTINENCE BEFORE AND AFTER IMPLEMENTATION (AIM 1) BY STUDY ARM. USING MIXED METHODS, WE WILL EXAMINE THE IMPACT OF IMPLEMENTATION STRATEGY AND CONTEXTUAL FACTORS ON UI-ASSIST’S REACH, ADOPTION, IMPLEMENTATION, AND MAINTENANCE (AIM 2) AND ON PATIENT-REPORTED OUTCOMES (AIM 3), INCLUDING SYMPTOM IMPROVEMENT, PHYSICAL AND SOCIAL FUNCTIONING, PSYCHOLOGICAL SYMPTOMS, QUALITY OF LIFE, COPING STRATEGIES, ECONOMIC CONCERNS, AND ADVERSE EVENTS). AS THE PREVALENCE OF URINARY INCONTINENCE CONTINUES TO INCREASE, AND AS PRIMARY CARE PRACTICES FACE INCREASING PRESSURE TO ADDRESS MORE WITH LESS TIME AND RESOURCES, SCALABLE INTERVENTIONS AND IMPLEMENTATION STRATEGIES TO IMPROVE CARE ARE URGENTLY NEEDED.

INFECTION DISEASE ENDEMIC TO KENYA VACCINE AND DRUG TRIALS AND ENTOMOLOGY

TRANSFORMATION OF MITOCHONDRIAL VDAC1 BETWEEN PROTECTIVE AND LETHAL STATES

(PQE3)A STATEWIDE RCT TO REDUCE USE OF INEFFECTIVE OR UNPROVEN BREAST CANCER CARE

EFFECTS OF STATE LAWS TO REDUCE OPIOID DIVERSION ON TRANSITIONS TO INJECTION DRUG USE AND HIV/HCV TRANSMISSION

STRUCTURAL BASIS FOR CHEMOKINE FUNCTION

MECHANISTIC INFLAMMATORY PATHWAYS IN GRAFT VERSUS HOST DISEASE

ANNUAL ANAL SAMPLING USING DNA SCREENING TO IDENTIFY MEN WHO HAVE SEX WITH MEN AT INCREASED RISK FOR ANAL CANCER

PERCEIVED IMMIGRATION LAWS IMPACT ON HISPANIC IMMIGRANTS HIV HEALTH BEHAVIOR

SOCIAL NETWORK INTERVENTION TO ENGAGE OUT-OF-CARE PLH INTO TREATMENT

SR-BI AND PCPE2: NOVEL PARTNERS IN BI-DIRECTIONAL CHOLESTEROL TRANSPORT

A MULTI-STATE ANALYSIS OF THE IMPACT OF HIV EXPOSURE LAWS

TESTING THE EFFICACY OF TWO INTERVENTIONS TO IMPROVE HEALTH OUTCOMES AND QUALITY OF LIFE AMONG RURAL OLDER ADULTS LIVING WITH HIV - MORE THAN 55,000 PEOPLE LIVING WITH HIV (PLH) IN THE US LIVE IN RURAL AREAS, AND MORE THAN 2,300 RURAL RESIDENTS ARE DIAGNOSED WITH HIV EACH YEAR. PLH WHO LIVE IN RURAL AREAS HAVE HIGHER MORTALITY RATES COMPARED WITH NON-RURAL PLH. RURAL PLH ARE DIAGNOSED WITH HIV AT A MORE ADVANCED STAGE THAN NON-RURAL INDIVIDUALS AND PRESENT FOR MEDICAL CARE LATER, MAKING THEM MORE LIKELY TO FACE COMORBIDITIES AND NEED COMPLEX MEDICAL CARE. RURAL PLH ARE ALSO LESS LIKELY THAN THEIR URBAN COUNTERPARTS TO REMAIN ENGAGED IN HIV CARE AND TO BE VIRALLY SUPPRESSED. COMPARED WITH YOUNGER PLH, OLDER PLH MAY FACE ADDITIONAL CHALLENGES TO MAINTAINING THEIR HEALTH AND WELLBEING, AND OLDER PLH WHO ALSO LIVE IN RURAL AREAS FACE THE DOUBLY CHALLENGING PROSPECT OF MAINTAINING ADHERENCE TO HIV CARE AND MANAGING MEDICAL CONDITIONS WHILE LIVING IN A RURAL ENVIRONMENT. FEW INTERVENTIONS AIMED AT INCREASING VIRAL SUPPRESSION AND IMPROVING HEALTH-RELATED QUALITY OF LIFE (HRQOL) EXIST FOR RURAL OLDER PLH. OUR PREVIOUS QUALITATIVE AND SURVEY RESEARCH WITH RURAL OLDER PLH NATIONWIDE (N = 476) IDENTIFIED LOW SOCIAL SUPPORT, HIV-RELATED STIGMA, SELF-EFFICACY, AND STRUCTURAL BARRIERS (SUCH AS DIFFICULTIES WITH HOUSING, FOOD ACCESS, TRANSPORTATION, AND INSURANCE) AS KEY PREDICTORS OF ENGAGEMENT IN HIV CARE, VIRAL SUPPRESSION, AND HRQOL FOR THIS POPULATION. BASED ON THIS, WE PREVIOUSLY PILOTED TWO REMOTELY-DELIVERED INTERVENTIONS FOR RURAL OLDER PLH: SUPPORTIVE-EXPRESSIVE PEER SOCIAL SUPPORT GROUPS AND STRENGTHS-BASED CASE MANAGEMENT. THE PILOT WITH OLDER PLH IN THE RURAL SOUTHERN U.S. FOUND THE INTERVENTIONS TO BE FEASIBLE, ACCEPTABLE, AND TO SHOW EVIDENCE OF PRELIMINARY IMPACT. BASED ON THIS WORK, WE PROPOSE A FULL-SCALE TRIAL TO EVALUATE THE EFFICACY OF THESE TWO INTERVENTIONS. WE WILL RECRUIT 352 RURAL OLDER PLH IN THE SOUTHERN U.S.— INCLUDING IN THE STATES PRIORITIZED IN THE US HHS’ “ENDING THE HIV EPIDEMIC” (ETHE) PLAN—THROUGH PARTNERSHIPS WITH COMMUNITY AGENCIES AND ONLINE ADVERTISEMENTS. FOLLOWING BASELINE SURVEYS (COMPLETED ONLINE, BY MAIL, OR BY PHONE) AND HIV VIRAL LOAD TESTING (VIA SELF-COLLECTED DRIED BLOOD SPOT SAMPLES), PARTICIPANTS WILL BE RANDOMIZED TO RECEIVE OR NOT RECEIVE EACH INTERVENTION IN A 2X2 FACTORIAL DESIGN. FOLLOW-UP SURVEYS WILL OCCUR AT 4, 8, AND 12 MONTHS, AND VIRAL LOAD TESTING AT 4 AND 12 MONTHS. SURVEYS WILL ASSESS MEDICATION ADHERENCE, DEPRESSIVE SYMPTOMS, HRQOL, COVARIATES, AND POTENTIAL MEDIATORS (E.G., SOCIAL SUPPORT, HIV STIGMA, SELF- EFFICACY, STRUCTURAL BARRIERS). PRIMARY OUTCOMES ARE VIRAL SUPPRESSION, ANTIRETROVIRAL THERAPY ADHERENCE, DEPRESSIVE SYMPTOMS AND HRQOL, AND SECONDARY OUTCOMES ARE POTENTIAL MEDIATING MECHANISMS. WE HYPOTHESIZE THAT BOTH INTERVENTIONS WILL INCREASE THE PROPORTION OF PARTICIPANTS THAT HAVE VIRAL SUPPRESSION, LEVELS OF ANTIRETROVIRAL THERAPY ADHERENCE, AND HRQOL AND DECREASE DEPRESSIVE SYMPTOMS. EXPLORATORY ANALYSES WILL EVALUATE MEDIATORS AND MODERATORS OF INTERVENTION EFFECTS. WE WILL ALSO ASSESS THE ACCEPTABILITY, FEASIBILITY, AND COSTS OF INTERVENTION DELIVERY. RESULTS FROM THIS STUDY WILL PROVIDE US WITH TOOLS TO IMPROVE HEALTH OUTCOMES FOR RURAL OLDER PLH AND TO ADVANCE THE ETHE PLAN TO ELIMINATE HIV TRANSMISSION IN THE U.S.

REDUCING INNATE INFLAMMATION IN NEW ONSET T1D WITH LACTOBACILLUS PLANTARUM

OMICS ANALYSIS OF THREE-DIMENSIONAL TRANSCRIPTIONAL REGULATION

INTESTINAL ENTEROCOCCAL DYNAMICS: MODELING HOST-COMMENSAL AND HOST-PATHOGEN INTERACTIONS

THE ROLE OF HEPATOCYTE TPA IN HEPATIC VLDL PRODUCTION. - ATHEROSCLEROSIS IS INITIATED AND PROMOTED BY THE ARTERIAL ACCUMULATION OF APOLIPOPROTEIN B (APOB)-CONTAINING LIPOPROTEINS WHICH ACTIVATE A CHRONIC INFLAMMATORY RESPONSE. THE HEPATOCYTE IS THE MAJOR SOURCE OF APOB- LIPOPROTEIN PARTICLES VIA ITS ABILITY TO SECRETE VERY-LOW-DENSITY LIPOPROTEIN (VLDL), WHICH IS THEN HYDROLYZED INTO INTERMEDIATE-DENSITY LIPOPROTEIN (IDL) AND THEN LOW-DENSITY LIPOPROTEIN (LDL) IN THE BLOOD. CURRENT CHOLESTEROL- LOWERING THERAPIES PRIMARILY TARGET LDL-CHOLESTEROL LEVELS BY ENHANCING LDL RECEPTOR (LDLR)-MEDIATED LDL CLEARANCE. HOWEVER, THESE LDL-LOWERING TREATMENTS (E.G., STATINS AND PCSK9 INHIBITORS) HAVE ONLY MODEST EFFECTS ON THE REMNANT ATHEROGENIC APOB-CONTAINING LIPOPROTEIN-CHOLESTEROL CONSTITUENTS, INCLUDING VLDL- AND IDL-CHOLESTEROL. DESPITE REACHING OPTIMAL LEVELS OF LDL-CHOLESTEROL WITH THESE LDL-LOWERING TREATMENTS, UNCONTROLLED VLDL- AND IDL-CHOLESTEROLS STILL SIGNIFICANTLY CONTRIBUTE TO THE HIGH RESIDUAL ATHEROSCLEROTIC CARDIOVASCULAR DISEASE (CVD) RISK IN THE POPULATION. OUR GROUP RECENTLY MADE THE NOVEL DISCOVERY THAT A KEY BLOOD CLOT LYSIS PROTEIN, TISSUE-TYPE PLASMINOGEN ACTIVATOR (TPA), IN HEPATOCYTES LIMITS THE PRODUCTION OF APOB- LIPOPROTEINS IN MICE AND CULTURED PRIMARY HEPATOCYTES. THE OVERARCHING OBJECTIVE OF THIS PROPOSAL IS TO EXPLORE THE UNDERLYING MECHANISMS BY WHICH HEPATOCYTE TPA LOWERS PLASMA APOB-CONTAINING LIPOPROTEIN-CHOLESTEROL LEVELS. AIM 1: DETERMINE THE MOLECULAR MECHANISMS BY WHICH HEPATOCYTE TPA LIMITS VLDL LIPIDATION. SECRETION OF VLDL PARTICLES REQUIRES PROPER APOB LIPIDATION, BUT MAJOR GAPS REMAIN IN OUR UNDERSTANDING OF THE MECHANISMS BY WHICH THIS HAPPENS. OUR PRELIMINARY DATA STRONGLY SUPPORT OUR HYPOTHESIS THAT SILENCING HEPATOCYTE TPA INCREASES PLASMA APOB LIPOPROTEIN-CHOLESTEROL BY PROMOTING HEPATIC VLDL LIPIDATION. COMPLETION OF THIS AIM WILL ADD NOVEL INSIGHTS TO THE UNDERSTANDING OF THE PRODUCTION OF ATHEROGENIC APOB-LIPOPROTEINS. AIM 2: DETERMINE WHETHER HEPATOCYTE TPA ENHANCES APOB-VLDL INTRACELLULAR DEGRADATION BEFORE SECRETION. INTRACELLULAR DEGRADATION OF APOB-VLDL PARTICLES PRIOR TO THEIR SECRETION IS IMPORTANT TO MAINTAIN THE OPTIMAL PLASMA LEVELS OF ATHEROGENIC CHOLESTEROL AND NORMAL LIVER LIPID LEVELS, BUT THE MECHANISM IS POORLY UNDERSTOOD. WE WILL INCREASE HEPATOCYTE TPA EXPRESSION IN MICE TO TEST HYPOTHESIS THAT HEPATOCYTE TPA ENHANCES VLDL INTRACELLULAR DEGRADATION BEFORE SECRETION. COMPLETION OF THIS AIM WILL PROVIDE A NOVEL MECHANISM TO MAINTAIN INTRAHEPATIC LIPID HOMEOSTASIS. AIM 3: DETERMINE WHETHER INCREASING HEPATOCYTE TPA IN DYSLIPIDEMIA REDUCES ATHEROSCLEROSIS, WITHOUT RAISING THE RISK OF FATTY LIVER DISEASE. LOWERING CIRCULATING REMNANT CHOLESTEROL (THE CHOLESTEROL FOUND IN VLDL AND IDL) WHILE MAINTAINING THE HOMEOSTASIS OF INTRAHEPATIC LIPID LEVELS IS A PROMISING STRATEGY TO REDUCE THE RESIDUAL ATHEROSCLEROTIC RISK. HOWEVER, THERAPEUTIC GAPS REMAIN IN LOWERING ATHEROGENIC CHOLESTEROL WITHOUT INCREASING LIVER LIPID ACCUMULATION. WE HYPOTHESIZE THAT INCREASING TPA EXPRESSION IN DYSLIPIDEMIC MICE REDUCES APOB LIPOPROTEIN-CHOLESTEROL, ALLEVIATES ATHEROSCLEROSIS, WITHOUT ACCUMULATING LIPIDS IN THE LIVER. COMPLETION OF THIS AIM WILL PROVIDE NOVEL THERAPEUTIC TARGETS TO REDUCE RESIDUAL ATHEROSCLEROTIC CVD RISK.

REGULATION OF DRUG METABOLIZING ENZYME ONTOGENY

DISCOVERING AND EXPLOITING SELECTIVITY WITHIN TANDEM BROMODOMAINS

CYTOKINE INFLAMMATORY MEDIATORS AND MUCIN REGULATION IN MIDDLE EAR EPITHELIUM

TECHNOLOGY-INTENSIFIED DIABETES EDUCATION/SKILLS INTERVENTION IN AAS WITH DM-2

THE ROLE OF STRUCTURAL RACISM ON DISPARITIES IN CLINICAL OUTCOMES FOR DIABETES: A MIXED METHODS STUDY - APPROXIMATELY 37.1 MILLION ADULTS 18 YEARS OR OLDER (14.7% OF ALL U.S. ADULTS) ARE ESTIMATED TO HAVE DIABETES, WHERE 90-95% OF CASES ARE CLASSIFIED AS TYPE 2 DIABETES MELLITUS (T2DM). ADULTS FROM RACIAL/ETHNIC MINORITY GROUPS CONTINUE TO BE DISPROPORTIONATELY IMPACTED BY HIGHER MORBIDITY AND MORTALITY AND POOR OUTCOMES COMPARED TO NON-HISPANIC WHITE ADULTS. THE REASONS FOR THESE DISPARITIES AMONG POPULATION GROUPS REMAIN ELUSIVE; HOWEVER, STRUCTURAL RACISM, DEFINED AS THE LAWS, POLICIES, INSTITUTIONAL PRACTICES, AND ENTRENCHED NORMS EMBEDDED WITHIN SOCIETY THAT FOSTER DISCRIMINATION THROUGH MUTUALLY REINFORCING INEQUITABLE SYSTEMS, HAS BEEN INDICATED AS A ROOT CAUSE OF INEQUITIES IN HEALTH OUTCOMES INCLUDING THOSE RELATED TO DIABETES. ONE FORM OF STRUCTURAL RACISM, HISTORIC REDLINING, KNOWN AS THE PRACTICE OF DENYING RESOURCES TO COMMUNITIES BASED ON RACE, LARGELY IMPACTS NEIGHBORHOODS POPULATED BY PERSONS FROM RACIAL AND ETHNIC MINORITY GROUPS WHERE DIABETES IS HIGHLY PREVALENT. IT HAS LED TO SOCIAL AND ECONOMIC DISADVANTAGE WITHIN HYPER-SEGREGATED AND UNDER-RESOURCED NEIGHBORHOODS DUE TO COMMUNITY DISINVESTMENT. DESPITE REPORTEDLY BEING BANNED DECADES AGO, THE RELATIONSHIP BETWEEN HISTORIC REDLINING AND CONTEMPORARY DIABETES OUTCOMES HAS NOT BEEN WELL- STUDIED. SINCE CURRENT EVIDENCE SUPPORTS AN ASSOCIATION BETWEEN REDLINING AND POPULATION HEALTH, THIS IS A SIGNIFICANT GAP THAT NEEDS TO BE ADDRESSED TO REDUCE DIABETES DISPARITIES. PRELIMINARY DATA FROM OUR GROUP SHOWS PEOPLE REPORT THAT CURRENT STUDIES DO NOT ACCOUNT FOR THEIR LIVED EXPERIENCES OR ACCOMMODATE FOR THE STRUCTURAL INEQUITIES THEY DEAL WITH THAT LIMITS THEIR ABILITY TO SELF-MANAGE DIABETES. THEREFORE, WE PROPOSE TO ASSESS THE ROLE OF STRUCTURAL RACISM, IN THE FORM OF HISTORIC REDLINING, ON DIABETES DISPARITIES AND HOW IT IMPACTS CURRENT-DAY CLINICAL AND BEHAVIORAL OUTCOMES, QUALITY OF LIFE, AND THE NEIGHBORHOOD ENVIRONMENT IN 2,000 ADULTS WITH T2DM. THIS STUDY OFFERS A UNIQUE OPPORTUNITY TO BRIDGE A GAP IN KNOWLEDGE WITHIN THE FIELD BY USING AN EXPERIMENTAL CONVERGENT MIXED METHODS STUDY DESIGN TO UNDERSTAND THE RELATIONSHIP BETWEEN HISTORIC REDLINING AND DIABETES-RELATED OUTCOMES IN ADULTS WITH T2DM. AIM 1 WILL USE QUALITATIVE RESEARCH METHODS TO EXPLORE BELIEFS AND ATTITUDES ABOUT HISTORIC REDLINING AND ITS IMPACT ON DIABETES SELF-MANAGEMENT AND OUTCOMES. AIM 2 WILL USE QUANTITATIVE RESEARCH METHODS TO IDENTIFY DIRECT AND INDIRECT PATHWAYS THROUGH WHICH HISTORIC REDLINING IMPACTS DIABETES- RELATED OUTCOMES (GLYCEMIC CONTROL, BLOOD PRESSURE CONTROL, LIPID CONTROL, SELF-CARE BEHAVIORS (DIET, PHYSICAL ACTIVITY, MEDICATION ADHERENCE, BLOOD GLUCOSE MONITORING), AND QUALITY OF LIFE) IN ADULTS WITH T2DM AND INVESTIGATE INVARIANCE BY RACE/ETHNICITY AND SEX/GENDER IN THE RELATIONSHIP. AIM 3 WILL USE HIERARCHICAL MODELING TO ASSESS THE IMPACT OF INDIVIDUAL, INTERPERSONAL, AND NEIGHBORHOOD LEVEL FACTORS ON INDIVIDUAL LEVEL DIABETES OUTCOMES; TO ASSESS THE CONTRIBUTION OF HISTORIC REDLINING EXPOSURE TOWARD NOTED NEIGHBORHOOD LEVEL ASSOCIATIONS; AND TO ASSESS WHETHER INDIVIDUAL LEVEL ASSOCIATIONS ARE MODERATED BY HISTORIC REDLINING EXPOSURE.

THE INFLAMMATORY INDEX AS A BIOMARKER FOR PAIN IN PATIENTS WITH SICKLE CELL DISEASE

TARGETING PIM-2 KINASE FOR IMPROVING CANCER IMMUNOTHERAPY - ABSTRACT THE ADAPTIVE IMMUNE SYSTEM HAS THE CAPACITY TO RECOGNIZE AND KILL MALIGNANT CELLS. HOWEVER, IMMUNE TOLERANT MECHANISMS THAT NORMALLY PROTECT HEALTHY TISSUES FROM AUTOIMMUNE ATTACK PREVENT THE DEVELOPMENT OF EFFECTIVE ANTI-TUMOR IMMUNITY. TUMOR USES NUMEROUS IMMUNOSUPPRESSIVE MECHANISMS TO EVADE OTHERWISE EFFECTIVE T-CELL RESPONSES. A GROWING NUMBER OF IMMUNE EVASION MECHANISMS HAVE BEEN CHARACTERIZED INCLUDING MOLECULAR AND CELLULAR MECHANISMS. DESPITE PROMISING RESULTS ACHIEVED BY TARGETING ONE OR MORE OF THESE IMMUNE EVASION MECHANISMS, THERE IS CLEARLY ROOM FOR IMPROVEMENT SINCE ONLY A SUBSET OF CANCER PATIENTS USUALLY RESPOND TO SUCH A TREATMENT. THE PIM KINASES HAVE BEEN STUDIED EXTENSIVELY IN TUMORIGENESIS AND AS POTENTIAL THERAPEUTIC TARGETS FOR VARIOUS CANCERS. PIM KINASES ARE ALSO EXPRESSED ON ACTIVATED T CELLS, BUT THEIR ROLES IN T-CELL ACTIVITY AND FUNCTION ARE INCONCLUSIVE AND THE FUNCTIONS OF EACH ISOFORM IN THESE CELLS REMAIN UNCLEAR. USING GENETICALLY MUTANT MICE, WE FOUND THAT INDIVIDUAL PIM KINASES PLAY UNIQUE AS WELL AS OVERLAPPING ROLES IN T-CELL RESPONSE TO ALLOANTIGENS. STRIKINGLY, WE CONSISTENTLY OBSERVED THAT PIM-2-DEFICIENT T CELLS HAD SIGNIFICANTLY INCREASED ABILITY TO INDUCE GRAFT-VERSUS-HOST DISEASE (GVHD) AFTER ALLOGENEIC BONE MARROW TRANSPLANTATION (BMT). MORE IMPORTANTLY, WE FOUND THAT CD8 T CELLS MOUNT SUBSTANTIALLY STRONG ANTI- TUMOR RESPONSES WHEN PIM-2 WAS DEFICIENT OR BLOCKED. OUR PRELIMINARY STUDIES HAVE BEEN EXTENDED FROM GENETIC TO PHARMACOLOGIC APPROACHES AND FROM MOUSE TO HUMAN T CELLS. THUS, OUR PRELIMINARY STUDIES PROVIDE COMPELLING EVIDENCE THAT PIM-2 SERVES AS A POWERFUL NEGATIVE REGULATOR OF T-CELL IMMUNITY AGAINST CANCER. OUR CENTRAL HYPOTHESIS IS THAT TARGETING PIM-2 SUBSTANTIALLY PROMOTES CANCER IMMUNOTHERAPY WHILE POTENTIALLY INHIBITING TUMOR PROGRESSION DIRECTLY. THIS HYPOTHESIS WILL BE TESTED IN THE FOLLOWING TWO SPECIFIC AIMS: 1) TO DELINEATE MECHANISTIC ACTION BY WHICH PIM-2 NEGATIVELY REGULATES T-CELL RESPONSE; 2) TO VALIDATE PIM-2 AS AN IMMUNOTHERAPY TARGET AGAINST CANCER. BASED ON OUR COMPELLING PRELIMINARY DATA DEMONSTRATING FOR THE FIRST TIME THAT PIM-2 NEGATIVELY REGULATES T-CELL IMMUNITY, WE EXPECT TO FIRMLY VALIDATE THIS OBSERVATION AND TO DEFINE THE CELLULAR AND MOLECULAR MECHANISMS BY WHICH THIS REGULATION OCCURS. WE ALSO EXPECT TO DEMONSTRATE THAT BLOCKADE OR INHIBITION OF PIM-2 WILL ENHANCE ANTI-TUMOR IMMUNITY AGAINST DIFFERENT TYPES OF CANCER MEDIATED BY BOTH MOUSE AND HUMAN T CELLS.

AUGMENTATION OF GVL REACTIVITY WITHOUT GVHD

EMOTION REGULATION IN COMPLICATED GRIEF

NEW TREATMENT MONITORING BIOMARKERS FOR BRAIN TUMORS USING MULTIPARAMETRIC MRI WITH MACHINE LEARNING - PROJECT SUMMARY/ABSTRACT THE GOAL OF THIS PROJECT IS TO DEVELOP AND EVALUATE NOVEL IMAGING BIOMARKER(S) THAT USE MULTIPARAMETER MRI METHODS TO IDENTIFY THE TRUE SPATIAL EXTENT OF GLIAL BRAIN TUMORS. THE STANDARD RANO (RESPONSE ASSESSMENT IN NEURO-ONCOLOGY) CRITERIA DEFINE TUMOR EXTENT AS THE REGION OF BRIGHT SIGNAL ON POST-CONTRAST AGENT T1W (T1+C) IMAGES, TERMED THE CONTRAST ENHANCING LESION (CEL), ALONG WITH THE PERITUMORAL BRIGHT SIGNAL ON T2W FLAIR IMAGES, REFERRED TO AS NON-ENHANCING LESION (NEL). YET, THE CEL REFLECTS THE PERMEABILITY OF THE BLOOD-BRAIN BARRIER TO CONTRAST AGENT AND CAN APPEAR THE SAME FOR BOTH TUMOR AND TREATMENT EFFECT. LIKEWISE, THOUGH NEL LIKELY CONTAINS TUMOR, CURRENT IMAGING CANNOT DISTINGUISH TUMOR FROM EDEMA. THESE DIFFICULTIES RESULT IN THE INABILITY OF CURRENT ANATOMICAL MRI METHODS TO DETERMINE THE TRUE SPATIAL EXTENT OF GLIAL TUMORS, A SERIOUS LIMITATION FOR TREATMENT MANAGEMENT OF BRAIN TUMOR PATIENTS. WE AND OTHERS HAVE SHOWN THAT ADVANCED MRI METHODS, INCLUDING PERFUSION AND DIFFUSION MRI, ARE USEFUL FOR ASSESSING TUMOR GRADE, PREDICTING OUTCOMES, OR DISTINGUISHING TUMOR FROM TREATMENT EFFECT. YET, ALMOST EXCLUSIVELY, THE APPROACH HAS BEEN TO EXTRACT MEAN VALUES OF A SINGLE PHYSIOLOGICAL PARAMETER FROM PREDETERMINED TUMOR REGIONS OF INTEREST AND THEN MEASURE THEIR CORRELATION WITH THE DESIRED CLINICAL INDEX. ALTHOUGH THIS APPROACH HAS BEEN USEFUL FOR INITIAL BIOMARKER DEVELOPMENT, IT UNDERUTILIZES THE RICH MULTIPARAMETER AND SPATIAL INFORMATION AVAILABLE, THUS MOTIVATING THE CURRENT STUDY. FIRST, TWO MULTIPARAMETER MRI BIOMARKERS WILL BE DEVELOPED TO IDENTIFY ENHANCING AND INFILTRATING TUMOR BURDEN. THEN, THEY WILL BE EVALUATED INDIVIDUALLY AND IN COMBINATION TO ASSESS THE TOTAL TUMOR BURDEN IN COMPARISON WITH THE STANDARD VOLUMETRIC METRICS IN CURRENT USE. THE DEVELOPMENT AND TESTING OF THESE BIOMARKERS WILL BE ACCOMPLISHED IN SEVERAL INDEPENDENT STEPS OUTLINED BY THE PROPOSED AIMS. FIRST (AIM 1), WE PROPOSE TO DEVELOP AN MRI BIOMARKER THAT GIVES THE VOXELWISE PROBABILITY OF ENHANCING TUMOR BURDEN WITHIN CEL, WITH EARLY RESULTS SHOWING THE ABILITY TO DISTINGUISH TUMOR FROM TREATMENT EFFECT. NEXT, WE WILL DEVELOP A MULTIPARAMETER BIOMARKER CAPABLE OF IDENTIFYING INFILTRATING TUMOR WITHIN NEL (AIM 2). THESE EFFORTS LEVERAGE OUR PREVIOUS RESULTS USING ARTIFICIAL INTELLIGENCE, RECENT ADVANCES IN MACHINE LEARNING, AND OUR UNIQUE BRAIN TUMOR TISSUE BANK WITH HUNDREDS OF BIOPSY SAMPLES SPATIALLY MATCHED TO IMAGING. FINALLY (AIM 3), THE SPATIAL EXTENT OF TUMOR BURDEN WITHIN CEL AND NEL WILL BE TESTED IN THEIR ABILITY TO DISTINGUISH PSEUDO-PROGRESSION/RESPONSE FROM TRUE PROGRESSION/RESPONSE, WHICH IS A PRIMARY QUESTION THAT CONFOUNDS TREATMENT MANAGEMENT TODAY. IN SUMMARY, MULTIPARAMETER ADVANCED MRI BIOMARKERS OF ENHANCING AND INFILTRATIVE BRAIN TUMOR HAVE THE POTENTIAL TO CAUSE A PARADIGM SHIFT IN HOW TREATMENT IS MANAGED, ULTIMATELY RESULTING IN IMPROVED OUTCOMES.

DIAGNOSIS AND PREDICTIVE VALUE OF THE OCULAR MANIFESTATIONS OF FABRY DISEASE

DEVELOPMENT OF AN IOP-LOWERING GENE THERAPY TREATMENT FOR GLAUCOMA - ABSTRACT C SUSTAINED OCULAR HYPERTENSION IN OPEN ANGLE GLAUCOMA (OAG) AND CONGENITAL GLAUCOMA CAUSES DEGENERATION OF THE OPTIC NERVE AND DEATH OF RETINAL GANGLION CELLS, LEADING TO IRREVERSIBLE VISION LOSS. WHILST REDUCING INTRA-OCULAR PRESSURE (IOP) USING A COMBINATION OF PHARMACOLOGICAL AND SURGICAL APPROACHES IS KNOWN TO EFFECTIVELY PREVENT GLAUCOMA PROGRESSION, THE THERAPEUTIC EFFICACY OF SUCH A STRATEGY IS CRITICALLY UNDERMINED BY POOR PATIENT COMPLIANCE, WITH FEWER THAN 25% OF PATIENTS MAINTAINING TREATMENT OVER A ONE- YEAR PERIOD. OWING TO POOR COMPLIANCE AND THE NEED MAINTAIN A LIFE-LONG DAILY TREATMENT REGIMEN, GLAUCOMATOUS PATIENTS REGULARLY SUFFER BOUTS OF UNCONTROLLED OCULAR HYPERTENSION THAT DRAMATICALLY INCREASE THE RISK OF DEVELOPING SEVERE SIGHT-THREATENING COMPLICATIONS, EVEN WHEN DIAGNOSED EARLY. AS A CONSEQUENCE, THERE IS A CLEAR NEED TO DEVELOP A LONG-ACTING THERAPY THAT LOWERS IOP WITHOUT REQUIRING DAILY INTERVENTION. HEREIN WE PROPOSE THAT IOP MAY BE PERMANENTLY AND SAFELY LOWERED USING A GENE THERAPY STRATEGY AIMED AT MODIFYING CELLS OF THE CORNEA AND AQUEOUS HUMOR OUTFLOW PATHWAY (AHOP) TO SYNTHESIZE AND SECRETE PROSTAGLANDIN F2A, (PGF2A), A DRUG THAT IS KNOWN CLINICALLY TO EFFECTIVELY LOWER IOP IN OAG PATIENTS WHEN ADMINISTERED DAILY AS AN EYE DROP. WE PRESENT ROBUST PRELIMINARY DATA DEMONSTRATING THAT CELLS OF THE CORNEA AND AHOP CAN BE EFFECTIVELY TARGETED USING INTRACAMERAL INJECTION OF RECOMBINANT ADENO-ASSOCIATED VIRUS (RAAV) VECTOR, THAT EXPRESSION OF PROSTAGLANDIN F SYNTHASE (PTGS2) AND PROSTAGLANDIN F RECEPTOR (PTGFR) CATALYZES DE NOVO BIOSYNTHESIS AND SECRETION OF PGF2A INTO THE AQUEOUS HUMOR, AND THAT THIS CAUSES A HIGHLY SIGNIFICANT, DOSE-DEPENDENT REDUCTION IN IOP THAT IS MAINTAINED FOR OVER 12-MONTHS IN NORMOTENSIVE ANIMALS. IN THIS MULTI-PI APPLICATION, WE WILL EVALUATE THE FEASIBILITY, SAFETY AND LONG-TERM THERAPEUTIC EFFICACY OF OUR NOVEL GENE THERAPY TREATMENT IN THE PITX2+/- MOUSE MODEL OF CONGENITAL GLAUCOMA (AIM 1) AND THE ADAMTS10 BEAGLE MODEL OF OAG (AIM 2). DEMONSTRATING THE ABILITY TO PERMANENTLY LOWER IOP IN GLAUCOMATOUS EYES WOULD REPRESENT A PARADIGM SHIFT IN THE CLINICAL MANAGEMENT OF GLAUCOMA BY OBVIATING THE NEED FOR ADHERENCE TO A DAILY TREATMENT REGIMEN AND THE DATA GENERATED FROM THIS WORK IS EXPECTED TO SUPPORT CLINICAL TRANSLATION AND THE INSTIGATION OF AN INVESTIGATOR LED CLINICAL TRIAL. THE OCULAR GENE THERAPY LABORATORY OF THE MEDICAL COLLEGE OF WISCONSIN (MCW), DIRECTED BY DR DANIEL LIPINSKI (CONTACT PI/PD), AND THE LABORATORY OF DR ANDRÁS KOMÁROMY (PI/PD) AT THE COLLEGE OF VETERINARY MEDICINE AT MICHIGAN STATE UNIVERSITY (MSU) PROVIDE THE PERFECT ENVIRONMENT IN WHICH TO COMPLETE THE PROPOSAL. FINALLY, OUR PROPOSAL ADDRESSES AN EMERGING NEED IDENTIFIED IN THE NEI PUBLICATION “VISION RESEARCH: NEEDS, GAPS, AND OPPORTUNITIES” SPECIFICALLY: 1) DEFINE THE GENETIC ARCHITECTURE OF GLAUCOMA TO PROVIDE DIRECT POTENTIAL TARGETS FOR THERAPY; 2) DEVELOP ANIMAL MODELS THAT BETTER APPROXIMATE HUMAN GLAUCOMA AND PREDICT SAFETY AND EFFICACY OF NOVEL TREATMENTS.

GENETICS OF CARDIOMYOCYTE AND CARDIAC MATRIX INTERACTION: THE HYPERGEN IPSC STUDY

OTITIS MEDIA DIAGNOSIS AND TREATMENT - PROJECT SUMMARY/ABSTRACT OTITIS MEDIA (OM) IS THE MOST COMMON DIAGNOSIS IN PEDIATRIC PATIENTS SEEN FOR ILLNESS IN THE UNITED STATES (1,2), AFFECTS 90% OF ALL CHILDREN (3,4) AND IS THE MOST COMMON INDICATION FOR ANTIMICROBIAL THERAPY AND SURGERY (5) IN YOUNG CHILDREN. DESPITE MANY ATTEMPTS TO IMPROVE DIAGNOSIS, TREATMENT, AND PREVENTION, OM CONTINUES ITS HIGHLY PREVALENT IMPACT ON CHILDREN AND SUBSTANTIAL ONGOING MORBIDITY (1,3,6-30). OM CONTINUES AS THE MOST COMMON CAUSE OF HEARING LOSS (HL) IN CHILDREN AND LEADS TO SPEECH, EDUCATIONAL AND OTHER DEVELOPMENTAL DELAYS (31-37). OM CAUSES LIFE-THREATENING COMPLICATIONS (22,27) AND IS EXPENSIVE, RESULTING IN OVER $5 BILLION ANNUALLY IN U.S. HEALTH CARE EXPENDITURES (3,38). DESPITE THE PREVALENCE AND DIFFICULTIES WITH OM, DIAGNOSTIC ACCURACY TO ALLOW APPROPRIATE TREATMENT IS LACKING, LEADING TO MISPLACED RESOURCES IN TREATING OM. THIS PROPOSAL BUILDS ON OUR CENTRAL HYPOTHESIS THAT ENHANCED DIAGNOSTIC TOOLS, SPECIFICALLY, OPTICAL COHERENCE TOMOGRAPHY (OCT), WILL YIELD IMPROVED DIAGNOSIS AND LEAD TO REDUCED NEED FOR ANTIBIOTICS TO TREAT ACUTE OM, REDUCED SURGICAL INTERVENTIONS FOR CHRONIC OTITIS MEDIA, AND OVERALL FEWER COMPLICATIONS AND COST ASSOCIATED WITH THIS DISEASE. IN THIS PROPOSAL WE WILL EXPLORE THREE SPECIFIC AIMS. THE FIRST AIM, PART A, WE WILL PERFORM A COMPARATIVE ASSESSMENT OF MIDDLE EAR (ME) PATHOLOGY USING PNEUMATIC OTOSCOPY (PO) AND OPTICAL COHERENCE TOMOGRAPHY (OCT) IN PEDIATRIC PATIENTS THAT PRESENT TO A PRIMARY CARE CLINIC WITH COMPLAINTS OF OTALGIA (EAR PAIN) OR OM, WITH THE HYPOTHESIS THAT OCT ADDED TO STANDARD PO WILL IMPROVE DIAGNOSTIC ACCURACY AND REDUCE OVERALL ANTIBIOTIC PRESCRIPTIONS. IN PART B OF THIS AIM, A COMPARATIVE ASSESSMENT OF ME PATHOLOGY USING PO ALONG WITH AUDIOLOGY/TYMPANOMETRY (TY) AND OCT WILL BE PERFORMED IN PEDIATRIC PATIENTS THAT PRESENT TO THE PEDIATRIC OTOLARYNGOLOGY CLINIC WITH A REFERRAL FOR CHRONIC OTITIS MEDIA WITH EFFUSION (OME), WITH THE HYPOTHESIS THAT OCT ADDED TO STANDARD PO AND TY WILL IMPROVE DIAGNOSTIC ACCURACY AND REDUCE OVERALL NEED FOR SURGERY IN PATIENTS WITH OME. IN THE SECOND AIM, USING THE OCT IMAGES CAPTURED IN THE PREVIOUS AIM, WE WILL DEVELOP IMAGE PROCESSING AND MACHINE LEARNING ALGORITHMS FOR AUTOMATED IDENTIFICATION OF EFFUSIONS AND BIOFILMS IN OCT IMAGE DATA TO AUGMENT OM DIAGNOSIS FOR MEDICAL DECISION MAKING. FINALLY, USING THE OCT IMAGES CAPTURED PREVIOUSLY, ALONG WITH OUR MACHINE LEARNING ALGORITHMS, WE WILL ESTABLISH OCT B-MODE AND M-MODE IMAGE-BASED FEATURES THAT PREDICT THE RESOLUTION OR PERSISTENCE OF MIDDLE EAR EFFUSIONS OVER TIME. COLLECTIVELY, THIS PROJECT WILL DEMONSTRATE HOW THESE ADVANCES IN DIAGNOSTIC TOOLS AND ALGORITHMS WILL IMPROVE DIAGNOSIS AND PROVIDE ADDED INFORMATION FOR CLINICAL DECISION MAKING IN THE MANAGEMENT OF OM.

LPTA-MEDIATED TRANSPORT OF LPS

COMMUNICATION TECHNOLOGY TO DISSEMINATE EVIDENCE-BASED HIV INTERVENTIONS TO NGOS

TARGETING PANCREATIC CANCER ENERGY METABOLISM, TUMOR GROWTH, AND METASTASIS

TARGETING DUSP-5 TO TREAT VASCULAR ANOMALIES

STRUCTURE-BASED INHIBITION OF CHEMOKINE SIGNALING IN THE INFLAMED PANCREAS - MODIFIED PROJECT SUMMARY/ABSTRACT SECTION THE GOAL OF THIS PROJECT IS TO ESTABLISH THE ROLE OF CCL28 IN CHRONIC PANCREATITIS AND USE STRUCTURE-BASED DRUG DISCOVERY METHODS TO IDENTIFY SMALL MOLECULE INHIBITORS OF THIS SECRETED PROTEIN. CCL28 IS A MUCOSAL CHEMOKINE THAT PROMOTES TUMOR GROWTH IN A VARIETY OF ORGANS BY RECRUITING REGULATORY T CELLS (TREGS) THAT EXPRESS THE G PROTEIN-COUPLED RECEPTOR CCR10. BASED ON OUR PUBLISHED AND PRELIMINARY RESULTS, WE POSTULATE THAT SECRETION OF THE CHEMOKINE CCL28 BY PANCREATIC DUCTAL EPITHELIAL CELLS ALSO DRIVES CHRONIC INFLAMMATION THAT PROGRESSES TO MALIGNANT DISEASE. WE HYPOTHESIZE THAT INHIBITION OF CCL28 ACTIVITY WILL ALTER THE PANCREATIC MUCOSAL MICROENVIRONMENT IN A MANNER THAT REDUCES PRE-MALIGNANT INFLAMMATION AND ENHANCES THE ACTIVITY OF EXISTING CHEMOTHERAPEUTICS AND IMMUNOTHERAPIES. TO ACHIEVE THIS OBJECTIVE, WE PROPOSE THREE CONCEPTUALLY LINKED BUT EXPERIMENTALLY INDEPENDENT SPECIFIC AIMS. FIRST, WE WILL TEST OUR MECHANISTIC HYPOTHESIS IN ANIMAL MODELS OF CHRONIC PANCREATITIS, TO DEMONSTRATE EXPERIMENTALLY THAT CCL28 ACTIVITY THROUGH CCR10 PLAYS A KEY ROLE IN THE FIBROINFLAMMATORY RESPONSE IN VIVO AND DEVELOP AN IN VITRO MODEL THAT CAN BE USED TO SCREEN PROMISING INHIBITORS (AIM 1). KEY ELEMENTS OF CCL28 RECOGNITION BY ITS G PROTEIN-COUPLED RECEPTOR CCR10 WILL BE MAPPED IN DETAIL USING NMR AND MOLECULAR MODELING, AND WE WILL DEFINE THE COMPLETE INTRACELLULAR SIGNALING PROFILE OF THIS CHEMOKINE RECEPTOR USING STATE-OF-THE-ART ASSAY PLATFORMS FOR RECEPTOR PHARMACOLOGY (AIM 2). USING THE SOLVED NMR STRUCTURE OF CCL28 AND KNOWLEDGE OF ITS SULFOTYROSINE BINDING POCKET, WE WILL EMPLOY A STRUCTURE-BASED STRATEGY DEVELOPED IN THE VOLKMAN LAB THAT ENABLES THE DISCOVERY OF SMALL MOLECULES THAT BIND A SPECIFIC CHEMOKINE TARGET AND INHIBIT CELL MIGRATION (AIM 3). COLLECTIVELY, THE PROPOSED STUDIES WILL PROVIDE FUNDAMENTAL ADVANCES IN OUR UNDERSTANDING OF (1) TREG FUNCTION AND PATHOPHYSIOLOGY IN THE PANCREAS, (2) THE STRUCTURAL BASIS FOR LIGAND-RECEPTOR SELECTIVITY AND GPCR PHARMACOLOGY IN A LARGELY UNEXAMINED CHEMOKINE SIGNALING AXIS, AND (3) THE DRUGGABILITY OF A MUCOSAL CHEMOKINE AT THE TUMOR-PROMOTING INTERFACE OF CHRONIC INFLAMMATION AND NEOPLASIA.

STRUCTURE AND FUNCTION OF A FLAVOPROTEIN DEHYDORGENASE

MEDICAL STUDENT SUMMER RESEARCH

ERK5 AND CD36 LINK OXIDATIVE STRESS TO PLATELET DYSFUNCTION AND ISCHEMIC INJURY

GENETIC INTERACTIONS AND MULTIFACTORIAL GENETICS MEDIATE MYOCARDIAL REGENERATION - PROJECT SUMMARY/ABSTRACT DOGMA IN THE CARDIOVASCULAR FIELD ARGUES THAT THE ADULT MAMMALIAN HEART IS ESSENTIALLY NON-REGENERATIVE AND THAT THIS FAILURE TO REGENERATE IS PRIMARILY ATTRIBUTED TO THE POST-MITOTIC AND POLYPLOID NATURE OF MOST CARDIOMYOCYTES (CMS). MULTIPLE PIECES OF EVIDENCE NOW SUPPORT THE IDEA THAT WITHIN THE ADULT MAMMALIAN MYOCARDIUM, MONONUCLEAR DIPLOID CARDIOMYOCYTES (MNDCMS) ARE A PRIVILEGED SUBPOPULATION OF CMS THAT HAVE AVOIDED THIS PROLIFERATIVE SENESCENCE. THIS ATTRIBUTE CONFERS A UNIQUE CAPACITY TO RE-ENTER THE CELL CYCLE AND REGENERATE MYOCARDIAL TISSUE. OUR RECENT WORK IN MICE DEMONSTRATES THAT THE FREQUENCY OF MNDCMS AND THE COMPETENCE TO REGENERATE ONE'S HEART ARE TWO INTERLINKED AND VARIABLE TRAITS INFLUENCED BY THE COMPLEX GENETIC BACKGROUND OF AN INDIVIDUAL. IN OTHER WORDS, CONTRARY TO LONGSTANDING BELIEFS, SOME INDIVIDUALS CAN MOUNT A MEANINGFUL REGENERATIVE RESPONSE AFTER AN INSULT, SUCH AS A MYOCARDIAL INFARCTION. WE THEN TOOK A GENOME- WIDE ASSOCIATION STRATEGY TO IDENTIFY THE GENES ASSOCIATED WITH THE OBSERVED VARIATION. FROM THIS ANALYSIS, WE IDENTIFIED TNNI3K AS ONE CANDIDATE THAT REGULATES CM SENESCENCE BY INHIBITING CYTOKINESIS, SPECIFICALLY. HERE, WE IDENTIFY TWO NEW CANDIDATE GENES EACH OF WHICH HAS A UNIQUE EFFECT ON CM CELL CYCLE AND PLOIDY. FURTHERMORE, WE HYPOTHESIZE THAT IDENTIFIED GENES WILL WORK COOPERATIVELY TO MAXIMIZE THE TRAIT EFFECT, THUS A MULTIFACTORIAL APPROACH TO HEART REGENERATION IS PRUDENT. AIM 1 WILL EXPLORE THE FIRST NOVEL CANDIDATE FOR ITS INDEPENDENT EFFECT ON HEART FUNCTION AND CM CELL CYCLE ACTIVITY IN BOTH UNINJURED AND POST-INFARCTION SETTINGS. IT WILL ALSO BE TESTED IN COMBINATION WITH TNNI3K. AIM 2 WILL EXAMINE THE EFFECT OF THE SECOND NOVEL CANDIDATE ON CM PLOIDY, CELL CYCLE, AND HEART REGENERATION BOTH INDEPENDENTLY AND IN COMBINATION WITH TNNI3K. OUR PRIOR GWAS STUDY AFFIRMS THAT CM PLOIDY AND CARDIAC REGENERATION ARE COMPLEX PHENOTYPES RELYING ON MULTIPLE GENETIC LOCI. HERE, WE USE GENETIC APPROACHES TO MODULATE MULTIPLE CANDIDATE GENES IN A SINGLE ANIMAL MODEL AND WE ANTICIPATE THAT THIS COMBINATORIAL APPROACH WILL POTENTIATE CM PROLIFERATION AND CARDIAC REGENERATION.

DUAL FUNCTIONALITY OF CERAMIDE IN HUMAN MICROVASCULAR ENDOTHELIAL FUNCTION - PROJECT SUMMARY ELEVATED LEVELS OF PLASMA CERAMIDE ARE AN INDEPENDENT RISK FACTOR FOR MAJOR ADVERSE CARDIAC EVENTS (MACE) AND ARE ASSOCIATED WITH CARDIOVASCULAR DISEASES INCLUDING CORONARY ARTERY DISEASE (CAD) AND HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFPEF). ENDOTHELIAL MICROVASCULAR DYSFUNCTION, THE LOSS OF NITRIC OXIDE (NO)- MEDIATED DILATION TO FLOW (FLOW-INDUCED DILATION; FID), PRECEDES THE DEVELOPMENT OF CAD AND OCCURS FOLLOWING CHRONIC EXPOSURE TO EXOGENOUS CERAMIDE. DURING DISEASE, FOLLOWING ACUTE STRESS (E.G. HIGH PRESSURE), OR AFTER CHRONIC CERAMIDE TREATMENT, FID IS MAINTAINED BY UTILIZING MITOCHONDRIAL-DERIVED HYDROGEN PEROXIDE (H2O2). ALTHOUGH EFFECTIVE AT ELICITING DILATION, UNLIKE THE ANTI-INFLAMMATORY EFFECTS OF NO, H2O2 PROMOTES AN INFLAMMATORY ENVIRONMENT WITHIN THE VASCULATURE AND SURROUNDING PARENCHYMAL TISSUE. THE MECHANISM(S) BY WHICH CERAMIDE PROMOTES MITOCHONDRIAL H2O2-MEDIATED FID REMAINS UNKNOWN. INTERESTINGLY, CERAMIDE HAS ALSO BEEN IMPLICATED AS A CRITICAL SIGNALING COMPONENT IN THE GENERATION OF NO. THE CERAMIDE METABOLITE SPHINGOSINE-1-PHOSPHATE (S1P) EXERTS OPPOSING EFFECTS ON THE ENDOTHELIUM, PROMOTES THE FORMATION OF NO, AND MAY EXPLAIN THE POSITIVE VASCULAR EFFECTS ASSOCIATED WITH CERAMIDE. A LARGE KNOWLEDGE GAP EXISTS REGARDING THE DUAL FUNCTIONALITY OF CERAMIDE WITHIN THE HUMAN MICROVASCULAR ENDOTHELIUM. WE HYPOTHESIZE THAT WHILE CERAMIDE FORMATION IS A CRITICAL MECHANISTIC COMPONENT IN NO-MEDIATED FID, PROLONGED EXPOSURE INITIATES A SIGNALING CASCADE THAT RESULTS IN THE RELEASE OF MITOCHONDRIAL H2O2 IN RESPONSE TO SHEAR. OUR AIMS ARE AS FOLLOWS; 1) DETERMINE THE NECESSARY ROLE OF CERAMIDE IN MAINTAINING NO-MEDIATED FID WITHIN THE HUMAN MICROCIRCULATION, AND 2) INVESTIGATE THE MECHANISM(S) BY WHICH CERAMIDE FORMATION DURING STRESS OR DISEASE INITIATES THE TRANSITION IN FID MEDIATOR FROM NO TO MITOCHONDRIAL-DERIVED H2O2. USING A NOVEL APPROACH, THESE MECHANISTIC STUDIES WILL BE COMPLEMENTED BY THE FIRST HUMAN IN VIVO STUDY TO EXAMINE THE EFFECT OF ELEVATED PLASMA CERAMIDE ON PERIPHERAL MICROVASCULAR FUNCTION. THE TRANSLATIONAL STUDIES PROPOSED IN THIS APPLICATION WILL ENHANCE OUR UNDERSTANDING OF CERAMIDE SIGNALING DURING HEALTH, DISEASE, AND FOLLOWING ACUTE STRESS. THIS INFORMATION WILL PROVIDE NEW TARGETS FOR THERAPEUTIC INTERVENTION IN INDIVIDUALS AT RISK FOR DEVELOPING CARDIOVASCULAR DISEASE INCLUDING CAD AND HFPEF.

GESTATIONAL DIABETES AND PHARMACOTHERAPY (GAP) ? A RANDOMIZED CONTROLLED TRIAL INVESTIGATING TIMING OF PHARMACOTHERAPY INITIATION FOR PATIENTS WITH GESTATIONAL DIABETES - PROJECT SUMMARY/ABSTRACT GESTATIONAL DIABETES (GDM) COMPLICATES 10% OF PREGNANCIES IN THE US ANNUALLY AND IS RISING DRAMATICALLY AS A RESULT OF THE OBESITY EPIDEMIC. GDM AND THE RESULTING MATERNAL HYPERGLYCEMIA LEAD TO SIGNIFICANT MATERNAL AND NEONATAL COMPLICATIONS THAT CAN BE REDUCED WITH GLYCEMIC CONTROL. THE EXTENT OF TREATMENT NEEDED IS BASED ON MATERNAL GLYCEMIC RESPONSE TO MEDICAL NUTRITION THERAPY (MNT) AND EXERCISE; YET AT LEAST 30-50% OF PATIENTS WILL FAIL THE INITIAL TRIAL OF MNT AND EXERCISE AND SUBSEQUENTLY REQUIRE PHARMACOTHERAPY. IT IS CRUCIAL TO NOTE, THAT THE DEFINITION OF WHAT CONSTITUTES AN UNSUCCESSFUL ATTEMPT AT MNT AND EXERCISE HAS NOT BEEN ESTABLISHED. CONSEQUENTLY, INITIATION OF PHARMACOTHERAPY IS AT A PROVIDER’S DISCRETION WITH A WIDE VARIATION IN PRACTICE. WE RECENTLY DEMONSTRATED THIS VARIATION IN A NATIONAL SURVEY OF 452 MATERNAL-FETAL MEDICINE PROVIDERS (MFMS), WITH >80% OF MFMS REQUESTING EVIDENCE-BASED RECOMMENDATIONS TO GUIDE INITIATION OF PHARMACOTHERAPY. WE ALSO SHOWED THAT EARLIER PHARMACOTHERAPY INITIATION AT 20% ELEVATED GLUCOSE VALUES IMPROVED COMPOSITE NEONATAL OUTCOME. HOWEVER, SUCH INTENSIFIED TREATMENT COULD ALSO INCREASE THE RISK OF A SMALL-FOR-GESTATIONAL AGE AND MAY CARRY A NEGATIVE IMPACT ON PATIENT REPORTED OUTCOMES SUCH AS ANXIETY, DEPRESSION AND STRESS. FINALLY, THE LACK OF STANDARDIZED GUIDELINES FOR PHARMACOTHERAPY INITIATION MAY INTRODUCE BIASES AND LEAD TO A VARIATION IN HEALTHCARE DELIVERY BY RACE AND ETHNICITY. THEREFORE, THERE IS A CRITICAL NEED TO ADDRESS THIS MAJOR GAP IN CLINICAL PRACTICE OF GDM AND INVESTIGATE THE EFFICACY, SAFETY, AND PATIENT REPORTED OUTCOMES OF EARLIER PHARMACOTHERAPY INITIATION FOR GDM. WE PLAN TO ADDRESS THIS GAP WITH GDM AND PHARMACOTHERAPY (GAP) STUDY, A RANDOMIZED CONTROLLED TRIAL OF 416 PATIENTS WITH GDM THAT WILL COMPARE TWO THRESHOLDS (20% VS. 40%) OF ELEVATED GLUCOSE VALUES PRIOR TO INSULIN INITIATION. OUR CENTRAL HYPOTHESIS IS THAT INITIATING INSULIN EARLIER, DEFINED AS 20% ELEVATED GLUCOSE VALUES, COMPARED WITH CONTROLS, DEFINED AS 40% ELEVATED GLUCOSE VALUES, WILL RESULT IN REDUCED GDM-RELATED ADVERSE OUTCOMES AND DISPARITIES IN GDM MANAGEMENT, WITHOUT ADVERSE HEALTH CONSEQUENCES. OUR HYPOTHESIS HAS BEEN FORMULATED BASED ON OUR PILOT DATA FAVORING THE 20% THRESHOLD FOR CLINICAL OUTCOMES. THE ACTIVE CONTROL GROUP CHOSEN TO BE 40% BASED ON OUR SURVEY RESULTS DEMONSTRATING THAT 75% OF MFMS START PHARMACOTHERAPY AT 40% ELEVATED GLUCOSE VALUES. WE WILL PURSUE THE FOLLOWING THREE SPECIFIC AIMS:1) DETERMINE THE EFFECT OF EARLIER INSULIN INITIATION FOR GDM MANAGEMENT ON ADVERSE NEONATAL AND MATERNAL OUTCOMES ASSOCIATED WITH GDM; 2) ASSESS THE SAFETY OF EARLIER INSULIN INITIATION IN PREGNANT PATIENTS AND THEIR NEONATES; AND 3) DETERMINE THE EFFECT OF EARLIER INSULIN INITIATION ON PATIENT-REPORTED OUTCOMES USING STANDARDIZED MEASURES AND QUALITATIVE INTERVIEWS. THE GAP STUDY WILL PROVIDE A HIGH-LEVEL EVIDENCE FOR PHARMACOTHERAPY INITIATION IN GDM AND WILL HAVE A DIRECT IMPACT ON CLINICAL PRACTICE. IF PROVEN EFFECTIVE AND SAFE, EARLIER PHARMACOTHERAPY INITIATION WILL IMPROVE THE HEALTH OF PREGNANT PATIENTS AND THEIR OFFSPRING AND WILL PROMOTE STANDARDIZATION OF GDM MANAGEMENT.

BIOPHYSICS OF HDL DYSFUNCTION

REGULATION OF ADRENAL VASCULAR TONE BY STEROIDOGENIC CELLS

ESOPHAGEAL MOTOR FUNCTION IN HEALTH AND DISEASE

IMPLEMENTATION EFFECTIVENESS AND COST-EFFECTIVENESS OF AN HIV INTERVENTION

FETAL ELECTROPHYSIOLOGIC ABNORMALITIES IN HIGH-RISK PREGNANCIES ASSOCIATED WITH FETAL DEMISE

RACISM, RESIDENTIAL RACIAL SEGREGATION, AND BREAST CANCER SURVIVAL DISPARITIES AMONG BLACK, HISPANIC AND NON-HISPANIC WHITE WOMEN

CONTROL OF GVHD BY PROBIOTICS WITH INDIVIDUAL COMMENSAL BACTERIA - ABSTRACT ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION (ALLO-HCT) CAN CURE A VARIETY OF BENIGN AND MALIGNANT HEMATOPOIETIC DISORDERS, BUT GRAFT-VERSUS-HOST DISEASE (GVHD) REMAINS A SIGNIFICANT CAUSE OF TRANSPLANT- RELATED MORTALITY AND MORBIDITY. INVOLVEMENT OF THE GASTROINTESTINAL (GI) TRACT IN THE PATHOGENESIS OF GVHD HAS BEEN SUBSTANTIATED BY THE TRANSLATION OF PRE-CLINICAL AND CLINICAL STUDIES. THE INTESTINAL MICROBIOTA CONSISTS OF A COMMUNITY OF DIVERSE MICROBES THAT RESIDE IN THE GUT AND ARE CRITICAL FOR THE HOST DEVELOPMENT, HOMEOSTASIS, AND IMMUNE REGULATION. EMERGING EVIDENCE SUGGESTS THAT PERTURBATIONS IN THE MICROBIOTA DIVERSITY RESULT IN ABERRANT SYSTEMIC IMMUNE RESPONSES AS WELL AS PATHOGEN COLONIZATION AND MUCOSAL INVASION, FOSTERING THE DEVELOPMENT OF GVHD. A CLEAR RATIONALE EXISTS FOR TARGETING THE MICROBIOTA WITH THE GOAL TO BENEFIT PATIENTS AFTER ALLO-HCT. SEVERAL INTERVENTIONAL STRATEGIES HAVE BEEN EXPLORED BY MEANS OF ANTIBIOTICS, DIET AND PREBIOTICS, PROBIOTICS, MICROBIAL METABOLITES, AND FECAL MICROBIAL TRANSPLANTATION (FMT). HOWEVER, THE IDENTIFICATION OF OPTIMAL FMT DONORS AND APPROPRIATE STOOL SCREENING FOR IMMUNE COMPROMISED PATIENTS IS OF A CONSIDERABLE CHALLENGE. IDENTIFYING AND APPLYING ONE OR MORE LIVE MICROORGANISMS THAT ARE SAFE AND EFFECTIVE IN IMPROVING HEALTH OF HCT PATIENTS ARE OF HIGH MERIT. IN THE PRELIMINARY STUDIES, WE OBSERVED THAT ABUNDANCE OF BARNESIELLA IN GUT MICROBIOTA WAS ASSOCIATED WITH THE REDUCTION OF GVHD IN MICE AFTER ALLO-HCT. FURTHERMORE, ADMINISTRATION OF A SINGLE BARNESIELLA STRAIN, BARNESIELLA INTESTINIHOMINIS (BI), WAS SAFE AND EFFECTIVE IN PREVENTING BOTH ACUTE AND CHRONIC GVHD IN PRECLINICAL MURINE MODELS. OUR PRELIMINARY STUDIES PROVIDE INITIAL SUPPORT THAT BARNESIELLA MAY BE A MEANS OF PROBIOTICS THAT COULD BENEFIT TO PATIENTS AFTER ALLO- HCT IN THE CLINIC. IN FACT, BI HAS BEEN SHOWN TO CLEAR OF INTESTINAL VANCOMYCIN-RESISTANCE ENTEROCOCCUS THAT POSITIVELY ASSOCIATES WITH GVHD SEVERITY IN PATIENTS AFTER ALLO-HCT. IN THIS PROPOSAL, WE WILL EXTEND OUR EXCITING PRELIMINARY STUDIES BY FURTHER PURSUING TWO SPECIFIC AIMS: 1) TO DEFINE THE MECHANISMS BY WHICH BI AND ITS DERIVED METABOLITES MODULATE GVHD THROUGH MAINTAINING GUT HOMEOSTASIS; 2) TO DETERMINE THE MECHANISMS BY WHICH BI AND ITS DERIVED METABOLITES MODULATE GVH/GVL RESPONSES THROUGH REGULATING DONOR T CELLS. WE EXPECT TO FIRMLY VALIDATE BARNESIELLA AS A SAFE AND EFFICACIOUS PROBIOTIC TO PREVENT AND TREAT GVHD WITHOUT COMPROMISING THE GVL EFFECT. FURTHERMORE, WE EXPECT TO UNDERSTAND THE CELLULAR AND MOLECULAR MECHANISMS BY WHICH BARNESIELLA REGULATES MICROBIOTA, ADAPTIVE IMMUNITY, AND INTESTINAL BARRIER FUNCTIONS. IF THE PROPOSED STUDIES ARE SUCCESSFULLY EXECUTED AS EXPECTED, WE WILL PROVIDE A COMPELLING RATIONALE THAT BARNESIELLA PROBIOTICS CAN BE A THERAPEUTIC APPROACH THAT BENEFITS TO PATIENTS AFTER ALLO-HCT.

MACHINE LEARNING ACCELERATED ON-LINE ADAPTIVE REPLANNING

IDENTIFICATION OF NOVEL ANTHELMINTICS THROUGH A TARGET-BASED SCREEN OF A PARASITE ION CHANNEL - PROJECT SUMMARY OVER A THIRD OF THE WORLD'S POPULATION IS INFECTED WITH PARASITIC WORMS. ONE OF THE MOST BURDENSOME INFECTIONS UNDERPINS THE NEGLECTED TROPICAL DISEASE SCHISTOSOMIASIS (BILHARZIA) CAUSED BY PARASITIC FLATWORMS OF THE GENUS SCHISTOSOMA, WHICH AFFLICTS ~200 MILLION PEOPLE WORLDWIDE. THE MAINSTAY PHARMACOTHERAPY FOR SCHISTOSOMIASIS, AND SEVERAL OTHER PARASITIC HELMINTH INFECTIONS, IS THE DRUG PRAZIQUANTEL (PZQ). HOWEVER, SEVERAL FEATURES OF PZQ ARE SEVERELY LIMITING. THESE INCLUDE AN INABILITY OF PZQ TO KILL ALL STAGES OF THE PARASITIC LIFE CYCLE, CLINICAL RELIANCE ON PZQ AS A MONOTHERAPY IN LIGHT OF SUB-OPTIMAL CURE RATES AND FIELD REPORTS OF PZQ RESISTANCE, AS WELL AS AN INABILITY TO IMPROVE UPON THE PZQ PHARMACOPHORE OR DEFINE MECHANISTICALLY HOW THIS DRUG WORKS. CONSEQUENTLY, THERE IS A NEED TO DEVELOP NEXT GENERATION ANTHELMINTICS, IDEALLY ACTIVE AGAINST A BROAD SPECTRUM OF PZQ-SENSITIVE HELMINTH PARASITES. OUR LABORATORY HAS PROVIDED NEW CRITICAL INSIGHT BY DISCOVERING THE TARGET OF PZQ IN PARASITIC SCHISTOSOMES [1, 2]. WE RECENTLY IDENTIFIED A CA2+-PERMEABLE TRANSIENT RECEPTOR POTENTIAL (TRP) ION CHANNEL (SM.TRPMPZQ) IN SCHISTOSOMA MANSONI THAT REPRODUCES THE CHARACTERISTICS OF PZQ ACTION ON SCHISTOSOMES: NANOMOLAR POTENCY, STEREOSELECTIVITY FOR (R)-PZQ, AND MEDIATION OF A SUSTAINED, CYTOTOXIC CA2+ ENTRY [1, 2]. WITH THIS TARGET IN HAND, IT IS NOW POSSIBLE TO CONDUCT A SCREENING CAMPAIGN TO IDENTIFY NOVEL LIGANDS/REGULATORS OF THIS CHANNEL WITH POTENTIAL AS NEXT GENERATION ANTHELMINTICS. THEREFORE, TO BUILD UPON THIS BREAKTHROUGH, WE HAVE ASSEMBLED A TEAM COMBINING EXPERTISE IN HIGH THROUGHPUT SCREENING (HTS), LEAD PRIORITIZATION AND OPTIMIZATION (SCRIPPS FLORIDA), TOGETHER WITH IN-HOUSE EXPERTISE IN PARASITIC FLATWORM BIOLOGY (MEDICAL COLLEGE OF WISCONSIN, MCW). THIS TEAM WILL (I) EXECUTE A PRIMARY SCREEN AGAINST SM.TRPMPZQ (SCRIPPS FLORIDA) AND (II) VALIDATE THE RESULTING HITS FOR EFFICACY AGAINST PARASITIC SCHISTOSOME WORMS EX VIVO, AND IN VIVO USING A MURINE MODEL OF SCHISTOSOMIASIS INFECTION (MCW). PRIORITIZED HITS WILL ALSO BE EVALUATED AGAINST OTHER SPECIES OF SCHISTOSOME WORMS, AND IN THE LONGER TERM OTHER PARASITIC FLATWORMS WITH CLINICAL RELEVANCE. A PILOT SCREEN AND VALIDATION DATA PRESENTED AS PRELIMINARY DATA SUPPORT THE RIGOR OF TARGET IDENTIFICATION, ASSAY OPTIMIZATION AND MINIATURIZATION, AND FEASIBILITY OF THE PROPOSED PIPELINE FOR HIT VALIDATION. THE PROPOSED ACTIVITIES HAVE RELEVANCE TO THIS FOA BY SUPPORTING (I) THE IDENTIFICATION OF NOVEL SMALL MOLECULES WITH POTENTIAL TO TREAT INFECTIOUS DISEASES AND (II) GENERATION OF NEW INSIGHT INTO THE BIOLOGY OF PARASITE TRP ION CHANNELS, WHICH HAVE RECEIVED LITTLE ATTENTION TO DATE AS NOVEL DRUG TARGETS. IF SUCCESSFUL, THESE ACTIVITIES WILL PROVIDE NEW LEADS WITH POTENTIAL FOR USAGE AS NEXT GENERATION ANTIPARASITICS.

AUTOREGULATION OF CEREBRAL BLOOD FLOW

ROLE AND REGULATION OF PEPTIDOGLYCAN SYNTHASES IN ENTEROCOCCAL ANTIMICROBIAL RESISTANCE

SES DISPARITIES IN BREAST CANCER: EFFECT OF PHARMACEUTICAL COVERAGE

TRANSCRIPTIONAL REGULATION OF MAMMALIAN HEPATIC DEVELOPMENT

MOLECULAR PATHWAYS OF CALCIUM PYROPHOSPHATE DEPOSITION DISEASE - CALCIUM PYROPHOSPHATE DEPOSITION DISEASE (CPDD) IS A COMMON TYPE OF ARTHRITIS DEFINED BY THE PRESENCE OF CALCIUM PYROPHOSPHATE (CPP) CRYSTALS IN ARTICULAR CARTILAGE. WHILE CPDD TYPICALLY AFFECTS ELDERLY PATIENTS IN A SPORADIC FASHION, IT ALSO OCCURS PREMATURELY IN FAMILIAL PATTERNS. STUDIES OF FAMILIAL FORMS OF THIS DISEASE PRESENT EXCITING OPPORTUNITIES TO IDENTIFY NOVEL THERAPEUTIC TARGETS FOR THIS CURRENTLY UNTREATABLE ARTHRITIS. WE RECENTLY CONFIRMED THAT A MUTATION IN THE STOP CODON OF TNFRSF11B CAUSES EARLY ONSET CPDD. TNFRSF11B CODES FOR OSTEOPROTEGERIN (OPG). OPG IS A DECOY RECEPTOR FOR RECEPTOR ACTIVATOR OF NUCLEAR FACTOR KAPPA B LIGAND (RANKL). RANKL PROMOTES OSTEOCLAST FORMATION. OUR PRELIMINARY DATA CLEARLY DEMONSTRATE THAT RECOMBINANT MUTANT OPG (OPGMT) DISPLAYS INEFFICIENT INHIBITION OF RANKL RESULTING IN EXCESS OSTEOCLASTOGENESIS IN VITRO. OUR GENETICALLY ENGINEERED MICE CARRYING OPGMT HAVE OSTEOPENIA AND PREMATURE ARTHRITIS MIRRORING THE EFFECTS OF OPGMT IN HUMANS. WE HAVE ALSO FOUND THAT OSTEOCLAST CONDITIONED MEDIA POTENTLY STIMULATES CHONDROCYTE PYROPHOSPHATE (PPI) PRODUCTION, A NECESSARY PROCESS FOR CPP CRYSTAL FORMATION. THE PURPOSE OF THIS WORK IS TO INVESTIGATE THE CONCEPTUALLY INNOVATIVE HYPOTHESIS THAT OPGMT PRODUCES CPDD BY INCREASING OSTEOCLASTOGENESIS IN SUBCHONDRAL BONE. WE PROPOSE THAT EXCESS OSTEOCLASTS IN SUBCHONDRAL BONE STIMULATE CARTILAGE PPI PRODUCTION AND THAT HIGH CARTILAGE-DERIVED PPI LEVELS TARGET PRE-OSTEOBLASTS TO EXAGGERATE SUBCHONDRAL OSTEOCLASTOGENESIS SEEN IN THE PRESENCE OF OPGMT. THE SCIENTIFIC PREMISE OF THIS WORK STEMS FROM CAREFUL OBSERVATIONS OF THE PHENOTYPE OF PATIENTS WITH OPGMT AND STRONG PRELIMINARY DATA. IN AIM 1 WE WILL USE OPGMT/+ AND OPGMT/MT KNOCK-IN MICE TO COMPREHENSIVELY DETERMINE THE ROLE OF OPGMT IN ARTHRITIS PATHOGENESIS IN MICE AND DETERMINE IF DISEASE CAN BE PREVENTED BY BLOCKING RANKL. IN AIM 2, WE WILL EMPLOY IN VITRO AND IN VIVO MODELS TO INVESTIGATE THE ROLE OF HIGH PPI LEVELS IN PROMOTING OPGMT-INDUCED ARTHRITIS AND ELUCIDATE THE UNDERLYING MECHANISMS. THIS WORK IS THE FIRST TO IDENTIFY THE OPG/RANKL/RANK PATHWAY IN CPDD AND TO IMPLICATE SUBCHONDRAL BONE AS A PRIMARY TARGET TISSUE IN THIS DISEASE. THIS PROPOSAL INCLUDES A NOVEL MOUSE MODEL THAT WILL SERVE AS THE BASIS FOR FURTHER MECHANISTIC AND PRE-CLINICAL STUDIES IN CPDD. THE SHARED CLINICAL FEATURES OF PATIENTS WITH THE OPG MUTATION AND THOSE WITH AGE-RELATED CPDD AND THE EXISTENCE OF AVAILABLE DRUGS WHICH TARGET THESE PATHWAYS SUPPORT RAPID TRANSLATION OF THIS WORK.

CANDIDATE GENES AFFECTING ADOLESCENT METABOLIC SYNDROME