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

RAT GENOME DATABASE

CURE SICKLE CELL

STEM CELL THERAPEUTIC OUTCOMES DATABASE (SCTOD) - ESTABLISH AND MAINTAIN A SCIENTIFIC DATABASE OF INFORMATION RELATING TO PATIENTS WHO HAVE BEEN RECIPIENTS OF A STEM CELL THERAPEUTICS PRODUCT (INCLUDING BONE MARROW OR CORD BLOOD) FROM A DONOR.

IGF::CT::IGF STEM CELL THERAPEUTIC OUTCOMES DATABASE (SCTOD)

IGF::CT::IGF CRITICAL FUNCTION MAINTAIN THE STEM CELL THERAPEUTIC OUTCOMES DATABASE WHICH COLLECTS AND MAINTAINS INFORMATION RELATED TO PATIENTS WHO HAVE RECEIVED STEM CELL THERAPEUTIC PRODUCTS IN A STANDARDIZED ELECTRONIC FORMAT

MGT SVCS/CONTRACT&PROCUREMENT SUP

DISSEMINATION AND COORDINATING CENTER FOR THE SCGE CONSORTIUM

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.

NOCICEPTIVE MECHANISMS UNDERLYING SICKLE CELL PAIN

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

ASSESSING PHOTORECEPTOR STRUCTURE AND FUNCTION IN NORMAL AND DISEASED RETINA

HYBRID RAT DIVERSITY PROGRAM

PLATELET-DERIVED FVIII GENE THERAPY OF HEMOPHILIA A

FY22 TP220227 - POINT-MTBI: PROSPECTIVE STUDY OF POINT-OF-CARE BLOOD-BASED BIOMARKERS IN ACUTE MILITARY, CIVILIAN, AND SPORT-RELATED MILD TRAUMATIC BRAIN INJURY (MTBI)

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

VACCINES AGAINST BOTULISM

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

PAIN MECHANISMS IN FABRY DISEASE

TRP CHANNELS IN REGULATION OF VASCULAR TONE

GENERAL ANESTHETICS AND CEREBRAL CORTICAL SENSORY INTEGRATION

ROLE OF INTERLEUKIN 23 IN GASTROINTESTINAL GVHD

INTEGRATED PHYSIOLOGY TRAINING: MOLECULE TO ORGANISM

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

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.

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

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

INVESTIGATION INTO PROTEIN QUALITY CONTROL PATHWAYS IN DICTYOSTELIUM DISCOIDEUM

NEUROIMAGING OF ANESTHETIC MODULATION OF HUMAN CONSCIOUSNESS

TRAINING IN SIGNATURE TRANSDISCIPLINARY CARDIOVASCULAR SCIENCES

MOLECULAR MECHANISMS OF AXENFELD-RIEGER SYNDROME

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

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.

CLINICAL AND TRANSLATIONAL SCIENCE AWARD

RESEARCH TRAINING PROGRAM IN VISION SCIENCE

IDENTIFICATION OF TARGETS OF THE ANTIPARASITIC DRUG PRAZIQUANTEL

MOLECULAR MECHANISMS OF G PROTEIN-COUPLED RECEPTOR BIASED SIGNALING

MITIGATION OF MULTI-ORGAN DELAYED EFFECTS OF ACUTE RADIATION EXPOSURE (DEARE) WITH ACE-INHIBITOR LISINOPRIL

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

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.

GENETIC MAPPING OF BREAST CANCER RISK IN THE TUMOR MICROENVIRONMENT