University Of Kansas Medical Center Research Institute

KANSAS IDEA NETWORK OF BIOMEDICAL RESEARCH EXCELLENCE

FRONTIERS: THE HEARTLAND INSTITUTE FOR CLINICAL AND TRANSLATIONAL RESEARCH

REIMBURSEMENT OF TRAVEL AND SUBSISTENCE EXPENSES FOR LIVING ORGAN DONATION

CANCER CENTER SUPPORT GRANT

PURPOSE/SCOPE: THE UNIVERSITY OF KANSAS CANCER CENTER RECEIVED COMPREHENSIVE CANCER CENTER DESIGNATION BY THE NATIONAL CANCER INSTITUTE IN 2022. THIS IS THE HIGHEST LEVEL OF RECOGNITION AWARDED BY THE NCI. THE UNIVERSITY OF KANSAS CANCER CENTER WILL BEGIN NEW CONSTRUCTION ON A COMBINATION OF 200,000GSF OF CLINICAL SPACE AND 250,000GSF OF RESEARCH SPACE FOR A TOTAL OF 450,000GSF. THE PROPOSED NIST FUNDED PROJECT WILL PROVIDE CONSTRUCTION OF THE 7TH FLOOR RESEARCH WING AND WILL BE A TOTAL OF 33,000GSF OF RESEARCH AND RESEARCH OFFICE SPACE.ACTIVITIES TO BE PERFORMED: ACHIEVING NCI COMPREHENSIVE CANCER CENTER DESIGNATION WAS NOT THE END OF OUR JOURNEY. FOR LEADERSHIP OF THE UNIVERSITY OF KANSAS AND THE UNIVERSITY OF KANSAS HEALTH SYSTEM, THE WORK IS ONGOING TO SUSTAIN OUR STATUS AS THE PREMIER ACADEMIC MEDICAL CENTER IN OUR COMMUNITY, STATE, AND REGION WHOSE REPUTATION IS RESPECTED NATIONWIDE. THE FUNDING FROM THIS GRANT WILL BE TARGETED TOWARD THE CONSTRUCTION OF ONE OF OUR PRIMARY BASIC RESEARCH FLOORS IN OUR NEW KU CANCER CENTER BUILDING.EXPECTED OUTCOMES: THIS NEW HOME WILL PUT PATIENTS AT THE CENTER OF SCIENCE AND CLINICAL CARE, MAKING THE KU CANCER CENTER A GLOBAL DESTINATION FOR THE BEST IN CANCER TREATMENT. CANCER PROJECTIONS UNDERSCORE OUR URGENCY TO BUILD A NEW CENTRALIZED RESEARCH FACILITY. BY 2040, THE NUMBER OF NEW CANCER CASES PER YEAR IS EXPECTED TO RISE TO 29.5 MILLION AND THE NUMBER OF CANCER-RELATED DEATHS TO 16.4 MILLION. IN ORDER TO CONTINUE TO GROW OUR CANCER CENTER AND EXPAND OUR FOCUS ON IMMUNOTHERAPY AND OTHER PROMISING NEW CANCER THERAPEUTICS, WE WILL NEED TO EXPAND OUR RESEARCH AND CLINICAL TEAMS. FOR EXAMPLE, WITH THE CONSTRUCTION OF THIS BUILDING WE PLAN TO ADD 26 NEW INVESTIGATORS OVER THE NEXT TEN YEARS. THIS WILL BE CRITICAL TO OUR EFFORTS TO EFFECTIVELY SERVE OUR CATCHMENT AREA. IT IS ALSO IMPORTANT TO NOTE THAT A PRIMARY PURPOSE OF OUR NEW BUILDING IS TO CO-LOCATE OUR BASIC SCIENTISTS, OUR CLINICIANS, AND OUR POPULATION HEALTH INVESTIGATORS IN A SINGLE BUILDING WHICH WILL ALLOW INCREASED INTERACTIONS AND COLLABORATIONS.INTENDED BENEFICIARIES:FOR THE PEOPLE IN OUR REGION, COMPREHENSIVE DESIGNATION MEANS GREATER ACCESS TO LEADING-EDGE TREATMENTS, INCLUDING CLINICAL TRIALS, AS WELL AS THE BEST AND BRIGHTEST MINDS IN CANCER. A FACILITY CONTAINING NEARLY ALL BASIC, TRANSLATIONAL AND POPULATION SCIENCE FACULTY ADJACENT TO OUR NEWLY CONSTRUCTED ONCOLOGY IN-PATIENT TOWER WILL BE A SIGNIFICANT CATALYST FOR FURTHER GROWTH AND STRENGTHENING OF OUR CENTER. THIS WILL BE PARTICULARLY IMPORTANT FOR OUR DIVERSITY, EQUITY, INCLUSION AND ACCESSIBILITY EFFORTS AS MANY OF OUR POPULATION HEALTH RESEARCHERS FOCUS THEIR WORK ON UNDERSERVED AND MARGINALIZED POPULATION GROUPS.SUBRECIPIENT ACTIVITIES: WITH A PROJECT AS AMBITIOUS AND COMPLEX AS THIS NEW KU CANCER CENTER BUILDING, COMMUNITY PARTNERS, ENGINEERING AND CONSTRUCTION SUBRECIPIENTS ARE ABSOLUTELY NECESSARY FOR THE OVERALL VISION AND EXECUTION.USEFUL LIFE: 20 YEARS

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THE KANSAS INSTITUTE FOR PRECISION MEDICINE

UNIVERSITY OF KANSAS ALZHEIMER'S DISEASE CORE CENTER

UNIVERSITY OF KANSAS ALZHEIMER'S DISEASE RESEARCH CENTER (KU ADRC) - ABSTRACT: OVERALL THE UNIVERSITY OF KANSAS ALZHEIMER'S DISEASE RESEARCH CENTER (KU ADRC) PROMOTES ALZHEIMER'S DISEASE AND RELATED DISORDERS (ADRD) RESEARCH AT LOCAL, NATIONAL, AND INTERNATIONAL LEVELS. OUR STRENGTHS IN BASIC AND TRANSLATIONAL MITOCHONDRIA, LIFESTYLE MODIFICATION, AND PREVENTION RESEARCH DEFINE A METABOLISM THEME WE PURSUED AND REFINED OVER THE PAST DECADE. WE BOAST A SOPHISTICATED AND MATURE INFRASTRUCTURE THAT ADVANCES A BETTER UNDERSTANDING OF AD, BETTER CARE OF AFFECTED PERSONS, AND NEW TREATMENT INTERVENTIONS. THE KU ADRC WILL USE ITS INTELLECTUAL AND INFRASTRUCTURE ASSETS THIS NEXT CYCLE TO DRIVE AD RESEARCH AT A UNIVERSITY VESTED AND INVESTING IN OUR SUCCESS, AND IN DOING SO MOVE THE FIELD CLOSER TO A CURE. OUR CENTER MOVES SEAMLESSLY BETWEEN BENCH AND BEDSIDE, BOTH IN TERMS OF THE RESEARCH PROJECTS WE SUPPORT, AND IN THE INFRASTRUCTURE REQUIRED TO BACK INVESTIGATOR PROJECTS. LIFESTYLE INTERVENTION RESEARCH GENERATES FUNDAMENTAL MECHANISTIC QUESTIONS WE CALL ON WET LAB INVESTIGATORS TO ADDRESS, AND QUESTIONS OF CLINICAL IMPLEMENTATION AND PRACTICE ARE NOW THE FOCUS OF DRY LAB, CLINICAL, AND HEALTH CARE DELIVERY INVESTIGATORS. RESEARCH ADDRESSING AD'S MITOCHONDRIAL COMPONENT DEMONSTRATE A ROLE FOR MITOCHONDRIAL GENES IN AD RISK, THAT MITOCHONDRIA PLAY A CRITICAL ROLE IN CELL PROTEOSTASIS AND PROTEIN AGGREGATION, SPECIFIC LINKS BETWEEN MITOCHONDRIA AND AD HALLMARK PROTEINS, AND HOW TO MANIPULATE BRAIN ENERGY METABOLISM THROUGH LIFESTYLE AND PHARMACOLOGIC APPROACHES. TO DATE THESE EFFORTS LED US TO CREATE NOVEL COMPOUNDS THAT CONSTITUTE A UNIQUE THERAPEUTIC PIPELINE, AND CLINICAL TRIAL INFRASTRUCTURE THAT SUPPORTS ACTUAL STUDIES OF METABOLISM INTERVENTIONS IN ACTUAL AD PATIENTS. FOR THE 2021-26 CYCLE WE WILL USE OUR INTELLECTUAL AND INFRASTRUCTURE ASSETS TO ADDRESS CRITICAL GAPS IN THE AD FIELD, INCLUDING GAPS IN FUNDAMENTAL KNOWLEDGE AND CARE IMPLEMENTATION. DURING THIS CYCLE THE KU ADRC WILL WORK TO (1) EMPOWER INNOVATIVE AD AND BRAIN AGING RESEARCH, EDUCATION, AND CLINICAL PROGRAMS; (2) DRIVE FIELD-DEFINING METABOLISM RESEARCH, AND (3) BRING PRACTICAL AND NOVEL METABOLISM-DIRECTED THERAPIES TO THE BEDSIDE AND CLINIC.

KANSAS IDEA NETWORK OF BIOMEDICAL RESEARCH EXCELLENCE

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION

DATA COORDINATING AND OPERATIONS CENTER FOR THE ECHO IDEA STATES PEDIATRIC CLINICAL TRIALS NETWORK - PROJECT SUMMARY MANY CHILDREN, PARTICULARLY THOSE IN RURAL AND UNDERSERVED COMMUNITIES, LACK VITAL ACCESS TO PEDIATRIC CLINICAL TRIALS. THIS PROJECT ADDRESSES THIS DISPARITY BY PROPOSING A DATA COORDINATING AND OPERATIONS CENTER (DCOC) FOR THE NIH ENVIRONMENTAL INFLUENCES ON CHILD HEALTH OUTCOMES (ECHO) IDEA STATES PEDIATRIC CLINICAL TRIALS NETWORK (ISPCTN), A NATIONAL LEADER IN THIS FIELD. THE PROJECT ACKNOWLEDGES CURRENT CHALLENGES FACED BY THESE COMMUNITIES, INCLUDING GEOGRAPHICAL LIMITATIONS, LACK OF TRUSTED LOCAL INFORMATION, LOGISTICAL HURDLES, AND HEALTHCARE PROVIDERS UNFAMILIAR WITH CONDUCTING CLINICAL TRIALS. THE PROPOSED ISPCTN DCOC AT THE UNIVERSITY OF KANSAS MEDICAL CENTER (KUMC) IN PARTNERSHIP WITH THE UNIVERSITY OF NEBRASKA MEDICAL CENTER (UNMC) AIMS TO BRIDGE THIS GAP BY LEVERAGING THE COMPLEMENTARY EXPERTISE OF BOTH INSTITUTIONS. THE KUMC-UNMC DCOC WILL ACTIVELY SUPPORT CLINICAL TRIAL ACTIVITY BY FACILITATING DEVELOPMENT, CONDUCT, AND RESULTS DISSEMINATION OF MULTICENTER TRIALS FOCUSED ON RURAL AND UNDERSERVED CHILDREN. ADDITIONALLY, THE DCOC WILL EMPOWER RESEARCHERS, CLINICIANS, AND COMMUNITY STAKEHOLDERS IN IDEA STATES BY PROVIDING THEM WITH THE NECESSARY TRAINING AND SUPPORT TO BUILD THEIR PEDIATRIC CLINICAL RESEARCH CAPACITY. FINALLY, THE PROJECT EMPHASIZES THE IMPORTANCE OF COMMUNITY ENGAGEMENT. THE DCOC WILL FOSTER COLLABORATION WITH COMMUNITIES, ALONG WITH NONPROFIT AND PROFESSIONAL SOCIETIES, TO ENSURE THAT CLINICAL TRIALS ARE CULTURALLY RELEVANT, RIGOROUSLY DESIGNED, AND HAVE A SIGNIFICANT IMPACT ON CHILD HEALTH OUTCOMES. THE KUMC-UNMC DCOC WILL BUILD UPON THE OUTSTANDING FOUNDATION OF POLICY AND PROCEDURES DEVELOPED IN THE FIRST TWO CYCLES OF THE NETWORK TO FURTHER INCREASE ACADEMIC PRODUCTIVITY AND ENHANCE THE IDENTIFICATION, DEVELOPMENT, EXECUTION, AND RESULTS DISSEMINATION OF HIGH QUALITY PEDIATRIC CLINICAL TRIALS IN THESE AREAS. THE DCOC WILL INTEGRATE QUALITY BY DESIGN; CONTINUOUS QUALITY IMPROVEMENT; REAL-TIME GOALS, OBJECTIVES, INDICATORS, AND TARGETS MONITORING; MULTI-FACETED PROFESSIONAL DEVELOPMENT; COMMUNITY RESEARCH ENGAGEMENT AND LITERACY; AND LEARNING COLLABORATIVE APPROACHES TO ISPCTN CLINICAL TRIAL OPERATIONS AND CAPACITY-BUILDING. THIS INITIATIVE PROMISES TO INCREASE ACCESS TO CLINICAL TRIALS FOR A WIDER RANGE OF CHILDREN, WHILE STRENGTHENING PEDIATRIC RESEARCH CAPABILITIES IN UNDERSERVED AREAS. ULTIMATELY, THE GOAL IS TO DELIVER HIGH-QUALITY, CULTURALLY SENSITIVE CLINICAL TRIALS THAT GENERATE VALUABLE KNOWLEDGE AND LEAD TO IMPROVED HEALTH OUTCOMES FOR CHILDREN ACROSS THE UNITED STATES AND BEYOND.

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HEARTLAND INSTITUTE FOR CLINICAL AND TRANSLATIONAL RESEARCH

REMOTE MONITORING AND VIRTUAL COLLABORATIVE CARE FOR HYPERTENSION CONTROL TO PREVENT COGNITIVE DECLINE - AGGRESSIVE MANAGEMENT OF HYPERTENSION (HTN) MAY REDUCE THE INCIDENCE OF COGNITIVE IMPAIRMENT, DEMENTIA, AND ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD). DESPITE THIS, 3 OUT OF 4 OLDER ADULTS WITH HTN FAIL TO REACH BLOOD PRESSURE (BP) GOALS. MULTIPLE BARRIERS CONSPIRE AGAINST THE EFFORTS OF PATIENTS AND THEIR CLINICIANS TO OPTIMIZE BP IN OLDER PATIENTS. WE BELIEVE THESE BARRIERS ARE LARGELY SURMOUNTABLE BY REORGANIZATION OF THE CURRENT MODEL OF HTN MANAGEMENT AND LEVERAGING NEW TECHNOLOGY, IMPLEMENTATION SCIENCE, AND TEAM-BASED SYSTEM-WIDE PROCESSES. GIVEN THE HIGH PREVALENCE OF HTN, THESE HEALTH SYSTEM-WIDE EFFORTS MAY HAVE A LARGE IMPACT ON THE PREVALENCE OF ADRD. AS A POTENTIAL PUBLIC HEALTH APPROACH TO ADRD PREVENTION, WE PROPOSE A PRAGMATIC-IMPLEMENTATION STUDY TESTING A HEALTH-SYSTEM WIDE STRATEGY LEVERAGING HOME BP MONITORING AND A “VIRTUAL” COLLABORATIVE CARE CLINIC (VCCC) DEPLOYED IN TWO HEALTH SYSTEMS. WE HYPOTHESIZE THIS APPROACH WILL SAFELY AND EFFECTIVELY LOWER BP AND SLOW AGE-RELATED DECLINE IN COGNITION WHILE REDUCING CARDIOVASCULAR RISK, MORTALITY, AND HEALTH CARE UTILIZATION. THE STUDY WILL BE STRUCTURED IN TWO PHASES. THE PRIMARY OBJECTIVE OF PHASE I (R61) IS TO DEMONSTRATE FEASIBILITY, ASSESS PATIENT ACCEPTABILITY AND SATISFACTION, AND REFINE PROCESSES AND PROCEDURES TO ENABLE HIGH SCALE DELIVERY OF THE VCCC AT THE HEALTH SYSTEM LEVEL. WE WILL OBTAIN IRB APPROVAL, ENGAGE KEY STAKEHOLDERS (HEALTH SYSTEM, PCP’S AND PATIENTS), OPTIMIZE ELECTRONIC HEALTH RECORD (EHR) PROCESSES (ALERTS AND REFERRALS), REFINE CARE ALGORITHMS AND PROCESSES, AND LAUNCH THE INTERVENTION IN 3 PRIMARY CARE CLINICS. WE WILL ENROLL N= 60 PATIENTS TO VCCC FOR 3 MONTHS TO ASSESS IMPORTANT IMPLEMENTATION OUTCOMES AND INFORM GO / NO-GO DECISIONS. UPON ACHIEVING THE MILESTONES OF PHASE I, WE WILL SCALE THE PROGRAM TO MEET THE PHASE II (R31) OBJECTIVE OF IMPLEMENTING THE INTERVENTION ACROSS TWO DIFFERENT HEALTH SYSTEMS (UNIVERSITIES OF KANSAS AND UTAH HEALTH SYSTEMS) TO RANDOMIZE N=1000 PATIENTS TO VCCC VS. CONTROLS (USUAL CARE WITH EDUCATION) FOR 2 YEARS. WE WILL ASSESS EFFECTIVENESS OF VCCC IN ACHIEVING BP GOALS (1º) AND REDUCING 2º MEASURES OF COGNITIVE DECLINE, MAJOR ADVERSE CARDIOVASCULAR EVENTS, ATHEROSCLEROTIC CARDIOVASCULAR DISEASE RISK, HEALTH CARE RESOURCE UTILIZATION, AND MORTALITY. WE WILL ALSO ASSESS CRITICAL IMPLEMENTATION OUTCOMES RELEVANT TO WIDE-SCALE ADOPTION INCLUDING FEASIBILITY, ACCEPTABILITY, APPROPRIATENESS, AND INTENTION TO ADOPT. OUR MULTIDISCIPLINARY COLLABORATIVE TEAM AND HISTORY OF COLLABORATION WITH OUR HEALTH SYSTEM PROVIDES AN EXCELLENT FOUNDATION FOR THIS STUDY. WE HAVE THE NECESSARY EXPERTISE IN CLINICAL TRIALS FOR ADRD PREVENTION, HTN MANAGEMENT, AND EHR FOCUSED PRAGMATIC TRIALS AT BOTH INSTITUTIONS. WITH THE SUCCESSFUL IMPLEMENTATION OF OUR BP LOWERING PROGRAM ACROSS THE TWO HEALTH SYSTEMS, WE WILL BE WELL-POSITIONED TO SCALE THE MODEL TO MULTIPLE HEALTH SYSTEMS FOR DEFINITIVE TESTING ON REDUCING THE INCIDENCE OF ADRD IN A MUCH LARGER COHORT.

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THE UNIVERSITY OF KANSAS CANCER CENTER'S- MCA RURAL NCORP

MOLECULAR REGULATION OF CELL DEVELOPMENT AND DIFFERENTIATION

KANSAS CENTER FOR METABOLISM AND OBESITY RESEARCH (KC-MORE) - CENTER OVERALL: PROJECT SUMMARY THIS COBRE PROPOSAL SEEKS TO ESTABLISH THE KANSAS CENTER FOR METABOLISM AND OBESITY RESEARCH (KC-MORE) WHICH WILL UNIFY INVESTIGATORS FROM MULTIPLE DEPARTMENTS AND RESEARCH CENTERS AT THE UNIVERSITY OF KANSAS MEDICAL CENTER TO FOCUS RESEARCH ON THE PATHOLOGY OF OBESITY, METABOLIC DYSFUNCTION, AND OBESITY-RELATED DISEASE. OBESITY IS A CRITICAL PROBLEM THAT IS HARMING THE HEALTH OF PEOPLE IN KANSAS AS WELL AS THE ENTIRE U.S. NEW RESEARCH-DRIVEN SOLUTIONS AND THERAPIES ARE NEEDED TO PREVENT AND TREAT OBESITY, INVESTIGATE METABOLIC SIGNATURES THAT UNDERLY OBESITY, AND EXAMINE MECHANISMS BY WHICH OBESITY INITIATES CHRONIC DISEASE. THE KC- MORE WILL SERVE TO MERGE THESE AREAS OF FOCUS BY (1) CREATING A SHARED INTELLECTUAL HOME FOR OBESITY-RELATED RESEARCHERS THROUGH A COMMON EDUCATIONAL AND SEMINAR PROGRAM, (2) PROVIDING FUNDING AND MENTORSHIP FOR EARLY STAGE OBESITY-RELATED INVESTIGATORS TO ESTABLISH INDEPENDENT RESEARCH CAREERS, (3) ESTABLISHING SCIENTIFIC CORES TO FACILITATE TRANSLATIONAL RESEARCH OF BOTH EARLY STAGE AND ESTABLISHED INVESTIGATORS, AND (4) PARTNERING WITH DEPARTMENTS TO JOINTLY RECRUIT NEW INVESTIGATORS TO KUMC FOCUSED ON THEMES OF THE KC-MORE. THIS CENTRAL ROLE IN LEADING AND COORDINATING OBESITY RESEARCH AND INCENTIVIZING FUTURE RESOURCES AND RECRUITMENT WILL ALLOW KUMC TO SYNERGIZE EFFORTS AND FORM MULTI-DISCIPLINARY COLLABORATIONS ON OBESITY, METABOLISM, AND OBESITY-INDUCED DISEASE RESEARCH IN WAYS THAT WOULD NOT OCCUR WITHOUT COBRE FUNDING. THE KC-MORE WILL BE LED BY TWO MULTI- PIS, DRS. STEVEN WEINMAN AND JOHN THYFAULT, AND A RENOWNED SENIOR INVESTIGATOR, DR. JOSEPH DONNELLY WHO WILL SERVE AS CHAIR OF THE STEERING COMMITTEE AND LEAD HUMAN ENERGY BALANCE RESEARCH. THESE LEADERS HAVE MULTI- DISCIPLINARY BUT COMPLIMENTARY EXPERTISE IN BASIC, CLINICAL, AND TRANSLATIONAL RESEARCH. PHASE 1 OF THE CENTER WILL SUPPORT THE DEVELOPMENT OF FOUR RESEARCH PROJECT LEADERS (RPLS) WITH STUDIES ON NEURAL CONTROL OF ENERGY BALANCE, CLINICAL-BASED APPROACHES TO WEIGHT LOSS IN RURAL COMMUNITIES, AND BASIC MECHANISMS OF OBESITY-RELATED FATTY LIVER DISEASE AND HYPERTENSION. KC-MORE WILL ALSO ADMINISTER A PILOT AWARDS PROGRAM TO DEVELOP ADDITIONAL KC-MORE RESEARCHERS. THE KC-MORE WILL LEAD 3 NEW SCIENTIFIC CORES THAT PROVIDE A FOUNDATION FOR TRANSLATIONAL RESEARCH CAPABILITIES (THE METABOLISM (MET) CORE, THE CELLS, TISSUES, BIOANALYSIS AND BIOINFORMATICS (CTBB) CORE, AND THE HUMAN ENERGY BALANCE (HEB) CORE). THE CORES WILL SUPPORT INFRASTRUCTURE AND METHODOLOGIES FOR THE RESEARCH PROJECT LEADERS, THE PILOT AWARD RECIPIENTS, AND A LARGE POOL OF ESTABLISHED OBESITY-RELATED RESEARCHERS ON CAMPUS. A CRITICAL GOAL OF PHASE 1 OF THE KC-MORE COBRE WILL BE TO HELP RPLS DEVELOP INDEPENDENT, R01-FUNDED RESEARCH PROGRAMS. OVERALL, THE ESTABLISHMENT OF THE KC-MORE WILL SERVE TO DEVELOP A TRANSLATIONAL AND MULTI-DISCIPLINARY OBESITY RESEARCH PROGRAM THAT WILL HAVE A SIGNIFICANT FUTURE IMPACT BY REDUCING THE BURDEN OF OBESITY-RELATED DISEASE CONDITIONS.

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION - THE UNIVERSITY OF KANSAS CANCER CENTER RECEIVED COMPREHENSIVE CANCER CENTER DESIGNATION BY THE NATIONAL CANCER INSTITUTE IN 2022. THIS IS THE HIGHEST LEVEL OF RECOGNITION AWARDED BY THE NCI. COMPREHENSIVE DESIGNATION AFFIRMS THAT OUR PROGRAM DEMONSTRATES AN EXCEPTIONAL DEPTH AND BREADTH OF RESEARCH, SIGNIFICANT TRANSDISCIPLINARY RESEARCH THAT BRIDGES SCIENTIFIC AREAS, AND AN EFFECTIVE COMMUNITY OUTREACH PROGRAM. WE ARE THE ONLY NATIONAL CANCER INSTITUTE (NCI)-DESIGNATED COMPREHENSIVE CANCER CENTER IN THE REGION, AND 1 OF ONLY 53 IN THE NATION, TO RECEIVE THIS ELITE DISTINCTION. WITH 350 CANCER RESEARCHERS AND CLINICIANS, AND 150-PLUS DISEASE-SPECIFIC ONCOLOGISTS, WE ARE ELEVATING THE STANDARDS IN CANCER CARE. AT THE RECOMMENDATION OF OUR EXTERNAL ADVISORY BOARD, AND TO MOVE FORWARD WITH OUR STATED VISION OF UNIFYING THE PHYSICAL SPACES OF OUR CANCER CENTER UNDER ONE ROOF, WE ARE EMBARKING UPON THE CONSTRUCTION OF THE UNIVERSITY OF KANSAS CANCER CENTER BUILDING, WITH CONSTRUCTION SLATED TO BEGIN IN SEPTEMBER 2024. THIS 205,000 SQUARE FOOT BUILDING COLLECTIVELY BRING TOGETHER AND SUPPORT THE WORK OF OUR CANCER CENTER SCIENTISTS, CLINICIANS AND RESEARCHERS IN A CENTRALIZED BUILDING. THIS NEW HOME WILL ALLOW FOR THE EXPANSION OF OUR RESEARCH TEAMS IN BASIC SCIENCE, CLINICAL, AND POPULATION HEALTH, AND WILL ENCOURAGE INCREASED INTERACTIONS AND COLLABORATIONS. FOR THE PEOPLE IN OUR REGION, THIS MEANS GREATER ACCESS TO LEADING-EDGE TREATMENTS, INCLUDING CLINICAL TRIALS, AS WELL AS THE BEST AND BRIGHTEST MINDS IN CANCER. A FACILITY CONTAINING BASIC, TRANSLATIONAL AND POPULATION SCIENCE FACULTY ADJACENT TO OUR NEWLY CONSTRUCTED ONCOLOGY IN-PATIENT TOWER WILL BE A SIGNIFICANT CATALYST FOR FURTHER GROWTH AND STRENGTHENING OF OUR CENTER. THIS WILL BE PARTICULARLY IMPORTANT FOR OUR DIVERSITY, EQUITY, INCLUSION AND ACCESSIBILITY EFFORTS AS MANY OF OUR POPULATION HEALTH RESEARCHERS FOCUS THEIR WORK ON UNDERSERVED AND MARGINALIZED POPULATION GROUPS WITHIN OUR C ATCHMENT AREA. COMPLETION OF THIS PREMIER NCI COMPREHENSIVE CANCER CENTER BUILDING WILL POSITION THE UNIVERSITY OF KANSAS CANCER CENTER TO LEAD THE REGION IN NEW CANCER THERAPEUTICS, IMMUNOTHERAPY, AND CUTTING EDGE TECHNOLOGY TO GIVE OUR CANCER CENTER COMMUNITY THE CARE THAT IT DESERVES. OVER $105 MILLION HAS ALREADY BEEN SECURED FOR THE CONSTRUCTION OF THIS BUILDING, AND AN ADDITIONAL $100 MILLION IS FORTHCOMING UPON THE APPROVAL OF A $75 MILLION STATE OF KANSAS BUDGET LINE ITEM THIS SUMMER AND MATCHING PRIVATE PHILANTHROPIC GIFTS. THESE HRSA FUNDS WILL SUPPLEMENT THE CONSTRUCTION OF THIS FACILITY FOR THE BREAST CANCER RESEARCH GROUP.

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION - UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC., MSN 1039, 3901 RAINBOW BLVD, KANSAS CITY, KS 66103-2937 KUCC DIRECTOR: ROY JENSEN, MD, 913-588-2568, RJENSEN@KUMC.EDU $10,000,000 THE UNIVERSITY OF KANSAS CANCER CENTER (KUCC) IS A MATRIX CONSORTIUM CANCER CENTER WITH THREE RESEARCH PROGRAMS: 1) CANCER BIOLOGY, 2) CANCER PREVENTION AND CONTROL, AND 3) DRUG DISCOVERY, DELIVERY AND EXPERIMENTAL THERAPEUTICS. IN 2020, 171 MEMBERS OF KUCC ACCOUNTED FOR $9.7M OF NCI FUNDING AND A TOTAL OF $57M IN OVERALL CANCER-RELATED FUNDING, AN INCREASE OF $8M SINCE THE LAST CCSG SUBMISSION. SUPPORTED BY AN EXPERIENCED, NATIONALLY RECOGNIZED LEADERSHIP TEAM, ROY A. JENSEN, MD, HAS LED KUCC ON A STRONG UPWARD TRAJECTORY THAT HAS BEEN CATALYZED BY OVER $467M PHILANTHROPIC SUPPORT SINCE 2004. THE RESEARCH OF THE KUCC FACULTY MEMBERS IS SUPPORTED IN PART BY SEVERAL CORE FACILITIES AND SHARED RESOURCES ON THE KUMC CAMPUS. THESE SHARED FACILITIES ARE THE BACKBONE FOR EXPANDING INNOVATIONS IN CANCER RESEARCH OVER THE NEXT DECADE, AND CRITICAL FOR THE ADVANCEMENT OF CANCER RESEARCH AS A WHOLE. THIS PROPOSAL REQUESTS CANCER RESEARCH EQUIPMENT FOR THE FOLLOWING AREAS: PROTEOMICS, BIOSPECIMEN REPOSITORY, IMAGING, FLOW CYTOMETRY, BIOINFORMATICS, MICROSCOPIC IMAGING, AND ESSENTIAL BASIC SCIENCE EQUIPMENT. THESE NEW INSTRUMENTS WILL HELP PROVIDE CUTTING EDGE TECHNOLOGY AND THE OPTIMAL ENVIRONMENT TO FOCUS THE POWER OF PRECISION MEDICINE, BASIC SCIENCE INQUIRY, DRUG DISCOVERY AND DEVELOPMENT, AND BEHAVIORAL INTERVENTIONS TO DECREASE CANCER INCIDENCE, MORBIDITY, AND MORTALITY. THESE ENHANCEMENTS WILL INCREASE OUR COMPETITIVE CAPABILITIES AND ALSO ADVANCE TEAM SCIENCE BY FOSTERING INNOVATIVE PARTNERSHIPS AND COLLABORATIONS.

MOLECULAR REGULATION OF CELL DEVELOPMENT AND DIFFERENTIATION

NUCLEAR RECEPTORS IN LIVER HEALTH AND DISEASE

INTERDISCIPLINARY CENTER FOR MALE CONTRACEPTIVE RESEARCH AND DRUG DEVELOPMENT

UNIVERSITY OF KANSAS CANCER CENTER MIDWEST PRE-CLINICAL IMAGING CENTER - ABSTRACT THE UNIVERSITY OF KANSAS MEDICAL CENTER SEEKS TO BUILD A STATE-OF-THE-ART MULTI-MODALITY PRE-CLINICAL IMAGING FACILITY AS A CRITICAL ELEMENT OF A CAMPUS-WIDE MASTER PLANNING PROCESS. THIS FACILITY WHILE SERVING THE ENTIRE KUMC CAMPUS WILL ALSO BE AN IMPORTANT ASSET FOR OUR CANCER CENTER AS IT SEEKS TO EXPAND ITS EFFORTS IN DEVELOPING AND UTILIZING MOUSE MODELS OF CANCER BY LEVERAGING CUTTING EDGE EXPERIMENTAL IMAGING TECHNIQUES. THE CAMPUS MASTER PLANNING EFFORT THAT HAS TAKEN PLACE OVER THE PAST YEAR HAS FOCUSED ON ACHIEVING BETTER ALIGNMENT OF THE CAPABILITIES OF OUR PHYSICAL PLANT WITH OUR BASIC AND TRANSLATIONAL RESEARCH ASPIRATIONS, WHILE SIMULTANEOUSLY ENABLING THE FUTURE EXPANSION OF OUR INPATIENT CLINICAL FACILITIES. THE ANIMAL IMAGING FACILITY WILL SERVE THE RESEARCH NEEDS OF THE ENTIRE MEDICAL CENTER CAMPUS AND WILL BE HOUSED WITHIN THE BARRIER OF A NEWLY CONSTRUCTED CAMPUS-WIDE VIVARIUM THAT WILL OCCUPY THE FIRST TWO FLOORS OF A PLANNED CANCER CENTER BUILDING. THIS FACILITY WILL BE AN IMPORTANT ASSET FOR THE UNIVERSITY AND REGION AS WE SEEK TO EXPAND, MODERNIZE AND OPTIMIZE THE USE OF ANIMAL MODELS FOR PRECLINICAL TRANSLATIONAL RESEARCH ACTIVITIES. PLACEMENT OF THE FACILITY WITHIN THE VIVARIUM BARRIER WILL ALLOW US TO REDUCE THE NUMBER OF ANIMALS NECESSARY FOR SPECIFIC RESEARCH PROJECTS BY ENABLING SERIAL IMAGING CAPABILITY VIA A WIDE VARIETY OF TECHNIQUES THAT ARE NOT POSSIBLE WITH OUR CURRENT FACILITIES. THE CURRENT VIVARIUM IS APPROXIMATELY 50 YEARS OLD, IS NEARING ITS USEFUL LIFESPAN, IS PROJECTED TO REACH CAPACITY WITHIN THE NEXT FIVE YEARS, CANNOT ACCOMMODATE CT OR MRI IMAGING, AND OCCUPIES LAND THAT IS NEEDED FOR A CRITICALLY IMPORTANT EXPANSION OF OUR INPATIENT HEALTH CARE FACILITIES. AS A RESULT, THIS C06 OPPORTUNITY REPRESENTS AN IDEAL TIME TO RETHINK, REIMAGINE, AND RENEW OUR LABORATORY ANIMAL FACILITIES AND ENSURE THAT THEY MEET THE NEEDS OF KUMC IN THE 21ST CENTURY. THE PROPOSED PROJECT IS A CRITICAL ELEMENT THE NEW VIVARIUM AND IN REALIZING THE NEW CAMPUS MASTER PLAN AND WILL PROVIDE TENANT FIT-OUT OF PLANNED SHELL SPACE ON THE UNIVERSITY OF KANSAS MEDICAL CENTER CAMPUS. CANCER CENTER, UNIVERSITY, AND HEALTH SYSTEM LEADERSHIP HAVE MADE THIS BUILDING THEIR HIGHEST COLLECTIVE PRIORITY AND ~$150 MILLION HAVE BEEN RAISED HAVE BEEN RAISED THUS FAR TO FUND THE JOINT FACILITY THROUGH PHILANTHROPIC EFFORTS AND THREE CONGRESSIONALLY DIRECTED SPENDING ALLOCATIONS.

NUCLEAR RECEPTORS IN LIVER HEALTH AND DISEASE

TROPHOBLAST DIFFERENTIATION

TAS::89 0222::TAS UNIVERSITY OF KANSAS MEDICAL CENTER CANCER RESEARCH EQUIPMENT AWARD TYPE: CONSTRUCTION GRANT

CENTRAL PLAINS CENTER FOR AMERICAN INDIAN HEALTH DISPARITIES (CPC-AIHD) REVISION

KANSAS UNIVERSITY AFFILIATED PROGRAM

MECHANISMS OF LIVER INJURY BY HEPATITIS C AND ALCOHOL

KANAWARE - KANAWARE IS A COLLABORATION OF THE UNIVERSITY OF KANSAS’ SCHOOL-BASED TELEHEALTH ROCKS PROGRAM, THE KANSAS STATE DEPARTMENT OF EDUCATION (SEA), THE KANSAS DEPARTMENT OF AGING AND DISABILITY SERVICES (SMHA), THREE LOCAL EDUCATION AGENCIES (LEAS), THREE COMMUNITY-BASED BEHAVIORAL HEALTH PROVIDERS, AND THEIR COMMUNITIES. THE ASPIRATIONAL MISSION FOR THIS COLLABORATION IS FOR EVERY CHILD TO HAVE THE EXACT SAME OPPORTUNITY FOR SUCCESS IN SCHOOL AND IN LIFE. MORE SPECIFICALLY, THE OVERARCHING GOAL IS TO IMPROVE STUDENT MENTAL HEALTH NEEDS THROUGH EVIDENCE-BASED INTERVENTIONS ACROSS THE MULTI-TIERED SERVICE MODEL. KANAWARE SUPPORTS INTERVENTIONS FOR STUDENTS AND SCHOOL PERSONNEL AND FAMILY/COMMUNITY MEMBERS LIVING IN SOUTHEAST KANSAS (COFFEYVILLE, PITTSBURG, AND DISTRICTS SERVED BY GREENBUSH). ADDITIONAL LEAS WILL BE ADDED IN YEARS 2 THROUGH YEAR 5. THE SELECTED RURAL SCHOOL COMMUNITIES HAVE A SIGNIFICANT IMPACT FROM THE COVID19 PANDEMIC, LONG-STANDING HEALTH DISPARITIES, AND UNMET NEEDS. KANAWARE WILL FOCUS ON THE SOUTHEAST KANSAS REGION AS THE POOREST AND LEAST-RESOURCED AREA OF THE STATE, WITH HIGH NEEDS AROUND SOCIAL DETERMINANTS OF HEALTH AND TRAUMA-INFORMED APPROACHES. THE CROSS-ORGANIZATIONAL TEAM BRINGS OVER TWENTY YEARS OF SCHOOL-BASED TELEBEHAVIORAL HEALTH EXPERIENCE, MOST RECENTLY WITH TELEHEALTH ROCKS SCHOOL-BASED TELEBEHAVIORAL HEALTH SERVICES ACROSS SPECIALTIES (E.G., PSYCHOLOGY, PSYCHIATRY, DEVELOPMENTAL MEDICINE, APPLIED BEHAVIOR) AND A STATEWIDE CAPACITY-BUILDING AND PRIMARY PREVENTION INITIATIVES USING THE PROJECT ECHO TELEMENTORING MODEL. BASED ON THE OVERWHELMING NEED TO ADDRESS SOCIAL DETERMINANTS OF HEALTH AS PART OF THE SUCCESSFUL IMPLEMENTATION OF THE MULTI-TIER SYSTEM, KANAWARE SCHOOLS AND COMMUNITIES WILL INTEGRATE SCHOOL-BASED COMMUNITY HEALTH WORKERS INTO THE BEHAVIORAL HEALTH APPROACH AND WORKFLOWS TO SUPPORT THE STUDENTS/FAMILIES AND TO MEET ALL KANAWARE GOALS. KANSAS’ LEADING EXPERTS WILL PROVIDE TECHNICAL ASSISTANCE IN THE RANGE OF EVIDENCE-BASED/ EVIDENCE-INFORMED APPROACHES RELATED TO RESILIENCE FOR STUDENTS AND SCHOOL PERSONNEL; SCHOOL-BASED MENTAL HEALTH; POST-TRAUMA APPROACHES; PARENTING; PREVENTION COLLABORATIVES PARTNERING FAMILY, SCHOOL, AND COMMUNITY; CHILD BEHAVIORAL HEALTH ADVANCES; SUBSTANCE USE PREVENTION/TREATMENT ADVANCES; AND MULTI-STAKEHOLDER ADVISORY GROUPS. GOALS INCLUDE: GOAL 1: TO STRENGTHEN PARTNERSHIPS ACROSS KEY SCHOOL-BASED BEHAVIORAL HEALTH STAKEHOLDERS IN SOUTHEAST KANSAS, THE POOREST AND LEAST RESOURCED RURAL AREA OF THE STATE. GOAL 2: LEVERAGING EXISTING EVIDENCE-BASED/EVIDENCE-INFORMED RESOURCES IDENTIFIED BY THE KANAWARE PARTNERS AND SECURING ADDITIONAL RESOURCES BASED ON NEED ASSESSMENT FINDINGS, INCREASE THE NUMBER OF STUDENTS SERVED ACROSS EACH OF THE THREE TIERS OF THE PYRAMID MODEL. GOAL 3: LEVERAGING AN ONLINE REFERRAL TRACKING AND OUTCOMES SYSTEM, DEVELOP/REFINE AND IMPLEMENT KANAWARE MULTI-SYSTEM REFERRAL PATHWAYS TO ADVANCE EVIDENCE-BASED/INFORMED, EQUITY-BASED, TRAUMA-INFORMED, RECOVERY ORIENTED SERVICES GOAL 4: BUILDING ON KANAWARE PARTNER INPUT, RESOURCES, AND ADULT LEARNING BEST PRACTICES SUCH AS PROJECT ECHO TELEMENTORING AND QI COACHING, ADVANCE A PROFESSIONAL COMMUNITY OF LEARNING THAT ADVANCES CAPACITY BUILDING AND AN EFFECTIVE WORKFORCE ACROSS CHILD-SERVING SYSTEMS. GOAL 5: BUILDING ON KANAWARE PARTNER INPUT, RESOURCES, AND ADULT LEARNING BEST PRACTICES, BUILD A FAMILY COMMUNITY OF LEARNING THAT MEETS NEEDS RELATED TO CHILD BEHAVIORAL HEALTH AND SOCIAL DETERMINANTS OF HEALTH.

DIFFERENTIAL EFFECTS OF EXERCISE MODALITY ON COGNITION AND BRAIN IN OLDER ADULTS - PROJECT SUMMARY OLDER ADULTS OFTEN EXPERIENCE PHYSICAL DECLINE THAT CAN BE DIRECTLY AMELIORATED BY PHYSICAL ACTIVITY AND EXERCISE. EVIDENCE IS BUILDING THAT EXERCISE PREVENTS COGNITIVE DECLINE OR DELAYS THE ONSET OF DEBILITATING DEMENTIA (E.G. ALZHEIMER'S DISEASE [AD]) YET, THE OPTIMAL DOSE AND COMBINATION OF EXERCISE MODALITIES FOR PROMOTING BRAIN HEALTH, HOWEVER, REMAINS UNKNOWN AND ESSENTIALLY UNTESTED. OUR LONG-TERM RESEARCH GOAL IS TO DEVELOP AND TEST STRATEGIES TO SUPPORT SUCCESSFUL AGING AND PREVENT AD. WE HAVE SUCCESSFUL ONGOING (R01AG053312, R01AG053952, R01AG049749, R01AG52954, R01AG043962) AND COMPLETED PROJECTS (R01AG033673, R01AG034614, KL2TR000119) AROUND A THEME OF COMMUNITY-BASED EXERCISE PROGRAMS FOR OLDER ADULTS. WE WILL ENROLL 280 INDIVIDUALS, AGE 65 TO 80 YEARS WITHOUT COGNITIVE IMPAIRMENT, INTO A 52-WEEK EXERCISE INTERVENTION TO TEST THE COMBINED AND INDEPENDENT EFFECTS OF AEROBIC AND RESISTANCE TRAINING ON COGNITION, BRAIN STRUCTURE, AND PHYSICAL FUNCTION. WE WILL ALSO EXPLORE UNDERLYING BIOLOGICAL MECHANISMS THAT MAY LINK EXERCISE WITH BRAIN HEALTH. PARTICIPANTS WILL BE RANDOMIZED INTO 1 OF 4 GROUPS: FLEXIBILITY, TONING AND BALANCE (CONTROL), AEROBIC EXERCISE TRAINING, PROGRESSIVE RESISTANCE TRAINING, OR COMBINED AEROBIC AND RESISTANCE TRAINING. ALL INTERVENTION GROUPS REPRESENT THE MOST COMMON MODALITIES OF EXERCISE AND DIRECTLY REFLECT THE PUBLIC HEALTH RECOMMENDATIONS FOR AEROBIC AND RESISTANCE TRAINING. EXERCISE TRAINING WILL OCCUR IN A COMMUNITY SETTING THROUGH THE NETWORK OF GREATER KANSAS CITY YMCAS. WE HYPOTHESIZE THAT 52 WEEKS OF EXERCISE WILL IMPROVE 1) COGNITIVE PERFORMANCE, 2) REGIONAL BRAIN VOLUME, 3) CARDIORESPIRATORY FITNESS AND STRENGTH 4) BIOMARKERS. THIS WILL BE THE LARGEST STUDY TO ASSESS THE COMBINED AND INDEPENDENT EFFECTS OF THE TWO MOST RECOMMENDED FORMS OF EXERCISE. DEMONSTRATING SPECIFIC EXERCISE EFFECTS ON COGNITIVE FUNCTION AND BRAIN HEALTH IN OLDER ADULTS WOULD HAVE ENORMOUS PUBLIC HEALTH IMPLICATIONS. THE STUDY'S RESULTS WILL ALSO IMPACT PUBLIC HEALTH POLICY AND EDUCATION BY PROVIDING EVIDENCE TOWARDS THE SPECIFIC OR SYNERGISTIC EFFECTS OF AEROBIC AND RESISTANCE TRAINING ON COGNITION AND BRAIN STRUCTURE. ENCOURAGING THE PUBLIC TO ADAPT MORE ACTIVE LIFESTYLES AND STIMULATE THE DEVELOPMENT OF EFFECTIVE EXERCISE DELIVERY PROGRAMS TO ENHANCE INITIATION AND MAINTENANCE OF PHYSICAL ACTIVITY INTERVENTIONS IS KEY TO INCREASING THE NUMBER OF QUALITY YEARS OF LIFE FOR AMERICA'S AGING POPULATION.

IMPLEMENTATION SCIENCE AND EQUITY - PROJECT SUMMARY/ABSTRACT: OVERALL COBRE ON IMPLEMENTATION SCIENCE & EQUITY SHRINKING THE TIME LAG FOR TRANSLATING RESEARCH EVIDENCE INTO CLINICAL PRACTICE WOULD IMPROVE HEALTH OUTCOMES ACROSS MULTIPLE DOMAINS AND REDUCE COSTS TO SOCIETY. UNTIL RECENTLY, HOWEVER, CLINICAL RESEARCH HAS DEVOTED LITTLE ATTENTION TO IMPLEMENTING EVIDENCE-BASED PRACTICES IN REAL-WORLD CLINICAL CARE. MOREOVER, RURAL, MINORITY, AND OTHER SUBPOPULATIONS EXPERIENCE EVEN GREATER GAPS IN HEALTH CARE QUALITY. IMPLEMENTATION SCIENCE IS AN EMERGING FIELD OF RESEARCH THAT SPECIFICALLY FOCUSES ON IDENTIFYING THE BEST APPROACHES TO INTEGRATING EVIDENCE- BASED PRACTICES INTO ROUTINE CLINICAL CARE. OUR PROPOSAL FOR A PHASE I CENTER OF BIOMEDICAL RESEARCH EXCELLENCE (COBRE) ON IMPLEMENTATION SCIENCE AND EQUITY SEEKS TO ESTABLISH A RESEARCH CENTER AT THE UNIVERSITY OF KANSAS MEDICAL CENTER (KUMC). THIS COBRE WILL DEVELOP AND TEST IMPLEMENTATION SCIENCE APPROACHES DESIGNED TO ACHIEVE EQUITABLE CARE FOR RURAL, MINORITY, AND OTHER UNDERSERVED POPULATIONS. THE GOAL OF THIS MULTIDISCIPLINARY RESEARCH CENTER IN AN INSTITUTIONAL DEVELOPMENT AWARD (IDEA) STATE IS TO DEVELOP SUSTAINABLE AND GENERALIZABLE APPROACHES TO REDUCING INEQUITIES IN CARE. THE ADMINISTRATIVE CORE INCLUDES AN INTERNAL ADVISORY COMMITTEE, AN EXTERNAL ADVISORY COMMITTEE, STRONG INSTITUTIONAL SUPPORT, AND SUBSTANTIAL FINANCIAL AND IN-KIND CONTRIBUTIONS FROM ALL SCHOOLS AND MAJOR CENTERS ACROSS KUMC. THE PROPOSED COBRE WILL CONSIST OF THREE RESEARCH CORES, WHICH WILL PROVIDE UNIQUE SERVICES FOR BUILDING INSTITUTIONAL CAPACITY IN IMPLEMENTATION SCIENCE AND WILL MENTOR FIVE PROMISING JUNIOR PROJECT LEADERS. OUR OVERALL SPECIFIC AIMS ARE TO: AIM 1. CREATE AND SUSTAIN AN ORGANIZATIONAL STRUCTURE TO PROVIDE SCIENTIFIC MENTORING AND INSTITUTIONAL SUPPORT FOR IMPLEMENTATION SCIENCE AND EQUITY AT KUMC. AIM 2. PROVIDE CORE INFRASTRUCTURE IN METHODOLOGY, ENGAGEMENT, AND ETHICAL ISSUES IN RESEARCH WITH HUMAN SUBJECTS, TO SUPPORT IMPLEMENTATION RESEARCH CONDUCTED BY PROJECT LEADERS AND THE BROADER KUMC COMMUNITY. AIM 3. SELECT AND TRAIN OUTSTANDING, MULTI-DISCIPLINARY, SENIOR AND EARLY-CAREER FACULTY WHO WILL DEVELOP IMPLEMENTATION SCIENCE APPROACHES FOR DELIVERING HIGH-QUALITY CARE TO UNDERSERVED GROUPS. THE PROPOSED COBRE WILL ADVANCE THE FIELD OF IMPLEMENTATION SCIENCE BY CREATING APPROACHES TO IDENTIFYING INEQUITIES, DIAGNOSING CAUSES, AND TESTING SOLUTIONS. IMPLEMENTATION SCIENCE AND EQUITY COBRE LEADS, DRS. KIMBER RICHTER AND CHRISTIE BEFORT HAVE STRONG TRACK RECORDS IN LEADERSHIP, ADMINISTRATION, AND MENTORING IN IMPLEMENTATION SCIENCE—ESPECIALLY WITH MINORITY INVESTIGATORS—TO ACHIEVE RESEARCH INDEPENDENCE. TAKEN TOGETHER, THE PROPOSED COBRE WILL CREATE A SUSTAINABLE AND GROWTH-ORIENTED PROGRAM IN IMPLEMENTATION SCIENCE THAT WILL HAVE LOCAL, NATIONAL, AND INTERNATIONAL IMPACT.

INSTITUTIONAL CAREER DEVELOPMENT CORE

NOVEL APPROACHES FOR THE CONTROL OF MICROBIAL PATHOGENS

PHYSICAL ACTIVITY AND ACADEMIC ACHIEVEMENT (A+PAAC)

STEM CELLS AND EPIGENETICS OF TROPHOBLAST LINEAGE DEVELOPMENT

MOLECULAR REGULATION OF CELL DEVELOPMENT AND DIFFERENTIATION PHASE III COBRE

MECHANISMS OF LIVER INJURY AND DISEASES

BIOLOGY OF GDNF IN DIABETIC NEUROPATHY

KANSAS PKD RESEARCH AND TRANSLATION CORE CENTER

NOVEL APPROACHES FOR THE CONTROL OF MICROBIAL PATHOGENS

PURPOSE: THIS APPLICATION REQUESTS CANCER RESEARCH EQUIPMENT FOR THE FOLLOWING AREAS: MICROSCOPIC IMAGING; LEAD DEVELOPMENT OPTIMIZATION; TRANSGENIC AND GENE TARGETING; CRYO-ELECTRON MICROSOPY & DNA REPAIR; CANCER PATHOLOGY SCANNING; CLINICAL PHARMACOLOGY; METABOLIC NUTRITION; AND ESSENTIAL BASIC SCIENCE.ACTIVITIES TO BE PERFORMED: KUCC WILL PROCURE $5.0 MILLION IN NEW EQUIPMENT TO REFRESH THE SHARED USE LABORATORIES SUPPORTING THE CANCER CENTER'S THREE RESEARCH PROGRAMS: CANCER BIOLOGY; CANCER PREVENTION AND CONTROL; AND DRUG DISCOVERY, DELIVERY, AND EXPERIMENTAL THERAPEUTICS.EXPECTED OUTCOMES: THESE NEW INSTRUMENTS WILL HELP PROVIDE THE OPTIMAL ENVIRONMENT TO FOCUS THE POWER OF PRECISION MEDICINE, BASIC SCIENCE INQUIRY, DRUG DISCOVERY AND DEVELOPMENT, AND BEHAVIORAL INTERVENTIONS TO DECREASE CANCER INCIDENCE, MORBIDITY, AND MORTALITY. INTENDED BENEFICIARIES: RESIDENTS OF THE STATE OF KANSAS (105 COUNTIES) AS WELL AS THE 18 NEIGHBORING COUNTIES OF WESTERN MISSOURI WILL BENEFIT FROM THE ENHANCED RESEARCH MADE POSSIBLE BY THE INVESTMENT IN THIS EQUIPMENT. THESE RESIDENTS ARE SERVED BY KUCC, AS IT IS THE ONLY ACADEMIC CANCER CENTER IN THIS REGION.SUBRECIPIENT ACTIVITIES: NO SUBAWARDS WITH THIS APPLICATION.

GATA FACTOR FUNCTION IN TROPHOBLAST

KANSAS UNIVERSITY AFFILIATED PROGRAM

DETERMINING THE MECHANISM OF IFIH1 DISEASE-ASSOCIATED VARIANTS ON BETA-CELL AND IMMUNE RESPONSES IN TYPE 1 DIABETES

SPECTRE: THE SUNFLOWER PEDIATRIC CLINICAL TRIALS RESEARCH EXTENSION

KANSAS PKD RESEARCH AND TRANSLATION CORE CENTER

REORGANIZATION OF MOTOR CORTEX FOLLOWING BRAIN INJURY

KANSAS COMMUNITY CANCER HEALTH DISPARITIES NETWORK

RURAL ENGAGEMENT IN TELEMEDTEAM FOR OPTIONS IN OBESITY TREATMENT SOLUTIONS (RE-TOOL) - PROJECT SUMMARY/ABSTRACT OBESITY INCREASES RISK FOR 13 TYPES OF CANCER AND NOW AFFECTS OVER 40% OF THE U.S. ADULT POPULATION, WITH EVEN HIGHER PREVALENCE AMONG RURAL AMERICANS. MOST WORRISOME, THE PREVALENCE OF CLASS 3 OBESITY (BMI = 40), WHICH CONTRIBUTES THE HIGHEST CANCER RISK, IS INCREASING AT A RATE 3 TIMES HIGHER IN RURAL COMMUNITIES COMPARED TO URBAN AREAS. RURAL RESIDENTS OFTEN LACK ACCESS TO WEIGHT CONTROL PROGRAMS AND FOOD AND PHYSICAL ACTIVITY RESOURCES THAT PROMOTE HEALTHY LIFESTYLES, ESPECIALLY IN SMALL OR REMOTE RURAL AREAS. IT IS PARAMOUNT THAT OBESITY TREATMENT BE OFFERED IN RURAL PRIMARY CARE, ESPECIALLY TO REACH THOSE WHO HAVE CLASS 3 OBESITY AND/OR CO- MORBID MEDICAL CONDITIONS WHO CARRY THE HIGHEST OBESITY-RELATED CANCER RISK. MEDICAL MANAGEMENT BY A PRIMARY CARE PROVIDER (PCP) DURING BEHAVIORAL WEIGHT LOSS IS ESSENTIAL TO ADDRESS CO-MORBID MEDICAL CONDITIONS, EVALUATE OBESOGENIC MEDICATIONS, AND EXPLORE OPTIONS FOR GUIDELINE-RECOMMENDED PHARMACOTHERAPY AND SURGICAL TREATMENT. HOWEVER, THERE HAS BEEN A MISSED OPPORTUNITY IN PRIMARY CARE- BASED OBESITY TREATMENT TRIALS FOR CAPITALIZING ON GUIDELINE-BASED MEDICAL MANAGEMENT. THE CURRENT TRIAL BUILDS ON LESSONS LEARNED IN OUR RECENTLY COMPLETED RE-POWER TRIAL CONDUCTED IN RURAL PRIMARY CARE CLINICS, WHICH DEMONSTRATED SIGNIFICANTLY GREATER WEIGHT LOSS WITH IN-CLINIC GROUP VISITS VERSUS INDIVIDUAL VISITS, AND HIGHLIGHTED THE NEED FOR MEDICAL MANAGEMENT BY THE LOCAL PCPS. RE-TOOL (RURAL ENGAGEMENT IN TELEMEDTEAM FOR OPTIONS IN OBESITY TREATMENT SOLUTIONS) IS A CLUSTER RCT (N = 16 CLINICS AND 560 PARTICIPANTS) DESIGNED TO ENHANCE SUSTAINABLE ACCESS TO OBESITY TREATMENT IN RURAL COMMUNITIES. TELEMEDTEAM IS A NOVEL TEAM-BASED TELEMEDICINE APPROACH THAT PAIRS INTENSIVE TELEMEDICINE GROUP VISITS WITH QUARTERLY INDIVIDUAL TEAM-BASED CLINIC VISITS THAT SIMULTANEOUSLY ENGAGE THE PATIENT, THE LOCAL PCP, AND THE LIFESTYLE COACH TO HELP ACTIVATE THE PATIENT. THIS NOVEL COLLABORATIVE TELEMEDICINE SOLUTION COMBINES THE BENEFITS OF GROUP-BASED TREATMENT WITH HOME- BASED TELEMEDICINE DELIVERY, AND CRITICALLY, INTEGRATES TEAM-BASED CARE IN LOCAL RURAL CLINICS TO CAPITALIZE ON THE IMPORTANCE OF MEDICAL MANAGEMENT AND ACCESS TO LOCAL SUPPORT AND RESOURCES. THE PRIMARY HYPOTHESIS IS THAT TELEMEDTEAM WILL RESULT IN GREATER % WEIGHT LOSS AT 24 MONTHS COMPARED TO ENHANCED USUAL CARE CONSISTING OF QUARTERLY PCP VISITS ONLY. SECONDARY OUTCOMES INCLUDE THE PROPORTION ACHIEVING =5% AND 10% WEIGHT LOSS, DIET QUALITY, PHYSICAL ACTIVITY, QUALITY OF LIFE, AND MEDICAL TREATMENT PROCESS OUTCOMES. EXPLORATORY ANALYSES WILL ASSESS REACH, ADOPTION, AND IMPLEMENTATION AND INVESTIGATE RURAL SOCIOCULTURAL AND SPATIAL PREDICTORS OF TREATMENT EFFECTS.

GENERAL CLINICAL RESEARCH CENTER

PROGRESSION OF DCIS TO INVASIVE BREAST CANCER THROUGH CCR2 CHEMOKINE SIGNALING

REGULATION OF CELL DIVISION

BIOMARKER-BASED PHASE IIB TRIAL OF (BAZEDOXIFENE-CONJUGATED ESTROGEN) TO REDUCE RISK FOR BREAST CANCER - ABSTRACT FEW RISK-ELIGIBLE WOMEN AGREE TO STANDARD ENDOCRINE INTERVENTIONS FOR BREAST CANCER RISK REDUCTION DUE TO FEAR OF SIDE EFFECTS COMBINED WITH INCOMPLETE EFFICACY AND LACK OF A RELIABLE MARKER OF RESPONSE. WORRY ABOUT INITIATION OR WORSENING VASOMOTOR SYMPTOMS IS A COMMON BARRIER. THE TISSUE SELECTIVE ESTROGEN COMPLEX OF BAZEDOXIFENE (BZA) 20 MG AND CONJUGATED ESTROGEN (CE) 0.45 MG MARKETED AS DUAVEE® IS FDA-APPROVED FOR RELIEF OF HOT FLASHES AND PREVENTION OF OSTEOPOROSIS. DUAVEE® IS PROMISING FOR BREAST CANCER RISK REDUCTION GIVEN THE ESTROGEN ANTAGONIST EFFECTS IN THE BREAST AND UTERUS, AND ESTROGEN AGONIST PROPERTIES IN BONE. THE BAZEDOXIFENE COMPONENT DOES NOT ANTAGONIZE CE'S FAVORABLE EFFECTS ON VASOMOTOR SYMPTOMS DESPITE ANTI- TUMOR EFFICACY OBSERVED FOR THE COMBINATION. IN OUR PILOT, 6 MONTHS OF DUAVEE® GIVEN TO SYMPTOMATIC WOMEN AT INCREASED RISK FOR BREAST CANCER ALLEVIATED HOT FLASHES AND FAVORABLY MODULATED RISK BIOMARKERS OF MAMMOGRAPHIC FIBROGLANDULAR VOLUME (VOLPARA™ FULLY AUTOMATED ASSESSMENTS), BENIGN BREAST TISSUE PROLIFERATION (KI-67), AND SERUM PROGESTERONE, IGF-1, AND BIOAVAILABLE TESTOSTERONE. A PHASE IIB MULTI- INSTITUTIONAL TRIAL OF 6 MONTHS OF DUAVEE® VS PLACEBO IS PROPOSED IN HIGH-RISK WOMEN WITH VASOMOTOR SYMPTOMS. BLOOD, MAMMOGRAM, AND BENIGN BREAST TISSUE, AND ANTHROPOMORPHIC AND QUALITY OF LIFE MEASURES WILL BE OBTAINED AT BASELINE. SUBJECTS WILL BE STRATIFIED BY ENROLLMENT SITE, FIBROGLANDULAR VOLUME, AND KI-67; AND RANDOMIZED TO BLINDED DUAVEE® OR MATCHED PLACEBO FOR 6 MONTHS, FOLLOWED BY REPEAT ASSESSMENTS. THE PRIMARY ENDPOINT IS CHANGE IN MAMMOGRAPHIC FIBROGLANDULAR VOLUME. SECONDARY ENDPOINTS ARE CHANGE IN BENIGN BREAST TISSUE KI-67, ESTROGEN AND PROGESTERONE RECEPTOR PROTEIN, ER AND PGR TARGET GENE EXPRESSION (RT-QPCR), SERUM IGF-1: IGFBP3, BIOAVAILABLE HORMONES, THE RATIO OF SOLUBLE RECEPTOR ACTIVATOR OF NUCLEAR FACTOR KAPPA- LIGAND (SRANKL) TO OSTEOPROTEGERIN, AND PATIENT REPORTED OUTCOME MEASURES RELATED TO VASOMOTOR SYMPTOMS, QUALITY OF LIFE, AND COGNITION. REVERSE PHASE PROTEIN ARRAY AND RNA-SEQ ARE PERFORMED ON BENIGN TISSUE TO AID IN ELUCIDATION OF MECHANISMS OF ACTION. THE POSSIBLE INFLUENCE OF BZA LEVELS, BODY FAT, VISCERAL FAT, INSULIN RESISTANCE, AND INFLAMMATORY CYTOKINES ON BIOMARKER MODULATION WILL BE EXAMINED. FAVORABLE BIOMARKER MODULATION WOULD PROVIDE EVIDENCE THAT DUAVEE® IS LIKELY TO REDUCE RISK FOR BREAST CANCER AND ESTABLISH POTENTIAL MARKERS TO PREDICT RESPONSE IN A PHASE III CHEMOPREVENTION TRIAL.

ALIGNING PCPS AND PATIENTS WITH ALZHEIMER'S RESEARCH EFFORTS: MYALLIANCE FOR COGNITIVE HEALTH

SEXUAL HEALTH EMPOWERMENT FOR CERVICAL HEALTH LITERACY AND CANCER PREVENTION

EFFECT OF IMMUNE-ENHANCING NUTRITION ON RADICAL CYSTECTOMY OUTCOMES

NRSA TRAINING CORE

THE PROMOTION OF PHYSICAL ACTIVITY FOR THE PREVENTION OF ALZHEIMER'S DISEASE IN ADULTS WITH DOWN SYNDROME

HLA-G AT THE MATERNAL FETAL INTERFACE

DHA SUPPLEMENTATION AND PREGNANCY OUTCOME

CHANGING TALK ONLINE TRAINING (CHATO): A NATIONAL TRIAL TO REDUCE BEHAVIORAL SYMPTOMS IN LONG TERM CARE RESIDENTS WITH ALZHEIMER'S DISEASE AND OTHER DEMENTIAS

OLFACTORY PHENOTYPES AS NON-INVASIVE BIOMARKERS FOR ALZHEIMER'S DISEASE: A MACHINE LEARNING APPROACH - PROJECT SUMMARY/ABSTRACT THERE ARE CURRENTLY 50 MILLION PEOPLE SUFFERING GLOBALLY WITH ALZHEIMER’S DISEASE (AD). 95% OF THE POPULATION OVER AGE 65 IS CONCERNED ABOUT THEIR DEMENTIA RISK AND 80% ARE INTERESTED IN DEMENTIA SCREENING. THERE IS A CRITICAL NEED FOR ACCESSIBLE AND COST-EFFECTIVE BIOMARKERS THAT CAN BE USED TO IDENTIFY THOSE ON THE ADRD CONTINUUM – INCLUDING THE ASYMPTOMATIC STAGES – NOT ONLY IN RESEARCH AND SPECIALTY-CARE CENTERS, BUT IN COMMUNITY-BASED AND PRIMARY CARE SETTINGS AS WELL. THIS INFORMATION COULD DRAMATICALLY IMPROVE REFERRALS FOR EARLY CLINICAL TRIAL ENROLLMENT, THE TRIAGE PROCESS FOR SPECIALTY EVALUATION, AND COMPREHENSIVE CARE PLANNING. THE METHODS USED MUST BE APPROPRIATE FOR POINT-OF-CARE, COMMUNITY, OR AT-HOME DEPLOYMENT WHILE MAINTAINING ACCURACY AND PREDICTIVE VALUE. OLFACTORY (SENSE OF SMELL) DYSFUNCTION (OD), IN COMBINATION WITH MACHINE LEARNING (ML) ALGORITHMS, IS A PROMISING NON-INVASIVE BIOMARKER FOR ADRD. WE HAVE PREVIOUSLY DEMONSTRATED THE RELIABILITY OF THE AFFORDABLE RAPID OLFACTORY MEASUREMENT ARRAY (AROMA) TO OBJECTIVELY MEASURE OD AND CATEGORIZE OLFACTORY PHENOTYPES (PATTERNS OF CORRECT AND INCORRECT RESPONSES TO VARIOUS ODORANTS AND MULTIPLE CONCENTRATIONS). AROMA USES ESSENTIAL OILS, WHICH ARE COMPLEX BLENDS OF ODOR MOLECULES AND MAY BE MORE REFLECTIVE OF “REAL WORLD” OLFACTION THAN THE SINGLE CHEMICALS USED IN MOST OTHER TESTS. THIS IS BECAUSE WHEN SCENTS ARE ENCOUNTERED IN REAL LIFE, THE BRAIN PROCESSES AND RECOGNIZES THE ODORANT COMBINATIONS MAKING UP EACH COMPLETE SCENT DIFFERENTLY FROM THE INDIVIDUAL COMPONENT CHEMICALS. OUR RESEARCH WITH AROMA IN ADRD HAS SHOWN THAT AROMA CAN DISTINGUISH COGNITIVELY UNIMPAIRED (CU), MILDLY COGNITIVELY IMPAIRED (MCI), AND AD PATIENTS FROM ONE ANOTHER. ADDITIONALLY, OLFACTORY PHENOTYPES WERE DETECTED USING MACHINE LEARNING AND DIFFERENTIATED BETWEEN DISEASE STATES. OUR ALGORITHMS HAD 100% SENSITIVITY, 83% SPECIFICITY FOR CORRECTLY CLASSIFYING CU VERSUS MCI/AD. ALGORITHMS TASKED WITH CLASSIFYING MCI VERSUS AD HAD 100% SENSITIVITY, 75% SPECIFICITY. WE PROPOSE LONGITUDINAL TESTING OF CU, MCI, AD SUBJECTS (N=324 MEN AND WOMEN > 55 YEARS) OVER 3 YEARS TO ASSESS CHANGES IN OD, FUNCTIONAL STATUS, AND NEUROCOGNITION. A GROUP OF NEUROLOGIC CONTROLS WILL BE INCLUDED TO ENSURE OLFACTORY PHENOTYPES ARE SPECIFIC FOR ADRD. USING TRADITIONAL STATISTICS AND MACHINE LEARNING TECHNIQUES TO EXAMINE THE RELATIONSHIP OF AROMA PERFORMANCE WITH ATN-BIOMARKERS AND CLINICAL MARKERS OF DISEASE (AIM 1); DEFINE PREDICTIVE MODELS USING AROMA DATA TO PREDICT CHANGES IN FUNCTION AND FRAILTY (AIM 2); AND DEVELOP A STREAMLINED ADRD-VERSION OF AROMA USING ONLY THE SCENTS AND CONCENTRATIONS OF HIGHEST INFLUENCE (AIM 3). OUR LONG-TERM GOAL IS FOR POINT-OF-CARE OLFACTORY BIOMARKER DATA, ANALYZED IN REAL-TIME BY ML ALGORITHMS, TO BE WIDELY ACCESSIBLE TO MEANINGFULLY INFORM CLINICAL, RESEARCH, AND CAREGIVER DECISIONS.

THE IMPACT OF MENTHOL FLAVORING ON SWITCHING IN ADULT MENTHOL SMOKERS - PROJECT SUMMARY/ABSTRACT TOBACCO CONTROL POLICIES TARGETING MENTHOL FLAVORING COULD HAVE A SIGNIFICANT IMPACT ON PUBLIC HEALTH. WHEN ADDED TO CIGARETTES, MENTHOL INCREASES ADDICTIVE POTENTIAL AND DEPENDENCE, LEADS TO GREATER INHALATION OF TOBACCO TOXICANTS, AND DECREASES THE LIKELIHOOD OF CESSATION. THESE EFFECTS ARE PARTICULARLY FELT IN THE AFRICAN AMERICAN (AA) COMMUNITY WHERE TARGETED MARKETING HAS RESULTED IN ˜85% OF AA VERSUS ˜20% OF WHITE SMOKERS USING MENTHOL CIGARETTES. THE FDA’S DECISION TO ADVANCE THE RULEMAKING PROCESS TO BAN MENTHOL CIGARETTES IS AN IMPORTANT STEP TOWARD CLOSING THE GAP IN TOBACCO-RELATED DISEASE AND DEATH DISPROPORTIONATELY EXPERIENCED BY AA SMOKERS. THE AGENCY’S REGULATORY ACTION STOPPED SHORT OF INCLUDING MENTHOL-FLAVORED E- CIGARETTES (ECS) AND DEBATE CONTINUES ABOUT WHETHER MORE COMPREHENSIVE ENFORCEMENT PRIORITIES INCLUSIVE OF MENTHOL FLAVORED E-LIQUIDS SHOULD BE ENACTED. WHILE A BAN ON MENTHOL FLAVORED EC MAY REDUCE YOUTH AND YOUNG ADULT INITIATION, IT MAY ALSO DISCOURAGE ADULT MENTHOL SMOKERS TO SWITCH FROM TOBACCO CIGARETTES TO EC. THIS COULD SLOW HARM REDUCTION AND RESULT IN A NEGATIVE PUBLIC HEALTH IMPACT THAT WOULD BE CONCENTRATED IN RACIAL/ETHNIC MINORITY COMMUNITIES ALREADY DISPROPORTIONATELY BURDENED BY TOBACCO. FDA HAS IDENTIFIED THE IMPACT OF EC FLAVORING ON SMOKING PATTERNS AS A RESEARCH PRIORITY AREA, AND THERE IS AN URGENT NEED FOR STUDIES THAT EXAMINE POSSIBLE UNINTENDED CONSEQUENCES OF REGULATORY ACTIONS ON TOBACCO-RELATED HEALTH DISPARITIES. OUR RECENTLY COMPLETED RANDOMIZED CLINICAL TRIAL (RCT) PROVIDED MENTHOL EC OR TOBACCO EC TO ADULT SMOKERS. AMONG MENTHOL SMOKERS, WE FOUND EQUIVALENT RATES OF SWITCHING FROM TOBACCO CIGARETTES TO EC, TOBACCO HARM REDUCTION, EC PRODUCT USE, AND ACCEPTABILITY BETWEEN THOSE WHO USED TOBACCO EC VERSUS MENTHOL EC, ALTHOUGH THE STUDY WAS LIMITED BY A SMALL SAMPLE SIZE AND WAS NOT PROSPECTIVELY DESIGNED FOR THESE COMPARISONS. THESE DATA ARE CONSISTENT WITH OBSERVATIONAL STUDIES THAT HAVE FOUND THAT NICOTINE – NOT FLAVOR – DRIVE USE IN ADULT EC USERS AND PROVIDE STRONG PRELIMINARY EVIDENCE TO SUPPORT RESTRICTIONS ON MENTHOL FLAVORED EC GIVEN POTENTIAL BENEFIT TO YOUTH AND LACK OF EVIDENCE OF HARM TO ADULT SMOKERS. HOWEVER, A PROSPECTIVELY DESIGNED AND FULLY POWERED RCT IS NEEDED TO EMPIRICALLY ANSWER THIS QUESTION. THE OBJECTIVE OF THIS APPLICATION IS TO PROVIDE MUCH NEEDED DATA TO THE FDA TO GUIDE REGULATORY ACTION ON EC FLAVORING. MENTHOL SMOKERS (N=800), STRATIFIED BY RACE AND GENDER, WHO ARE INTERESTED IN SWITCHING TO EC, WILL BE RANDOMIZED 1:1 INTO A 12-WEEK OPEN LABEL, NON-INFERIORITY RCT COMPARING MENTHOL EC VERSUS TOBACCO EC. FOLLOW-UP WILL CONTINUE THROUGH WEEK 26. THE CENTRAL HYPOTHESIS IS THAT TOBACCO EC ARE NOT INFERIOR TO MENTHOL EC AT FACILITATING A SWITCH TO EC IN MENTHOL CIGARETTE SMOKERS. WE FURTHER HYPOTHESIZE NO DIFFERENCE IN TOBACCO HARM REDUCTION, EC PRODUCT USE, OR ACCEPTABILITY BETWEEN PARTICIPANTS RANDOMIZED TO TOBACCO EC VERSUS MENTHOL EC. THE STUDY WILL PROVIDE CRITICAL DATA TO THE FDA TO INFORM REGULATORY ACTION FOR MENTHOL EC THAT COULD SLOW YOUTH INITIATION WITH NO RESULTING NEGATIVE IMPACT ON SWITCHING IN ADULT COMBUSTIBLE CIGARETTE SMOKERS.

STRUCTURAL AND MECHANISTIC STUDIES OF DNA REPAIR

CHANGING THE DEFAULT FOR TOBACCO TREATMENT

USING CBPR TO IMPLEMENT SMOKING CESSATION IN AN URBAN AMERICAN INDIAN COMMUNITY

PRIMARY PREVENTION OF ALZHEIMER'S DISEASE: EXAMINING THE EFFECTS OF COGNITIVE BEHAVIORAL THERAPY ON COGNITIVE FUNCTION AND AMYLOID-BETA IN OLDER ADULTS WITH SYMPTOMS OF INSOMNIA

MODULATION OF CHEMOKINE SIGNALING TO MITIGATE RADIATION INDUCED INFLAMMATION - PROJECT SUMMARY CURRENTLY, THERE IS A NEED FOR STRATEGIES THAT MITIGATE ACUTE AND DELAYED RADIATION SYNDROME. THE RISK OF LARGE POPULATIONS ENCOUNTERING RADIATION EXPOSURE IS REAL AND GROWING. RADIATION INDUCED INFLAMMATION PLAYS SIGNIFICANT ROLE IN INDUCING RADIATION TOXICITY. CHEMOKINE SIGNALING PLAYS KEY ROLE IN SYSTEMIC AND LOCAL INFLAMMATION BY MODULATING EGRESS AND RECRUITMENT INFLAMMATORY IMMUNE CELLS SUCH AS INFLAMMATORY MONOCYTES AND T CELLS. RADIATION EXPOSURE INDUCES RECRUITMENT OF INFLAMMATORY CELLS AND PROMOTES SYSTEMIC AND LOCAL INFLAMMATION. WE HAVE OBSERVED THAT DELETION OF GENES EXPRESSING CHEMOKINE RECEPTOR 2 IN MICE PROMOTES RADIATION RESISTANCE. PHARMACOLOGICAL INHIBITION OF CCR2 SIGNALING MITIGATES ACUTE RADIATION SYNDROME IN MICE. MOREOVER THESE ANIMALS RECEIVING CCR2 ANTAGONIST TREATMENT DID NOT DEVELOP DELAYED EFFECT OF ACUTE RADIATION EXPOSURE (DEARE) SUCH AS RADIATION INDUCED PULMONARY SYNDROME. IN THIS PROPOSAL WE WILL EXAMINE THE EFFECT OF CCR2 INHIBITOR AGAINST RADIATION INDUCED ACUTE AND DELAYED INFLAMMATION USING MICE MODEL OF ACUTE AND DELAYED RADIATION INJURY. WE WILL FULLY CHARACTERIZE CCR2 ANTAGONIST TREATMENT WITH A DETERMINATION OF AN OPTIMUM DOSE AND SCHEDULE FOR MITIGATION OF RADIATION INDUCED ACUTE AND DELAYED INFLAMMATION. WE WILL EXAMINE THE GENERAL APPLICABILITY OF THIS STRATEGY IN YOUNG AND AGED ANIMALS. WE WILL ALSO CHARACTERIZE THE EFFECT OF CCR2 ANTAGONIST IN IN MODULATION OF BONE MARROW DERIVED INFLAMMATORY IMMUNE CELL RELEASE AND RECRUITMENT IN INJURED TISSUE. DETERMINATION OF MECHANISM OF ACTION OF WILL FACILITATE CCR2 INHIBITOR AS A MEDICAL COUNTERMEASURE AGAINST RADIATION UNDER THE FDA’S ANIMAL RULE.

PROMOTING WALKING IN AFRICAN AMERICANS WITH PERIPHERAL ARTERIAL DISEASE

DISEASE MANAGEMENT FOR SMOKERS IN RURAL PRIMARY CARE

EFFECT OF NEONATAL AND ADULT STRESS ON PELVIC PAIN DISORDERS AND COMORBIDITY

INDIVIDUALIZING PHARMACOTHERAPY: A NOVEL OPTIMIZATION STRATEGY TO INCREASE SMOKING CESSATION IN THE AFRICAN AMERICAN COMMUNITY.

ADAPTING THE CHATO COMMUNICATION INTERVENTION FOR DIVERSE NURSING HOME COMMUNITIES - DEMENTIA IS MOST PREVALENT IN BLACK AND HISPANIC OLDER ADULTS WHO ARE INCREASINGLY CARED FOR IN NURSING HOMES (NHS). STAFF SHORTAGES AND LACK OF DEMENTIA CARE SKILLS LIMIT CARE QUALITY, ESPECIALLY IN NHS WITH HIGH PROPORTIONS OF ETHNORACIALLY DIVERSE RESIDENTS. CARE FOR PERSONS LIVING WITH DEMENTIA (PLWD) IN NHS IS COMPLICATED BY BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA (BPSD) WHEN RESIDENTS CANNOT EXPRESS UNMET PHYSICAL AND PSYCHOSOCIAL NEEDS. BPSD INCREASE STAFF STRESS AND TIME TO COMPLETE CARE, CONTRIBUTE TO STAFF TURNOVER AND INJURY, AND LEAD TO USE OF INAPPROPRIATE PSYCHOACTIVE MEDICATION TO CONTROL RESIDENT BPSD. OUR TEAM DEMONSTRATED THAT BPSD OCCUR WHEN STAFF USE ELDERSPEAK (SPEECH THAT SOUNDS LIKE BABY TALK). ELDERSPEAK FEATURES INAPPROPRIATELY INTIMATE TERMS OF ENDEARMENT (DIMINUTIVES SUCH AS “HONEY”), BELITTLING PRONOUN SUBSTITUTIONS THAT IMPLY DEPENDENCE (“WE” NEED A BATH), AND HARSH TASK-ORIENTED COMMANDS (“SIT DOWN”). ELDERSPEAK CONVEYS A MESSAGE OF DISRESPECT AND INCOMPETENCE TO PLWD WHO REACT WITH WITHDRAWAL OR BPSD. OUR PRIOR RESEARCH ESTABLISHED THAT ELDERSPEAK USE MORE THAN DOUBLED THE OCCURRENCES OF BPSD RESPONSES IN NH RESIDENTS WITH DEMENTIA. WE LATER CONFIRMED THAT THE THREE-SESSION CHANGING TALK (CHAT) COMMUNICATION EDUCATION INTERVENTION REDUCED STAFF ELDERSPEAK USE THAT SIGNIFICANTLY REDUCED RESIDENT BPSD. CHAT IN ONLINE FORMAT (CHATO) HAS DEMONSTRATED COMMUNICATION KNOWLEDGE AND CONFIDENCE GAINS AND IS CURRENTLY BEING TESTING IN A NATIONAL CLINICAL TRIAL. HOWEVER, NHS SERVING HIGHER PROPORTIONS OF DIVERSE RESIDENTS HAVE NOT SHOWN INTEREST IN PARTICIPATION, DESPITE HAVING MORE FREQUENT AND SERIOUS CARE DEFICIENCIES INCLUDING HIGHER RATES OF BPSD AND ANTIPSYCHOTIC MEDICATION USE. RESEARCH HAS ESTABLISHED THAT TAILORING AND INTENSIFICATION APPROACHES ARE OFTEN NEEDED FOR INTERVENTIONS ACROSS CARE SETTINGS TO REDUCE CARE DISPARITIES. WE WILL FIRST ENGAGE STAFF IN SIX NHS CARING FOR DIVERSE RESIDENTS AND OUR EXPERT STAKEHOLDER PANEL TO ADAPT THE CURRENT CHATO INTERVENTION USING THE ADAPT FRAMEWORK TO INCREASE CULTURAL COMPETENCY. WE WILL TEST THE ADAPTED INTERVENTION (CHATO-I) IN A WAITLIST-CONTROLLED TRIAL IN 40 NHS THAT CARE FOR HIGH PROPORTIONS OF MINORITY RESIDENTS (<75% WHITE, NON-HISPANIC). NHS WILL BE RANDOMIZED TO FOUR GROUPS AND STAFF WILL COMPLETE THE ADAPTED INTERVENTION WITH HIGH-INTENSITY IMPLEMENTATION SUPPORT (I.E., WEEKLY MEETINGS, TROUBLESHOOTING, EXPERT CONSULTATION, LEADERSHIP/CHAMPION TRAINING, INCENTIVES, TABLETS, AND TECHNOLOGY SUPPORT). WE WILL EVALUATE FEASIBILITY AND ACCEPTABILITY (PARTICIPATION AND COMPLETION RATES) AND USE MIXED MODELING OF ELECTRONIC MEDICAL RECORD DATA TO ASSESS PRELIMINARY EFFECTS ON RESIDENT BPSD AND PSYCHOACTIVE MEDICATION USE. THE NIA HEALTH DISPARITIES FRAMEWORK WILL GUIDE ADAPTATION AND TESTING IN NHS SERVING DIVERSE RESIDENTS WITH A GOAL OF REDUCING HEALTH DISPARITIES (BPSD AND PSYCHOACTIVE MEDICATION USE), ADDRESSING NATIONAL PLAN TO ADDRESS ALZHEIMER’S DISEASE GOALS, NIA’S MILESTONES FOR NONPHARMACOLOGICAL INTERVENTIONS, AND THE NATIONAL ACADEMY IMPERATIVE TO IMPROVE NH CARE EQUITY THROUGH CULTURALLY TAILORED INTERVENTIONS.

PEER REVIEWED CANCER RESEARCH PROGRAM ADVANCING CANCER CARE THROUGH CLINICAL TRIALS AWARD

ENHANCED MEDITERRANEAN DIET FOR ALZHEIMER'S DISEASE PREVENTION

PATHOLOGICAL MECHANISMS OF WHITE MATTER HYPERINTENSITIES - SUMMARY THIS PROJECT APPLIES ADVANCED IN VIVO IMAGING TO DETERMINE THE PATHOLOGICAL MECHANISMS OF WHITE MATTER HYPERINTENSITIES (WMHS) AND THEIR CONTRIBUTION TO COGNITIVE DECLINE IN OLDER ADULTS AT RISK OF ALZHEIMER'S DISEASE (AD). WMHS ARE BRIGHT PATCHES ON T2- MRI BUT DO NOT INFORM THE PATHOLOGY UNDERLYING THEIR APPEARANCE. OUR WORK IS INNOVATIVE BECAUSE IT UTILIZES, FOR THE FIRST TIME, NON-INVASIVE METHODS TO QUANTIFY AXON AND MYELIN RAREFACTION, FLUID RETENTION, WMHS-ASSOCIATED CORTICAL ATROPHY, AND BLOOD-BRAIN BARRIER DYSFUNCTION AS IN VIVO DRIVERS OF WMHS FORMATION. WE WILL ALSO TEST TYPICAL PATHOLOGICAL MARKERS OF WMHS, I.E., HYPOPERFUSION AND COMPROMISED VASCULAR REACTIVITY. ALL IMAGING MEASUREMENTS WILL BE VALIDATED AGAINST WELL-ESTABLISHED CSF MARKERS. OUR SCIENTIFIC PREMISE IS THAT DIFFERENT LOCATIONS OF WMHS (DEEP VS. PERIVENTRICULAR) CORRESPOND TO DISTINCT MECHANISMS (VASCULAR VS. NEURODEGENERATIVE) AND COGNITIVE PROFILES. THUS, OUR WORK WILL ALLOW THE USE OF PATHOLOGICAL DRIVERS OF WMHS TO DEVELOP TARGETED STRATEGIES TO STOP THEIR GROWTH AND AMELIORATE ASSOCIATED COGNITIVE DECLINE IN THE FUTURE. IN AIM 1, WE WILL TEST THE HYPOTHESIS THAT VASCULAR PATHOLOGY PREDOMINATES IN DEEP WMHS BY MEASURING CORTICAL CEREBRAL BLOOD FLOW, VASCULAR REACTIVITY, AND BLOOD-BRAIN BARRIER DYSFUNCTION. WE WILL USE SPECIALIZED ARTERIAL SPIN LABELING AND A HYPERCAPNIC FUNCTIONAL MRI APPROACH FOR THESE MEASUREMENTS. WE WILL VALIDATE MEASUREMENTS WITH CSF MARKERS OF VASCULAR INJURY (E-SELECTIN), INFLAMMATION (ADHESION MOLECULES, VCAM/ICAM), AND BLOOD-BRAIN BARRIER PERMEABILITY (ALBUMIN EXTRAVASATION). IN AIM 2, WE WILL TEST THE HYPOTHESIS THAT NEURODEGENERATIVE PATHOLOGY PREDOMINATES IN PERIVENTRICULAR WMHS BY MEASURING AXON RAREFACTION, DEMYELINATION, AND FLUID RETENTION USING ADVANCED DIFFUSION IMAGING AND MYELIN WATER FRACTION IMAGING. VALIDATION MARKERS WILL BE CSF LEVELS OF TAU AND MYELIN BASIC PROTEIN. IN INDEPENDENT EX VIVO SAMPLES OF DONOR BRAIN TISSUE, WE WILL QUANTIFY VASCULAR PATHOLOGY USING SMOOTH MUSCLE ACTIN AND ALBUMIN IMMUNOHISTOCHEMICAL STAINS IN THE TWO WMHS. WE WILL ALSO QUANTIFY AXON AND MYELIN DENSITY IN THE WMHS AND NORMAL-APPEARING WHITE MATTER AND PERFORM NEURON COUNTING IN GRAY MATTER USING AN ARRAY OF STAINS. POSTMORTEM MRI WILL BE USED TO IDENTIFY WMHS ON DONOR BRAINS. THE QUANTITATIVE NEUROPATHOLOGY WILL SERVE AS AN INDEPENDENT VALIDATION OF OUR HYPOTHESES REGARDING WMHS LOCATION AND MECHANISMS. IN AIM 3, WE WILL TEST THE HYPOTHESIS THAT DEEP WMHS INTERRUPT DISCRETE SHORT-RANGE ASSOCIATION FIBERS AND STRIATAL FIBERS, CAUSING SPECIFIC COGNITIVE DEFICITS, ESPECIALLY THOSE RELATED TO PROCESSING SPEED. PERIVENTRICULAR WMHS, ON THE OTHER HAND, INTERRUPT LONG-RANGE ASSOCIATION TRACTS CAUSING GLOBAL COGNITIVE IMPAIRMENT. WE WILL USE MEDIATION ANALYSIS TO EXPLAIN WHETHER THE TWO TYPES OF WMHS INFLUENCE THE RELATIONSHIP BETWEEN THE DIFFERENT IMAGING MARKERS AND DISTINCT COGNITIVE SYMPTOMS. THE PROPOSAL TAKES ADVANTAGE OF THE CORES AND AFFILIATES OF THE UNIVERSITY OF WASHINGTON'S ALZHEIMER'S DISEASE RESEARCH CENTER FOR RECRUITMENT, LUMBAR PUNCTURES, CSF ANALYSES, POSTMORTEM MRI MATCHED TO EX VIVO TISSUE SECTIONS, AND SYSTEMATIC ANATOMIC SAMPLING OF THOSE SECTIONS, ENSURING THE SUCCESS OF THE PI'S FIRST INDEPENDENT R01.

EVALUATING THE HITSYSTEM TO IMPROVE PMTCT RETENTION AND MATERNAL VIRAL SUPPRESSION IN KENYA

VALIDATION AND MECHANISTIC INTERROGATION OF METABOLISM TARGETING FOR AD

FFA PRODUCTION FROM TRIGLYCERIDE-RICH LIPOPROTEINS

CONSORTIUM FOR RADIOLOGIC IMAGING STUDIES OF POLYCYSTIC KIDNEY DISEASE (CRISP) IV: PROGNOSIS FOR END-STAGE RENAL DISEASE AND BIOMARKER VALIDATION

EXTRACELLULAR VESICLE PROTEOMIC FINGERPRINTING OF OVARIAN CANCER FOR EARLY DETECTION WITH A NANOENGINEERED MICROSYSTEM - PROJECT SUMMARY/ABSTRACT DIVERSITY SUPPLEMENT TITLE: IDENTIFICATION OF PLASMA MICROBIOTA BIOSIGNATURES FOR EARLY EPITHELIAL OVARIAN CANCER DETECTION ANNUALLY OVER 21,000 WOMEN ARE DIAGNOSED IN THE UNITED STATES WITH OVARIAN CANCER AND NEARLY 14,000 WOMEN DIE OF THE DISEASE. ADVANCED EPITHELIAL OVARIAN CANCER (EOC) IS ASSOCIATED WITH AN OVERALL SURVIVAL OF 30% BUT CAN BE CURED IN UP TO 90% OF CASES IF DIAGNOSED AT AN EARLY STAGE. THEREFORE, DEVELOPING NONINVASIVE AND HIGHLY SPECIFIC BLOOD-BASED TESTS IS HIGHLY APPEALING AS SCREENING METHODS IN CLINIC SETTINGS. RESEARCH SUGGESTS THAT HUMAN MICROBIOTA, A COLLECTION OF MICROORGANISMS THAT LIVE IN THE BODY, ARE HARBORED IN EOC TUMOR TISSUE THAT ARE DISTINCTLY UNIQUE BETWEEN WOMEN WITH AND WITHOUT DISEASE. HOWEVER, ADDITIONAL RESEARCH IS NEEDED TO DETERMINE IF THESE OBSERVED MICROBIOTA DIFFERENCES CAN BE DETECTED OUTSIDE THE OVARIAN TUMOR MICROENVIRONMENT AND SERVE AS BIOMARKERS OF EARLY DISEASE. RECENT INVESTIGATIONS HAVE IDENTIFIED NONINFECTIOUS MICROBIAL DEOXYRIBONUCLEIC ACID (DNA) ISOLATED IN BLOOD PLASMA FROM INDIVIDUALS WITH OTHER CANCERS, WHICH CREATES AN EXCITING OPPORTUNITY FOR OVARIAN CANCER SCREENING INNOVATION. THE PURPOSE OF THIS DIVERSITY SUPPLEMENT PROPOSAL IS TO IDENTIFY AND VALIDATE PLASMA MICROBIAL BIOSIGNATURES DETECTED IN EOC THAT CAN DRIVE THE DEVELOPMENT OF NON-INVASIVE BLOOD TESTS FOR EARLY DISEASE SCREENING. THIS STUDY APPLIES A RETROSPECTIVE DESIGN THAT WILL USE EXISTING CONSORTIUM BIOBANK PLASMA SPECIMENS INCLUDING EOC CASES, NON-EOC SOLID TUMOR CASES, BENIGN GYNECOLOGIC DISEASE CASES, AND CONTROL CASES. WE WILL EVALUATE THE MICROBIAL SIGNATURES OF PLASMA SAMPLES WITH 16S RRNA GENE SEQUENCING AND ASSESS THE CLINICAL SENSITIVITY AND SPECIFICITY OF THE MOST INFORMATIVE MICROBIAL TAXA SIGNATURE THAT RIGOROUSLY DISCRIMINATES BETWEEN CASES WITH AND WITHOUT EOC. THIS PROPOSAL MARKS A DYNAMIC CHANGE IN THINKING TO POSTULATE THAT EOC-FAVORABLE MICROBIOTA MAY COALESCE IN THE BLOODSTREAM EARLY AND SIGNIFY OVARIAN CARCINOGENESIS. WE BELIEVE THIS INNOVATIVE STUDY WILL ALLOW US TO DEVELOP A METHOD TO DETECT EARLY EOC DURING A ROUTINE WELL WOMEN EXAM BY SCREENING BLOOD SAMPLES FOR UNIQUE BACTERIAL DNA SIGNATURES, ESPECIALLY IN WOMEN WHO ARE AT HIGH RISK.

REVEALING LIM DOMAIN TRANSCRIPTIONAL COMPLEXES THAT ESTABLISH AND MAINTAIN BETA CELL MASS

ADAPTIVE INTERVENTION TO MAXIMIZE COLORECTAL SCREENING IN SAFETY NET POPULATIONS

MOLECULAR CHARACTERIZATION OF HEPATIC ORGANIC ANION TRANSPORTING POLYPEPTIDES

EVALUATION OF THE HITSYSTEM TO IMPROVE EARLY INFANT DIAGNOSIS OUTCOMES IN KENYA

DOCOSAHEXAENOIC ACID (DHA) SUPPLEMENTATION IN PREGNANCY TO REDUCE EARLY PRETERM BIRTH

REORGANIZATION OF MOTOR CORTEX AFTER BRAIN INJURY

IMPLEMENTING SCALABLE TOOLS IN PRIMARY CARE FOR EARLY ALZHEIMER’S DISEASE DETECTION ACROSS A HEALTH SYSTEM - PROJECT SUMMARY / ABSTRACT ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD) AFFECT NEARLY 7 MILLION OLDER AMERICANS, PROJECTED TO NEARLY DOUBLE BY 2050. EARLY, ACCURATE DIAGNOSIS HAS BECOME INCREASINGLY IMPORTANT WITH ADVANCES IN DISEASE- MODIFYING THERAPIES MOST EFFECTIVE AT INITIAL DISEASE STAGES. HOWEVER, SHORTAGES OF SPECIALISTS LEAD TO DELAYED DIAGNOSES AND MISSED THERAPEUTIC OPPORTUNITIES. ADDRESSING THIS CHALLENGE REQUIRES SCALABLE STRATEGIES TO EQUIP PRIMARY CARE PROVIDERS (PCPS) WITH EFFECTIVE TOOLS FOR TIMELY ADRD DIAGNOSIS AND CARE. WE WILL IMPLEMENT AND RIGOROUSLY EVALUATE THE BRAIN HEALTH CARE ACCELERATOR (BHCA), A COMPREHENSIVE CLINICAL AND SYSTEMS INTERVENTION DESIGNED TO TRANSFORM DEMENTIA CARE IN PRIMARY CARE. BHCA INTEGRATES STRUCTURED COGNITIVE ASSESSMENTS, BLOOD BIOMARKERS (I.E., PLASMA P-TAU217), EHR-EMBEDDED DECISION SUPPORT TOOLS, AND MULTIDISCIPLINARY SPECIALTY CO-MANAGEMENT CLINICS, SUPPORTED BY STRUCTURED PCP TRAINING, CLINICAL CHAMPIONS, AND WORKFLOW AND FINANCIAL INCENTIVES. USING A PRAGMATIC STEPPED-WEDGE TRIAL DESIGN, WE WILL EVALUATE BHCA ACROSS 15 DIVERSE PRIMARY CARE CLINICS (~120 PCPS) WITHIN THE UNIVERSITY OF KANSAS HEALTH SYSTEM (UKHS). WE WILL EVALUATE BHCA’S CLINICAL EFFECTIVENESS AND IMPLEMENTATION OUTCOMES USING THE ESTABLISHED RE-AIM FRAMEWORK (REACH, EFFECTIVENESS, ADOPTION, IMPLEMENTATION, MAINTENANCE) AROUND THREE SPECIFIC AIMS: • AIM 1 (EFFECTIVENESS): EVALUATE THE EFFECT OF BHCA ON INCREASING OVERALL ADRD DIAGNOSIS RATES IN PRIMARY CARE AND SHIFTING IDENTIFICATION TO EARLIER COGNITIVE STAGES, WITH SECONDARY OUTCOMES ASSESSING DIAGNOSTIC ACCURACY (VIA EXPERT ADJUDICATION) AND APPROPRIATE BIOMARKER USAGE (EHR AUDIT) TO ENSURE HIGH-QUALITY DIAGNOSES. • AIM 2 (REACH, ADOPTION, IMPLEMENTATION): ASSESS PCP ADOPTION AND IMPLEMENTATION OF BHCA TOOLS, HYPOTHESIZING INCREASED PCP DIAGNOSTIC CONFIDENCE, SUSTAINED ADOPTION OF STRUCTURED COGNITIVE ASSESSMENTS, ENHANCED BIOMARKER UTILIZATION, INCREASED COGNITIVE CARE BILLING (CMS CODE 99483), AND IMPROVED REFERRAL PATTERNS TO SPECIALIZED DEMENTIA SERVICES. • AIM 3 (IMPLEMENTATION AND MAINTENANCE): IDENTIFY CONTEXTUAL BARRIERS AND FACILITATORS INFLUENCING SUSTAINED BHCA USE IN PRIMARY CARE, SPECIFICALLY EVALUATING FEASIBILITY, ACCEPTABILITY, AND APPROPRIATENESS OF THE INTERVENTION THROUGH PCP SURVEYS AND QUALITATIVE INTERVIEWS GUIDED BY THE CONSOLIDATED FRAMEWORK FOR IMPLEMENTATION RESEARCH (CFIR). THE BHCA REPRESENTS A SCALABLE, EHR-INTEGRATED CLINICAL INTERVENTION DESIGNED TO EMPOWER PCPS TO DIAGNOSE AD EARLIER AND MORE ACCURATELY, SHIFTING DEMENTIA CARE FROM SPECIALTY-DEPENDENT TO PRIMARY CARE–LED. SUCCESSFUL IMPLEMENTATION OF THE BHCA INTERVENTION COULD SERVE AS A NATIONAL MODEL, SIGNIFICANTLY REDUCING DIAGNOSTIC DELAYS AND IMPROVING DEMENTIA CARE COORDINATION ACROSS DIVERSE PRIMARY CARE SETTINGS.

KANSAS BIRCWH CAREER DEVELOPMENT PROGRAM IN WOMEN'S HEALTH

O-GLCNAC HOMEOSTASIS REGULATES MITOCHONDRIAL FUNCTION IN ALZHEIMER'S DISEASE

UNDERSTANDING DISPARITIES IN QUITTING IN AFRICAN AMERICAN AND WHITE SMOKERS

KANSAS UNIVERSITY TRAINING PROGRAM IN NEUROLOGICAL AND REHABILITATION SCIENCES

HYPERPOLARIZED 129XE MRI TO IDENTIFY STRUCTURAL DETERMINANTS OF LOW LUNG FUNCTION AND RESPIRATORY SYMPTOMS IN YOUNG ADULTS FROM THE LUNG HEALTH COHORT - PROJECT SUMMARY/ABSTRACT CHRONIC LUNG DISEASE IS A LEADING CAUSE OF DISABILITY AND DEATH, IN LARGE PART BECAUSE IT IS OFTEN DIAGNOSED AFTER IRREVERSIBLE LUNG DAMAGE HAS OCCURRED. THE AMERICAN LUNG ASSOCIATION (ALA) LUNG HEALTH COHORT (LHC) WAS FUNDED BY NHLBI TO ELUCIDATE FACTORS ASSOCIATED WITH PEAK LUNG HEALTH AND THE EARLY DEVIATIONS FROM LUNG HEALTH THAT MAY PROGRESS TO CHRONIC LUNG DISEASE. THE LHC WILL BE COLLECTING SPIROMETRY, NASAL EPITHELIAL TRANSCRIPTOME, AND CT IMAGING, ALONGSIDE COMPREHENSIVE ENVIRONMENTAL EXPOSURE, SOCIO-BEHAVIORAL, FITNESS, AND RESIDENTIAL HISTORY IN A NATION-WIDE COHORT OF 4000 YOUNG ADULTS BETWEEN THE AGES OF 25 AND 35. DESPITE THIS WEALTH OF INFORMATION, THERE IS CONCERN THAT THE EARLIEST STAGES OF DISEASE MAY GO UNDETECTED IN THE LHC, AS EARLY DISEASE IS THOUGHT TO ORIGINATE IN THE MOST DISTAL AIRSPACES, REGIONS WHICH THE LHC TESTING REGIMEN IS UNABLE TO PROBE. TO THAT END, WE ARE PROPOSING AN ANCILLARY STUDY TO THE LUNG HEALTH COHORT IN WHICH WE AIM TO COLLECT HYPERPOLARIZED 129XE MRI IN A SUBSET OF LHC PARTICIPANTS. HYPERPOLARIZED 129XE MRI (XE-MRI) IS A NOVEL IMAGING TECHNIQUE THAT CAN BE USED TO MEASURE LUNG STRUCTURE AND FUNCTION. SPECIFICALLY, XE-MRI CAN BE USED TO IMAGE AIRWAY FUNCTION (“VENTILATION IMAGING”), ALVEOLAR-AIRSPACE SIZE (“DIFFUSION IMAGING”), AND PULMONARY GAS EXCHANGE (“GAS EXCHANGE IMAGING”). NOTABLY, THESE IMAGING TECHNIQUES ARE ABLE TO PROVE STRUCTURE AND FUNCTION IN THE SMALLEST AIRSPACES OF THE LUNGS. AS SUCH, XE-MRI IS EXPECTED TO BE SENSITIVE TO THE EARLIEST MANIFESTATIONS OF PULMONARY DISEASE AND THUS COMPLEMENTS THE INFORMATION BEING ACQUIRED BY THE LHC. IN THIS SUB-STUDY, WE WILL USE XE-MRI TO IMAGE 260 LHC PARTICIPANTS ACROSS 6 OF THE 17 SITES INVOLVED IN THE PARENT LHC. IN AIM 1, WE WILL USE XE-MRI DIFFUSION IMAGING TO ASSESS THE PULMONARY MICROSTRUCTURE IN LHC PARTICIPANTS WITH LOW NORMAL (<85% PREDICTED) LUNG FUNCTION. BY DOING SO, WE AIM TO DETERMINE THE STRUCTURAL BASIS OF DEVIATIONS FROM PEAK LUNG HEALTH. IN AIM 2, WE WILL USE XE-MRI TO ASSESS PULMONARY STRUCTURE AND FUNCTION IN LHC PARTICIPANTS WITH RESPIRATORY SYMPTOMS (COUGH, SPUTUM, WHEEZE, DYSPNEA). BY DOING SO, WE AIM TO ELUCIDATE STRUCTURAL AND FUNCTIONAL DETERMINANTS OF RESPIRATORY SYMPTOMS THAT ARE POORLY EXPLAINED BY CLINICAL MARKERS SUCH AS SPIROMETRY AND CT IMAGING. THE EXPECTED OUTCOME OF THIS STUDY IS TO IDENTIFY STRUCTURAL AND FUNCTIONAL ABNORMALITIES THAT ARE ASSOCIATED WITH THE CLINICALLY MEASURABLE DEVIATIONS FROM PEAK LUNG HEALTH (LOW NORMAL LUNG FUNCTION AND RESPIRATORY SYMPTOMS). SUCH INFORMATION WILL ULTIMATELY PROVIDE A TREATABLE TARGET FOR THESE INDIVIDUALS. MOREOVER, AS THE LHC INTENDS TO FOLLOW PARTICIPANTS LONGITUDINALLY, WE EXPECT TO BE ABLE TO LINK EARLY STRUCTURAL AND FUNCTIONAL ABNORMALITIES TO THE DEVELOPMENT OF CHRONIC LUNG DISEASE. ULTIMATELY, OUR ABILITY TO MEASURE LUNG STRUCTURE AND FUNCTION USING XE-MRI IN YOUNG ADULTS AT THE AGES OF PEAK LUNG HEALTH WILL ENABLE THE IDENTIFICATION OF DISEASE PRIOR TO THE DEVELOPMENT OF IRREVERSIBLE LUNG DAMAGE, ALLOWING CLINICIANS TO TRANSITION FROM PALLIATION TO PREVENTION OF CHRONIC LUNG DISEASE.

ADVANCING TOBACCO USE TREATMENT FOR AFRICAN AMERICAN SMOKERS

HEARTLAND INSTITUTE FOR CLINICAL AND TRANSLATIONAL RESEARCH

WEIGHT MANAGEMENT FOR ADULTS WITH MOBILITY RELATED DISABILITIES

REMOTE DELIVERY OF WEIGHT MANAGEMENT IN ADULTS WITH IDD

MECHANISMS REGULATING AUTOPHAGY IN ALCOHOL-INDUCED LIVER INJURY

4TH GENERATION E-CIGARETTES IN AFRICAN AMERICAN SMOKERS: REDUCING HARM AND QUITTING COMBUSTIBLE CIGARETTES IN DUAL USERS - PROJECT SUMMARY E-CIGARETTES (EC) ARE AN EFFECTIVE HARM REDUCTION STRATEGY IN ADULT COMBUSTIBLE CIGARETTE SMOKERS WHO EXCLUSIVELY SWITCH TO EC, YET AFRICAN AMERICAN (AA) HAVE BEEN SLOWER TO ADOPT EC AND ARE UNDERREPRESENTED IN EC RESEARCH, CONTRIBUTING TO AN ALMOST COMPLETE LACK OF KNOWLEDGE ABOUT EC AS A HARM REDUCTION STRATEGY FOR A GROUP EXPERIENCING THE HIGHEST RISK OF TOBACCO-RELATED MORBIDITY AND MORTALITY. RELATIVELY LITTLE IS KNOWN ABOUT 4TH GENERATION NICOTINE SALT-BASED POD SYSTEMS (NSPS), WHICH ARE THE LEADING CLASS OF EC. NSPS EC CONTAIN HIGH NICOTINE CONCENTRATIONS WITH RAPID NICOTINE DELIVERY THAT FACILITATES EXCLUSIVE SWITCHING. OUR PILOT DATA PROVIDE STRONG PRELIMINARY EVIDENCE OF EC AS A HARM REDUCTION STRATEGY FOR AA SMOKERS BUT THERE IS AN URGENT NEED TO CONDUCT A FULLY POWERED TRIAL WITH LONGER FOLLOW-UP. MOREOVER, TO ENHANCE EC AS A HARM REDUCTION STRATEGY, THERE IS A CRITICAL NEED FOR INTERVENTIONS TO SUPPORT EXCLUSIVE SWITCHING IN DUAL CIG-EC USERS WHO TRY BUT INITIALLY FAIL. NO SUCH INTERVENTIONS EXIST. A RECENT OPEN LABEL STUDY FOUND THAT VARENICLINE (VAR) HELPED DUAL USERS ELIMINATE CIGARETTE USE BUT THIS HAS STRATEGY NOT BEEN TESTED IN AN RCT. FAILURE TO INTERVENE WITH DUAL USERS IS A MISSED OPPORTUNITY AMONG A GROUP WHO COMPRISES THE LARGEST PROPORTION OF EC USERS (> 50%) AND IS ALREADY MOTIVATED TO REDUCE THEIR HARM FROM SMOKING. THE OBJECTIVES OF THIS APPLICATION ARE TO 1) COMPARE SHORT- AND LONG-TERM HARM REDUCTION AND ABUSE LIABILITY POTENTIAL (I.E., WITHDRAWAL, CRAVING, DEPENDENCE) OF A NSPS EC IN AA EXCLUSIVE EC, DUAL CIG-EC, AND EXCLUSIVE CIG USERS, 2) CHARACTERIZE FACTORS THAT PREDICT WHO SWITCHES FULLY, PARTIALLY, OR NOT AT ALL, AND 3) EXAMINE IF HARM REDUCTION CAN BE FURTHER ENHANCED BY TREATING DUAL USERS WITH VAR TO ELIMINATE CIGARETTE SMOKING. OBJECTIVES WILL BE ACCOMPLISHED BY CONDUCTING A 6-WEEK OPEN- LABEL TRIAL OF A NSPS EC AND COUNSELING TO FACILITATE A COMPLETE SWITCH TO EC IN AA CIGARETTE SMOKERS (N=500) WHO ARE NOT INTERESTED IN QUITTING ALL NICOTINE PRODUCTS BUT ARE INTERESTED IN SWITCHING TO EC. WE ENHANCE HARM REDUCTION POTENTIAL AND CAPITALIZE ON A MISSED OPPORTUNITY BY OFFERING DUAL USERS ADDITIONAL SUPPORT TO MAKE A COMPLETE SWITCH. AT SIX WEEKS, THOSE WHO ARE DUAL USERS (N= ~221) WILL RECEIVE AN ADDITIONAL 12 WEEKS OF THE NSPS EC, ONGOING COUNSELING TO MAKE A COMPLETE SWITCH, AND BE RANDOMIZED TO RECEIVE 12 WEEKS OF VAR OR PLACEBO (PBO) TO SUPPORT QUITTING COMBUSTIBLE CIGARETTES. FOLLOW-UP WILL CONTINUE FOR ONE-YEAR, PROVIDING, TO OUR KNOWLEDGE, THE FIRST EVIDENCE ON THE LONG-TERM HARM REDUCTION POTENTIAL OF NSPC EC. THE CURRENT STUDY IS THE FIRST TO EXAMINE THE SHORT- AND LONG-TERM HARM REDUCTION POTENTIAL OF NSPS EC IN A PRIORITY POPULATION AND THE FIRST TO EXAMINE PHARMACOLOGICAL SUPPORT FOR DUAL CIG-EC USERS IN MAKING A COMPLETE SWITCH TO EC. FINDINGS HAVE THE POTENTIAL TO SUPPORT EC AS A HARM REDUCTION STRATEGY AMONG A DISPARATE GROUP THAT ARGUABLY STANDS TO BENEFIT FROM IT THE MOST, CONTRIBUTE TO THE OVERALL GOAL OF REDUCING TOBACCO-RELATED MORBIDITY AND MORTALITY, AND NARROW THE HEALTH DISPARITY GAP FOR AA SMOKERS.

REST/NRSF, MIRNAS, AND TISSUE REMODELING IN ADENOMYOSIS PATHOPHYSIOLOGY - PROJECT SUMMARY ADENOMYOSIS IS A NONMALIGNANT UTERINE DISEASE CHARACTERIZED BY ENDOMETRIAL STROMA AND GLANDS FOUND WITHIN THE MYOMETRIUM. ADENOMYOSIS HAS BEEN ASSOCIATED WITH HEAVY AND PAINFUL MENSTRUAL PERIODS, PELVIC PAIN, PAIN WITH INTERCOURSE, AND REPRODUCTIVE DYSFUNCTION. HOWEVER, NOW THAT IMAGING IS IDENTIFYING ADENOMYOSIS IN YOUNGER AND MORE VARIED WOMEN THAN THOSE ELECTING HYSTERECTOMY WHERE PATHOLOGICAL DIAGNOSIS OCCURRED, MANY OF OUR ASSUMPTIONS ABOUT THE CLINICAL DISEASE ARE CHANGING. ADDITIONALLY, THE ONLY WIDELY ACCEPTED AND EFFECTIVE TREATMENTS FOR ADENOMYOSIS, HYSTERECTOMY AND HORMONAL SUPPRESSION, ARE UNACCEPTABLE FOR THIS WIDER GROUP OF WOMEN. MUCH OF OUR UNCERTAINTY ON DIAGNOSIS AND TREATMENT FOR ADENOMYOSIS STEM FROM OUR UNCERTAINTY ON ITS' PATHOGENESIS. THE MOST COMMON THEORY OF ADENOMYOSIS DEVELOPMENT CENTERS ON THE INVOLVEMENT OF TISSUE INJURY AND REPAIR MECHANISMS WITH RESULTING ADENOMYOSIS DEVELOPMENT FROM INVAGINATION OF THE ENDOMETRIAL BASALIS INTO THE MYOMETRIUM (THE INVASION/INVAGINATION THEORY). WHILE EMERGING DATA SUPPORT A ROLE FOR THIS THEORY AND THE INVOLVEMENT OF CELL MIGRATION, PROLIFERATION AND INVASION IN ADENOMYOSIS DEVELOPMENT, A DETAILED UNDERSTANDING ON THE MEDIATORS AND MECHANISMS IS CLEARLY LACKING. TO FILL THIS CRITICAL GAP IN OUR KNOWLEDGE WE WILL PERFORM A SERIES OF EXPERIMENTS WHICH INTEGRATE WELL-DEFINED HUMAN SPECIMENS, NOVEL MOUSE MODELS AND RIGOROUS IN VITRO APPROACHES TO IDENTIFY KEY COMPONENTS OF A REST-MIRNA-TISSUE REMODELING CASCADE AND DEMONSTRATE THE FUNCTIONALITY OF THIS PATHWAY IN THE PATHOGENESIS OF ADENOMYOSIS. THE SPECIFIC HYPOTHESIS TO BE TESTED IN THIS APPLICATION IS THAT REDUCED EXPRESSION OF ENDOMETRIAL AND/OR MYOMETRIAL REST INDUCES ALTERATIONS IN A MIRNA-MEDIATED TISSUE REMODELING CASCADE WHICH AUGMENTS ADENOMYOSIS DEVELOPMENT. TO TEST THIS HYPOTHESIS, WE WILL DELINEATE EXPRESSION OF A NOVEL REST-MIRNA MEDIATED TISSUE REMODELING PATHWAY IN ADENOMYOSIS AND DEFINE REST'S FUNCTION USING NOVEL EXPERIMENTAL MOUSE MODELS. USING IN VITRO MODELS FOR CELL PROLIFERATION, MIGRATION AND INVASION, WE WILL DECIPHER CELL TO CELL COMMUNICATION BETWEEN MYOMETRIAL-ENDOMETRIAL REST-MIRNA TISSUE REMODELING PATHWAY SIGNALING RELEVANT TO ADENOMYOSIS PATHOPHYSIOLOGY. TOGETHER, THESE EXPERIMENTS WILL PROVIDE NOVEL INSIGHT INTO THE ROLE OF REST IN ADENOMYOSIS DEVELOPMENT AND IN TURN, MAY LEAD TO IDENTIFICATION OF NOVEL TREATMENT TARGETS FOR THIS DISEASE.

IMPACT OF PHOSPHATURIA ON RENAL OSTEOPONTIN PRODUCTION AND PKD PROGRESSION

TELEMEDICINE FOR SMOKING CESSATION IN RURAL PRIMARY CARE

PRENATAL DHA & NEUROFUNCTIONAL DEVELOPMENT

O-GLCNAC HOMEOSTASIS REGULATES MITOCHONDRIAL FUNCTION IN ALZHEIMER'S DISEASE - PROJECT SUMMARY: CURRENTLY, 6.9 MILLION AMERICANS ARE SUFFERING FROM ALZHEIMER'S DISEASE (AD), WHICH IS THE ONLY MAJOR DISEASE LACKING GOOD PREVENTION METHODS, TREATMENTS, OR A CURE. OUR OBJECTIVE IS TO DETERMINE THE MECHANISMS AS TO HOW NUTRIENT SENSING AS INTERPRETED BY O-GLCNACYLATION, A DYNAMIC SINGLE SUGAR MODIFICATION, INFLUENCES MITOCHONDRIAL FUNCTION IN ALZHEIMER'S DISEASE (AD). O-GLCNAC IS CATEGORIZED BY THE ADDITION OF A SINGLE O- LINKED Β-N-ACETYL-D-GLUCOSAMINE MOIETY TO SERINE/THREONINE AMINO ACIDS OF NUCLEAR AND CYTOPLASMIC PROTEINS. THIS MODIFICATION IS RESPONSIVE TO EXTRACELLULAR SIGNALS SUCH HORMONES, NUTRIENTS, AND ENVIRONMENTAL CUES AND IS INVOLVED IN REGULATING NUMEROUS CELLULAR FUNCTIONS SUCH AS THE CELL CYCLE, STRESS RESPONSE, TRANSCRIPTION, AND TRANSLATION. THE ENZYMES RESPONSIBLE FOR PROCESSING THE MODIFICATION ARE O-GLCNAC TRANSFERASE (OGT), WHICH ADDS THE MODIFICATION, AND O-GLCNACASE (OGA), WHICH REMOVES THE MODIFICATION. IMPORTANTLY, CHANGES IN O- GLCNACYLATION ALTER MITOCHONDRIAL FUNCTION. CELLS ACTIVELY MAINTAIN HOMEOSTATIC LEVELS IN O-GLCNAC, AND CELLS WILL ALTER THE EXPRESSION OF OGT AND OGA TO MODULATE O-GLCNACYLATION DUE TO CHANGES IN THE ENVIRONMENT. WE HYPOTHESIZE THAT THE LOSS OF O-GLCNAC HOMEOSTASIS CAUSES MITOCHONDRIAL DYSFUNCTION PROMOTING THE ONSET AND PROGRESSION OF AD. SUPPORTING THIS HYPOTHESIS, WE RECENTLY DEMONSTRATED THAT O-GLCNAC REGULATES MITOCHONDRIAL RESPIRATION, MITOPHAGY, AND MITOCHONDRIAL RETROGRADE SIGNALING; THUS, WE GENERATED TWO SPECIFIC AIMS TO TEST THIS HYPOTHESIS, AND WE HAVE DEVELOPED SEVERAL O-GLCNAC RELATED TOOLS TO ACCOMPLISH OUR GOALS. IN AIM 1, WE WILL ELUCIDATE O-GLCNAC MECHANISTIC CONTROL OF MITOCHONDRIAL FUNCTION BY IDENTIFYING THE OGT AND OGA MITOCHONDRIAL INTERACTOME IN CONTROL AND AD MITOCHONDRIA AND TEST HOW THESE INTERACTIONS IMPACT MITOCHONDRIAL FUNCTION; IDENTIFY ELECTRON TRANSPORT PROTEINS THAT PREFER TO INTERACT WITH O-GLCNACYLATED PROTEINS AND HOW THESE INTERACTIONS AFFECT ENERGETICS; ELUCIDATE THE FUNCTION OF O-GLCNAC ON PINK1 (PTEN INDUCED KINASE 1), WHICH IS KEY REGULATOR OF MITOPHAGY, AND LASTLY EXPLORE SEX-SPECIFIC EFFECTS OF OGA INHIBITION (A POTENTIAL AD THERAPEUTIC) ON MITOCHONDRIAL FUNCTION. THESE DATA WILL PROVIDE NOVEL MECHANISTIC INFORMATION ON HOW O-GLCNAC AND THE FUNCTIONS OF OGT AND OGA CONTRIBUTE TO MITOCHONDRIAL FUNCTION AND AD DEVELOPMENT. IN OUR SECOND AIM, WE WILL ASCERTAIN HOW ALTERED O-GLCNAC NUTRIENT SENSING AFFECTS MITOCHONDRIAL RETROGRADE SIGNALING TO THE NUCLEUS. WE IDENTIFIED THAT THE FUNCTION OF RETROGRADE SIGNALING TRANSCRIPTION FACTORS ATF4 (ACTIVATING TRANSCRIPTION FACTOR 4) AND NRF2 (NUCLEAR FACTOR ERYTHROID 2) ARE MODULATED BY O-GLCNAC. WE WILL EMPLOY A NOVEL CRISPR BASED TARGETING OF OGT AND OGA TO ATF4 AND NRF2 TARGET GENE PROMOTERS TO DETERMINE HOW O-GLCNACYLATION ORGANIZES CIS-REGULATORY ELEMENTS AT THESE PROMOTERS. NEXT, WE WILL IDENTIFY HOW O-GLCNAC ON NRF2 AFFECTS NRF2 FUNCTION. TOGETHER, THESE DATA WILL DEMONSTRATE THE ROLE OF O-GLCNAC HOMEOSTASIS IN REGULATING NUCLEAR MITOCHONDRIAL GENE EXPRESSION THROUGH MITOCHONDRIA RETROGRADE SIGNALING. COLLECTIVELY, THESE RESULTS WILL PROVIDE NEW MECHANISTIC PATHWAYS IN OUR UNDERSTANDING OF AD.

GROWTH AND ADIPOSITY IN NEWBORNS: THE INFLUENCE OF PRENATAL DHA SUPPLEMENTATION

IMPACT OF CLDN1 INHIBITION ON CHEMORESISTANCE AND METASTASIS OF COLON CANCER - CRC IS THE THIRD LEADING CAUSE OF TUMOR-RELATED DEATHS ATTRIBUTED TO VITAL ORGAN METASTASIS. CRC PATIENT SURVIVAL IS HIGHLY DEPENDENT ON THE CANCER STAGING AT THE TIME OF DIAGNOSIS AND, DESPITE THE RECENT PROGRESSES MADE IN THE CLINICAL MANAGEMENT OF THIS DISEASE, IT REMAINS A MEAGRE 13% FOR THE PATIENTS DIAGNOSED WITH CANCER METASTASIS. REMARKABLY, RESISTANCE TO THE ANTI-CANCER THERAPY CONTRIBUTES HEAVILY TO THE METASTASIS AS ~90% OF PATIENTS WITH METASTATIC CANCER ARE ALSO RESISTANT TO THE THERAPIES. THUS, DEVELOPING NOVEL AND TARGETED THERAPIES FOR INHIBITING CRC PROGRESSION AND METASTASIS IS ESSENTIAL AND URGENT. IN THIS REGARD, EXTENSIVE PRECLINICAL AND CLINICAL STUDIES FROM OUR LABORATORY, AND OF OTHER LABORATORIES, HAVE NOW VALIDATED A CAUSAL ROLE FOR THE UPREGULATED CLAUDIN-1 EXPRESSION IN PROMOTING CRC METASTASIS. IN A COMPREHENSIVE ANALYSIS EXAMINING A LARGE CRC-PATIENT COHORT, CELL LINES AND MOUSE MODELS, WE HAVE REPORTED A HIGHLY SIGNIFICANT ASSOCIATION OF THE DEREGULATED CLAUDIN-1 EXPRESSION WITH CRC METASTASIS. MECHANISTIC INVESTIGATIONS INTO THESE FINDINGS REVEALED PHYSICAL BINDING OF CLAUDIN-1 WITH PROTO-ONCOGENE SRC, IN PROMOTING CRC METASTASIS. SO FAR, NO KNOWN SMALL MOLECULE INHIBITOR FOR CLAUDIN-1 EXISTS. USING A RIGOROUS ANALYTICAL DESIGN THAT INCLUDED IN VITRO AND IN VIVO TESTING, WE IDENTIFIED A CLAUDIN-1 SPECIFIC INHIBITOR. FURTHER ANALOGS WERE SYNTHESIZED, WE NOW HAVE NARROWED DOWN OUR SEARCH TO A NOVEL AND SPECIFIC SMALL MOLECULE INHIBITOR, PDS-0330, FOR EFFICIENT INHIBITION OF THE CLDN1 DEPENDENT CRC PROGRESSION. THESE DATA HAVE LED TO THE CENTRAL HYPOTHESIS OF THIS PROPOSAL THAT PDS-0330 CAN INHIBIT CLDN1/SRC ASSOCIATION TO INHIBIT CRC PROGRESSION AND METASTASIS. IN THIS GRANT PROPOSAL, WE WILL OPTIMIZE THE POTENCY, PHARMACOKINETIC PROPERTIES OF PDS-0330 ANALOGS TO DEVELOP NOVEL TOOL COMPOUNDS. WE WILL ALSO DETERMINE BINDING SPECIFICITY AND CHARACTERIZE THE BINDING EPITOPE OF PDS-0330 TO INHIBIT COLON CANCER PROGRESSION. FINALLY, WE WILL DETERMINE THE EFFICACY OF PDS0330 IN INHIBITING CLAUDIN- 1-DEPENDENT PHENOTYPES IN MOUSE AND ORGANOID MODEL OF AGGRESSIVE CRC.

TRI-CITY CERVICAL CANCER PREVENTION STUDY AMONG WOMEN IN THE JUSTICE SYSTEM

ROLE OF PERIOSTIN IN POLYCYSTIC KIDNEY DISEASE

GERIATRICS WORKFORCE ENHANCEMENT PROGRAM

STATINS: MITOCHONDRIAL FUNCTION AND AEROBIC CAPACITY

IAMHEALTHY PARENTS FIRST - PROJECT SUMMARY/ABSTRACT BOTH CHILDREN AND ADULTS IN RURAL AREAS HAVE HIGHER OBESITY RATES THAN THEIR URBAN COUNTERPARTS. WITH LESS ACCESS TO EVIDENCE-BASED WEIGHT LOSS INTERVENTIONS, OBESITY POSES A MAJOR RISK FACTOR CONTRIBUTING TO ELEVATED MORBIDITY AND MORTALITY FROM CARDIOVASCULAR DISEASE, DIABETES, AND CANCER AMONG RURAL AMERICANS. OBESITY RUNS IN FAMILIES DUE TO MULTIPLE FACTORS INCLUDING HEREDITARY COMPONENTS, HOME ENVIRONMENT, AND BEHAVIORAL MODELING AROUND DIETARY INTAKE, PHYSICAL ACTIVITY, AND SCREEN TIME. THUS, TARGETING THE RURAL FAMILY UNIT HAS THE POTENTIAL TO ENHANCE WEIGHT LOSS FOR ADULTS AND CHILDREN SIMULTANEOUSLY. PREVIOUS RESEARCH FROM OUR TEAM INDICATES THAT MHEALTH IS FEASIBLE AND ACCEPTABLE FOR THE DELIVERY OF OBESITY INTERVENTIONS TO RURAL FAMILIES AS THIS TYPE OF INTERVENTION LOWERS CHILD BODY MASS INDEX Z SCORE (BMIZ) AND HELPS CHILDREN AND FAMILIES TO SIGNIFICANTLY CHANGE THEIR HEALTH BEHAVIORS. THE CURRENT APPLICATION EXTENDS THIS WORK IN A NEW AND INNOVATIVE DIRECTION, TARGETING PARENTS FIRST WITH AN EMPIRICALLY SUPPORTED OBESITY INTERVENTION, AND THEN MOVING ON TO TREAT THE FAMILY UNIT. IN A RANDOMIZED TRIAL, WE PROPOSE TO COMPARE A 4-MONTH PARENT-ONLY INTERVENTION FOLLOWED BY A 6-MONTH FAMILY BASED BEHAVIORAL GROUP INTERVENTION (IAMHEALTHY-PARENTS FIRST) TO A PARENT WAIT-LIST CONTROL FOLLOWED BY THE FAMILY BASED BEHAVIORAL GROUP INTERVENTION (IAMHEALTHY). PARENT/CHILD DYADS WILL BE RECRUITED FROM BOTH RURAL ELEMENTARY SCHOOLS AND RURAL MEDICAL CLINICS IN 8 TOWNS. EACH TOWN WILL CONSIST OF A SINGLE SITE AND WILL RECRUIT 30 PARENT/CHILD DYADS, 15 OF WHOM WILL BE RANDOMLY ASSIGNED TO IAMHEALTHY-PARENTS FIRST AND 15 TO IAMHEALTHY, FOR A TOTAL OF 240 PARENTS AND 240 CHILDREN. EACH RURAL TOWN WILL HAVE A POPULATION < 20,000 AND/OR THE RURAL URBAN COMMUTING AREA CODES OF 4 OR GREATER, AND FOR THE PURPOSES OF THE STUDY WILL INCLUDE A NURSE AT A RURAL HEALTH CLINIC PARTNERING WITH A NURSE AT A RURAL ELEMENTARY SCHOOL TO MAKE A SINGLE SITE. IN AIM 1 WE PROPOSE TO STUDY EFFECTIVENESS THROUGH CHANGE IN CHILD BMIZ AND PARENT PERCENT WEIGHT LOSS FROM BASELINE TO MONTH 10 (POST-INTERVENTION), AS WELL AS THROUGH CHANGE IN DIET, CHANGE IN PHYSICAL ACTIVITY AND CHANGE IN PARENT AND CHILD WEIGHT RELATED QUALITY OF LIFE. IN AIM 2, WE PROPOSE TO ASSESS MEDIATORS AND MODERATORS THAT WE BELIEVE ARE SPECIFICALLY IMPORTANT TO THE TREATMENT MODEL AND TO THE RURAL POPULATION. IN AIM 3 WE PROPOSE TO EXPLORE THE REACH AND REPRESENTATIVENESS OF THE INTERVENTION, AND TO EXPLORE A CONCEPT WE HAVE FOUND KEY IN BOTH OUR ADULT AND PEDIATRIC TRIALS – NURSE ENGAGEMENT. OUR EXPERIENCE SUGGESTS THAT NURSE ENGAGEMENT PLAYS A KEY ROLE IN RECRUITMENT, RETENTION, AND ENGAGEMENT OF THE FAMILIES, AND HERE WE PROPOSE TO ASSESS NURSE ENGAGEMENT AS WELL AS FOSTER IT THROUGH THE DEVELOPMENT OF A RURAL NURSE ENGAGEMENT COLLABORATIVE. THIS EXPLORATORY AIM WILL PROVIDE CRITICAL PRAGMATIC DATA TO INFORM FUTURE STUDIES AIMED AT TESTING LOCAL IMPLEMENTATION AND DISSEMINATION STRATEGIES. THE IAMHEALTHY PARENTS FIRST INTERVENTION IS AN EASILY SCALABLE, WIDELY DISSEMINABLE OBESITY INTERVENTION OPTION WHICH COULD SIGNIFICANTLY IMPROVE THE WAY WE TREAT OBESITY AMONG RURAL FAMILIES.

MECHANISMS OF LIVER REGENERATION AFTER ACETAMINOPHEN-INDUCED ACUTE LIVER FAILURE

POST-TRANSCRIPTIONAL REGULATION OF PARVOVIRUS CAPSID GENE EXPRESSION

BIOMEDICAL INCUBATOR

EFFECT OF AEROBIC EXERCISE ON ALZHEIMER'S PATHOPHYSIOLOGY IN PRECLINICAL AD

HOME-BASED AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION TO IMPROVE OUTCOMES AND DECREASE COSTS

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION

INCREASING POST-DISCHARGE FOLLOW UP AMONG HOSPITALIZED SMOKERS

NEUROIMAGING STUDIES OF REWARD IMPULSIVITY AND ADHERENCE TO AN EXERCISE PROGRAM

CULTURALLY-TAILORED SMOKING CESSATION FOR AMERICAN INDIANS

SIEMENS MAGNETOM VERIO MRI SCANNER

PYK2 FUNCTION DURING FERTILIZATION

THE H3AFRICA KIDNEY DISEASE COHORT STUDY

RELATIONSHIPS BETWEEN APP AND MITOCHONDRIA - PROJECT SUMMARY/ABSTRACT WE WILL DETERMINE THE EFFECTS OF APP AND APP PROTEOLYTIC PRODUCTS ON MITOPHAGY AND BIOENERGETIC FUNCTION. WE HYPOTHESIZE THAT AMYLOID PRECURSOR PROTEIN (APP) FACILITATES MITOPHAGY THROUGH DIRECT INTERACTIONS WITH PINK1 AND P62. WE FURTHER HYPOTHESIZE THAT LOSS OF APP EXPRESSION OR REDUCED MITOCHONDRIAL LOCALIZATION AFFECTS MITOCHONDRIAL FUNCTION THROUGH INHIBITION OF MITOPHAGY. METABOLIC DEFICIENCIES ARE PROMINENT IN ALZHEIMER’S DISEASE (AD). A CLEAR RELATIONSHIP BETWEEN AMYLOID PRECURSOR PROTEIN (APP) AND MITOCHONDRIA IS DESCRIBED IN THE LITERATURE BUT THE FUNCTION OF APP AT MITOCHONDRIA IS NOT WELL UNDERSTOOD. APP AND ASS LOCALIZE TO MITOCHONDRIA AND CAN ALTER MITOCHONDRIAL FUNCTION. OUR DATA SHOW THAT MITOCHONDRIAL MEMBRANE POTENTIAL DIRECTLY CORRELATES WITH ASS PRODUCTION AND APP MITOCHONDRIAL LOCALIZATION. UNDER CONDITIONS OF INCREASED MITOPHAGY APP MITOCHONDRIAL LOCALIZATION IS INCREASED. OUR DATA INDICATE LOSS OF APP AT MITOCHONDRIA OR LOSS OF APP EXPRESSION, REDUCES MITOCHONDRIAL ELECTRON TRANSPORT CHAIN (ETC) FUNCTION AND MITOPHAGY. OVERALL, OUR DATA SUPPORT A ROLE OF APP IN MODULATING MITOPHAGY AND BIOENERGETIC FLUX. A CURRENT GAP IN OUR KNOWLEDGE IS IF THESE OBSERVATIONS ARE ATTRIBUTED TO FULL-LENGTH APP OR APP PROCESSING PRODUCTS. WE WILL ADDRESS THIS KNOWLEDGE GAP HERE. A RELATIONSHIP BETWEEN MITOCHONDRIA, BIOENERGETICS, MITOPHAGY, AND APP IS EVIDENT. OUR DATA SUPPORT A RELATIONSHIP BETWEEN APP LOCALIZATION AT MITOCHONDRIA, BIOENERGETIC FUNCTION, AND MITOPHAGY. WE HYPOTHESIZE THAT LOSS OF APP AT MITOCHONDRIA ALTERS BIOENERGETIC FLUX (AIM 1) AND MITOCHONDRIAL LOCALIZED APP FACILITATES MITOPHAGY (AIM 2). THE OVERALL GOAL OF THIS STUDY IS TO UNDERSTAND THE ROLE OF APP AND ITS DERIVATIVES IN MITOPHAGY AND BIOENERGETIC FLUX. WE WILL USE IN VIVO AND IN VITRO MODELS ACROSS TWO AIMS. IN VITRO MODELS INCLUDE ENGINEERED INDUCED PLURIPOTENT STEM CELLS (IPSC) CELLS WITH EITHER WILD-TYPE (WT) APP, APP KNOCKOUT, OR MITOCHONDRIAL LOCALIZATION INCOMPETENT APP (3M APP) EXPRESSION. ENGINEERED IPSCS WILL BE DIFFERENTIATED TO NEURONS AND ASTROCYTES. IN VIVO MODELS WILL INCLUDE NON-TRANSGENIC, TRANSGENIC WT APP MICE AND APP KNOCKOUT MICE. USE OF BOTH IN VIVO AND IN VITRO MODELS ALLOWS FOR ELUCIDATION OF CELL TYPE SPECIFIC EFFECTS (IN VITRO MODELS) AND SEX DIFFERENCES (IN VIVO). WE WILL MEASURE ENDPOINTS IN THE MODELS PROPOSED UNDER NATIVE CONDITIONS AND UNDER CONDITIONS WHERE APP PROCESSING IS INHIBITED OR INCREASED. WE WILL DETERMINE THE ROLE OF FULL-LENGTH APP VERSUS APP PROCESSING PRODUCTS IN MITOPHAGY AND BIOENERGETIC FLUX PATHWAYS.

PRESCRIBING SMART AGING: INTEGRATING HEALTH SYSTEMS WITH COMMUNITY-BASED LIFESTYLE INTERVENTIONS

PROGENITOR CELL BASED THERAPY TO MITIGATE RADIATION INDUCED GASTRO INTESTINAL SYNDROME

KANSAS INTERDISCIPLINARY CENTER FOR PKD RESEARCH

WEB-BASED SMOKING CESSATION PROGRAM FOR TRIBAL COLLEGE STUDENTS

GUIDED EPISODIC FUTURE THINKING TO INCREASE PHYSICAL ACTIVITY ADHERENCE AND PROMOTE HEALTHY BRAIN AGING AMONG MID-LIFE ADULTS - PROJECT SUMMARY/ABSTRACT NOVEL INTERVENTION STRATEGIES TO INCREASE PHYSICAL ACTIVITY NEED TO REDUCE BARRIERS TO EXERCISE AND INCREASE ADHERENCE TO ACHIEVE OPTIMAL BRAIN HEALTH BENEFITS. DESPITE CONSIDERABLE PHYSICAL AND BRAIN HEALTH BENEFITS ASSOCIATED WITH EXERCISE, MOST ADULTS FAIL TO ADHERE TO RECOMMENDED PHYSICAL ACTIVITY GUIDELINES. BARRIERS, INCLUDING LACK OF TIME AND LOW ENJOYMENT OF EXERCISE, CAN LEAD TO REDUCED ADHERENCE. DUAL-SYSTEM NEURAL MODELS OF BEHAVIOR THEORIZE TWO SYSTEMS THAT DRIVE BEHAVIOR AND CAN BE ENGAGED IN INTERVENTIONS. THE REWARD BRAIN SYSTEM RESPONDS TO AND EVALUATES THE REWARDING PROPERTIES OF STIMULI IN THE ENVIRONMENT AND DRIVES BEHAVIORS. THE REGULATION BRAIN SYSTEM DOWNREGULATES RESPONSES TO REWARDING STIMULI AND PROMOTES HEALTHY BEHAVIORS BY HELPING INDIVIDUALS ADHERE TO AND ACHIEVE THEIR GOALS. OUR LONG-TERM GOAL IS TO DEVELOP ENHANCEMENTS TO HEALTH BEHAVIOR INTERVENTIONS THAT ENGAGE THE REWARD AND REGULATION MECHANISMS RELATED TO INCREASE ADHERENCE AND PROMOTE OPTIMAL BRAIN HEALTH. THE RATIONALE FOR THE PROPOSED STUDY IS BASED ON PREVIOUS STUDIES SHOWING RELATIONSHIPS BETWEEN REGULATION, POSITIVE AFFECT, AND EXERCISE AND OUR PRELIMINARY DATA THAT SHOW TARGETING THE REGULATION AND REWARD SYSTEMS INCREASES HEALTHY CHOICES AND POSITIVE AFFECT. WE WILL APPLY THE NIH STAGE MODEL TO DEVELOP GUIDED IMAGERY TO TARGET REWARD AND REGULATION BRAIN SYSTEMS AND ASSESS THE IMPACT ON EXERCISE ADHERENCE. FIRST, WE WILL TEST A BRIEF GUIDED IMAGERY APPROACH TO ENGAGE REGULATION AND REWARD BRAIN SYSTEMS AND THE ACCEPTABILITY OF HIIT IN MID-LIFE ADULTS (R61). WE WILL USE GUIDED IMAGERY THAT INCLUDES PAI TO INCREASE POSITIVE ASSOCIATIONS WITH EXERCISE AND/OR EFT TO INCREASE FOCUS ON ONE'S HEALTHY, PHYSICALLY ACTIVE, FUTURE SELF AND INCREASE REGULATION. WE WILL DYNAMICALLY REFINE THE HIIT EXERCISE INTERVENTION TO INCREASE ACCEPTABILITY. SYSTEMATICALLY TESTING THE INDEPENDENT EFFECTS OF ENGAGING REWARD OR REGULATION ON CHANGES IN REWARD AND REGULATION INDICES AND REFINING THE HIIT PROTOCOL WILL HELP US DEVELOP THE OPTIMAL BEHAVIORAL AND EXERCISE INTERVENTION APPROACH. NEXT, WE WILL TEST THIS APPROACH AND THE IMPACT ON EXERCISE ADHERENCE AND PHYSICAL ACTIVITY IN A 6-WEEK HIIT EXERCISE INTERVENTION (R33). THIS INNOVATIVE STUDY FILLS A GAP IN THE CURRENT LITERATURE BY EXAMINING THE IMPACT OF EFT AND POSITIVE AFFECT GUIDED IMAGERY AMONG MID-LIFE ADULTS AND WILL INFORM FUTURE INTERVENTIONS TO IMPROVE HEALTH DECISION-MAKING, PROMOTE HEALTHY BEHAVIORS AND BRAIN HEALTH, AND REDUCE THE RISK OF DEVELOPING ALZHEIMER'S DISEASE.

IMPROVING SMOKING ABSTINENCE OUTCOMES IN THE AFRICAN AMERICAN COMMUNITY THROUGH EXTENDED TREATMENT - PROJECT SUMMARY / ABSTRACT AFRICAN AMERICANS ARE DISPROPORTIONALITY BURDENED BY TOBACCO IN THE UNITED STATES. AFRICAN AMERICAN SMOKERS EXPERIENCE THE HIGHEST RATES OF TOBACCO-ATTRIBUTABLE DISEASE, CANCER INCIDENCE AND MORTALITY. STRIKING HEALTH DISPARITIES EXIST DESPITE THE FACT THAT AFRICAN AMERICANS HAVE SIMILAR SMOKING PREVALENCE AS WHITES, YET SMOKE FEWER CIGARETTES PER DAY (CPD). TO HAVE AN IMPACT ON THE PREMATURE MORTALITY OF AFRICAN AMERICAN SMOKERS, EFFECTIVE TREATMENT FOR SMOKERS ACROSS THE SMOKING CONTINUUM MUST BE IDENTIFIED. FURTHER, BECAUSE SMOKING CESSATION RATES TEND TO BE LOWER FOR AFRICAN AMERICAN SMOKERS, IT IS NECESSARY TO FIND METHODS OF INCREASING RESPONSE TO PHARMACOTHERAPY TO BETTER PROMOTE ABSTINENCE IN THIS HIGH-RISK GROUP. EXTENDED TREATMENT HAS BEEN DEMONSTRATED TO INCREASE ABSTINENCE IN WHITE SMOKERS BUT HAS NEVER BEEN EXAMINED IN AFRICAN AMERICAN SMOKERS, WHO MIGHT BENEFIT FROM EXTENDED MEDICATION SUPPORT FOR QUITTING AND FOR REDUCING RELAPSE. THE PRIMARY OBJECTIVE OF THIS STUDY IS TO EVALUATE EXTENDED USE OF VARENICLINE, THE LEADING FDA-APPROVED MEDICATION FOR TOBACCO TREATMENT, WITH THE GOAL OF ENHANCING ABSTINENCE IN AFRICAN AMERICAN DAILY SMOKERS, INCLUDING THE FULL SPECTRUM OF LIGHT, MODERATE, AND HEAVY SMOKERS. OUR SPECIFIC AIMS ARE TO 1) EVALUATE THE EFFICACY OF EXTENDED VARENICLINE TREATMENT TO PROMOTE SMOKING CESSATION AT END OF TREATMENT (MONTH 6) AND AT LONG-TERM FOLLOW-UP (MONTHS 9 AND 12), 2) EXAMINE MEDICATION ADHERENCE OVER THE COURSE OF TREATMENT AND ITS IMPACT ON TREATMENT OUTCOMES, 3) EVALUATE CHANGE IN NEGATIVE AFFECT, WITHDRAWAL, AND CRAVING ACROSS TREATMENT CONDITIONS AND THEIR IMPACT ON TREATMENT OUTCOMES, 4) IDENTIFY INDIVIDUAL FACTORS PREDICTING SMOKING ABSTINENCE, AND 5) CHARACTERIZE PATTERNS OF TOBACCO USE AND ABSTINENCE OVER THE COURSE OF STANDARD AND EXTENDED TREATMENT. THESE AIMS WILL BE ACCOMPLISHED USING A TWO-ARM, RANDOMIZED DESIGN TO EVALUATE THE EFFICACY OF EXTENDED (6 MONTHS) VARENICLINE TREATMENT COMPARED TO STANDARD (12 WEEKS) VARENICLINE TREATMENT. BASELINE RANDOMIZATION STRATIFIED BY GENDER WILL ASSIGN PARTICIPANTS (N=500) TO RECEIVE EXTENDED TREATMENT (EXT; 26 WEEKS OF VARENICLINE, N=250) OR STANDARD TREATMENT (ST; 12 WEEKS OF VARENICLINE, N=250). ALL PARTICIPANTS WILL RECEIVE CULTURALLY-RELEVANT, INDIVIDUALIZED SMOKING CESSATION COUNSELING, INCLUDING SUPPORT FOR MEDICATION ADHERENCE, AND WILL BE FOLLOWED THROUGH MONTH 12. THIS STUDY IS THE FIRST TO EXAMINE THE EFFICACY OF EXTENDED VARENICLINE TREATMENT TO INCREASE ABSTINENCE AMONG AFRICAN AMERICAN SMOKERS, INCLUDING THE FULL SPECTRUM OF DAILY SMOKING LEVEL. IT IS THE FIRST TO EXAMINE EXTENDED VARENICLINE FOR ALL SMOKERS, NOT ONLY CONFIRMED QUITTERS, AND AMONG THE FIRST TO EXAMINE PATTERNS OF QUITTING, LAPSE, AND RELAPSE AMONG AFRICAN AMERICAN SMOKERS. FINDINGS WILL ENRICH OUR UNDERSTANDING OF THE INTERRELATIONSHIP OF KEY BIOLOGICAL FACTORS TO SMOKING FACTORS AND TREATMENT RESPONSE. SUCCESS IN INCREASING LONG-TERM ABSTINENCE RATES WOULD SIGNIFICANTLY IMPACT CLINICAL PRACTICE FOR TREATMENT OF THIS HIGH-RISK GROUP. INCREASED TREATMENT EFFICACY WILL HAVE MAJOR IMPACT ON REDUCING TOBACCO-RELATED DISPARITIES, MORBIDITY, AND MORTALITY.

GROUP PHONE-BASED WEIGHT CONTROL AMONG RURAL BREAST CANCER SURVIVORS

DRUG ABUSE AND HIV-ASSOCIATED PULMONARY VASCULAR INJURY - PROJECT SUMMARY UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC. ADVANCEMENT IN ANTIRETROVIRAL THERAPY (ART) HAS CLEARLY LED TO A SERIOUS INCREASE IN THE PREVALENCE OF NON- INFECTIOUS CARDIO-PULMONARY COMPLICATIONS AMONG HIV-INFECTED INDIVIDUALS INCLUDING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND HIV-RELATED PULMONARY ARTERIAL HYPERTENSION (HIV-PAH). IN FACT, RECENT REPORTS SUGGEST THAT PULMONARY VASCULAR REMODELING AND PULMONARY HYPERTENSION (PH) PRECEDE THE AIRWAY DESTRUCTION/EMPHYSEMA DEVELOPMENT AND THAT PH AND COPD COEXIST IN HIV-INFECTED INDIVIDUALS. SIGNIFICANT NUMBER OF PREVIOUS FINDINGS INCLUDING FROM OUR LAB CONSISTENTLY SUGGEST INCREASED RISK FOR PULMONARY VASCULAR DYSFUNCTION IN HIV-INFECTED INDIVIDUALS WHO ABUSE ILLICIT DRUGS COMPARED TO HIV-INFECTED NON-DRUG USERS OR UN- INFECTED DRUG ABUSERS. UNDERSTANDING THE MECHANISMS BY WHICH COCAINE AND HIV-1 TRIGGER PULMONARY VASCULAR INJURY IS NEEDED TO DEVELOP PREVENTIVE AND EARLY DIAGNOSIS STRATEGIES FOR PATIENTS AT RISK OF HIV-PAH. PULMONARY ARTERIAL SMOOTH MUSCLE CELLS (PASMCS) ARE ONE OF THE PRIMARY CELL-TYPES THAT UNDERGO HYPERPLASIA DURING VASCULAR REMODELING. THE SALIENT FINDING IN ALL OUR PUBLISHED REPORTS IS THE SYNERGISTIC OR ADDITIVE ENHANCEMENT IN THE PROLIFERATION OF PASMCS EXPOSED TO BOTH HIV PROTEIN(S) AND COCAINE. RECENTLY, LONG NONCODING RNAS (LNCRNAS) HAVE EMERGED AS IMPORTANT REGULATORS OF DIVERSE BIOLOGICAL PROCESS INCLUDING CELL PROLIFERATION AND APOPTOSIS. BASED ON OUR PUBLISHED AND RECENT PRELIMINARY FINDINGS WE HYPOTHESIZE THAT ALTERATION IN THE LEVELS OF LNCRNA:ENST-536 IN RESPONSE TO HIV-PROTEIN(S) AND/OR COCAINE IN SMOOTH MUSCLE CELLS PROMOTE PULMONARY VASCULAR REMODELING AND CARDIO-PULMONARY COMPLICATIONS. IN THE FIRST AIM WE WILL EXAMINE IF CHANGES IN THE EXPRESSION OF ENST-536 LNCRNA AND ITS NEARBY TUMOR SUPPRESSIVE GENE, HOXB13 REGULATE THE HIV-TAT AND COCAINE MEDIATED CHANGES IN THE SMOOTH MUSCLE PHENOTYPE. IN THE SECOND AIM, WE WILL INVESTIGATE HOW THE INTERACTIONS BETWEEN LNCRNA ENST-536 AND RNA BINDING PROTEIN(S) (RBP) REGULATE THE HIV-TAT AND COCAINE MEDIATED SMOOTH MUSCLE DYSFUNCTION.THIRD AIM WILL BE FOCUSED ON INVESTIGATING THE IN- VIVO ROLE OF LNCRNA ENST-536 AND HOXB13 IN THE PULMONARY VASCULAR DYSFUNCTION AND RIGHT VENTRICULAR FAILURE USING PRE-CLINICAL ANIMAL MODEL THESE STUDIES ARE INNOVATIVE BECAUSE TO THE BEST OF OUR KNOWLEDGE IT WILL BE THE FIRST ATTEMPT TO UNDERSTAND THE POTENTIAL LINK BETWEEN THE ROLE OF LNCRNA, RBP AND HOXB13 IN THE HIV-1 AND/OR COCAINE MEDIATED PULMONARY VASCULAR REMODELING. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE IT WILL ENHANCE OUR UNDERSTANDING OF PATHOGENIC MECHANISMS INVOLVED IN THE DEVELOPMENT OF HIV-PAH AND WILL FULFILL THE PURPOSE OF NOT-HL-19-677 (SEARCH: STIMULATING EXPLORATORY RESEARCH ON HIV/AIDS CONTRIBUTION TO HEART, LUNG, BLOOD AND SLEEP COMORBIDITIES) IN SEARCH OF NOVEL MECHANISMS INVOLVED IN HIV-ASSOCIATED COMORBIDITIES.

WEIGHT MANAGEMENT FOR ADOLESCENTS WITH IDD

AUTOPHAGY AND DRUG-INDUCED LIVER INJURY

ANTI-INFLAMMATORY THERAPY TO AUGMENT CFTR RESCUE IN CF PATIENTS

BITTER MELON COMPONENT AND COLON CANCER PREVENTION

WEIGHT LOSS AND MAINTENANCE FOR INDIVIDUALS WITH IDD

MECHANISMS OF MUCOCILIARY DYSFUNCTION IN CYSTIC FIBROSIS RELATED DIABETES - PROJECT SUMMARY/ABSTRACT CYSTIC FIBROSIS (CF)-RELATED DIABETES MELLITUS (CFRD) IS A MAJOR PREDICTOR OF WORSE LUNG FUNCTION AND AFFECTS ~20% OF ADOLESCENTS AND >40% OF ADULTS WITH CF. HIGHLY EFFECTIVE CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR (CFTR) MODULATOR THERAPIES CAN IMPROVE GLYCEMIC CONTROL IN PATIENTS AND REDUCE PREVALENCE OF CFRD. HOWEVER, THE FOLLOW UP OF THE IRISH IVACAFTOR COHORT SHOWS THAT FEV1 IN THE >18-YEAR OLD GROUP STILL DECLINES AFTER AN INITIAL INCREASE (NOT DISTINGUISHING BETWEEN PATIENTS WITH AND WITHOUT CFRD). THIS IS OPPOSED TO FINDINGS IN YOUNGER AGES WHERE FEV1 CONTINUES TO RISE. SINCE PREVALENCE OF CFRD INCREASES WITH AGE, WE WONDERED WHETHER LUNG FUNCTION DECLINE IN THE OLDER IRISH CF POPULATION ON IVACAFTOR COULD BE RELATED TO CFRD. IN SUPPORT OF THIS HYPOTHESIS, OUR CF CENTER-SPECIFIC DATA SHOW THAT LUNG FUNCTION DECLINE IN PATIENTS ON IVACAFTOR WITH CFRD REMAINS WORSE THAN IN PATIENTS WITHOUT CFRD. THUS, IT IS IMPERATIVE TO INITIATE EPIDEMIOLOGICAL, MECHANISTIC, AND THERAPEUTIC STUDIES ON LUNG FUNCTION PRESERVATION IN CF PATIENTS WITH ALTERED GLUCOSE CONTROL THAT GO BEYOND ACHIEVING NORMOGLYCEMIA AND TAKE THE NEW ERA OF HIGHLY EFFECTIVE MODULATORS INTO ACCOUNT. WE HAVE SHOWN THAT, IN CF BRONCHIAL EPITHELIAL (CFBE) CELLS, HYPERGLYCEMIA SIGNALS THROUGH THE RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (RAGE OR AGER), WHICH IS HIGHLY EXPRESSED IN THE LUNG AND LINKED TO THE PATHOGENESIS OF CHRONIC INFLAMMATORY AIRWAY DISEASES, INCLUDING CF. ACTIVATION OF RAGE BY HYPERGLYCEMIA OR THE RAGE AGONIST HIGH- MOBILITY GROUP BOX-1 (HMGB1) DECREASES THE ACTIVITY OF APICALLY EXPRESSED LARGE-CONDUCTANCE, CA2+-ACTIVATED, VOLTAGE-DEPENDENT K+ (BK) CHANNELS AND REDUCES AIRWAY SURFACE LIQUID (ASL) VOLUME. CLINICALLY LOW BUT RELEVANT CONCENTRATIONS OF METFORMIN, APPROVED FOR TREATING DIABETES MELLITUS AND KNOWN TO BLOCK RAGE SIGNALING, REVERSED HYPERGLYCEMIA-INDUCED BK DYSFUNCTION AND ASL VOLUME DEPLETION IN CFBE CELLS DESPITE THE CONTINUED PRESENCE OF HIGH GLUCOSE. FURTHERMORE, METFORMIN IMPROVED ELEXACAFTOR/TEZACAFTOR/IVACAFTOR TRIPLE COMBINATION- MEDIATED RESCUE OF CFTR FUNCTION AND ASL VOLUMES IN CFBE CELLS UNDER HIGH GLUCOSE. FINALLY, CONTINUOUS MONITORING OF GLUCOSE LEVELS IN CF AND CFRD PATIENTS OVER A ONE-WEEK PERIOD REVEALED THAT HYPERGLYCEMIC EPISODES INVERSELY CORRELATED WITH MRNA EXPRESSION OF LRRC26, THE G SUBUNIT OF BK CRITICAL FOR ITS FUNCTION IN NON-EXCITABLE CELLS. WE THEREFORE HYPOTHESIZE THAT WORSENING LUNG FUNCTION IN CF PATIENTS WITH ABNORMAL GLUCOSE CONTROL IS ASSOCIATED WITH BK AND EVEN MODULATOR-RESCUED CFTR DYSFUNCTION DUE TO RAGE SIGNALING AND THAT LOW DOSE METFORMIN AMELIORATES RAGE-INDUCED ION CHANNEL DYSFUNCTION, INCLUDING CFTR IN THE PRESENCE OF HIGHLY EFFECTIVE MODULATORS, INDEPENDENT OF GLUCOSE CONTROL. WE WILL TEST THIS HYPOTHESIS IN MECHANISTIC AND TRANSLATIONAL STUDIES IN VITRO (AIMS 1 AND 2) AND IN VIVO (AIM 3).

FEMALE PELVIC PAIN, HORMONES,AND NEUROPLASTICITY

ENVIRONMENTAL EXPOSURES, AHR ACTIVATION, AND PLACENTAL ORIGINS OF DEVELOPMENT

DOES TBI AFFECT MTDNA HETEROPLASMY

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION

TARGETING NA,K-ATPASE ALPHA4 FOR MALE CONTRACEPTION

ADVANCED NURSING EDUCATION WORKFORCE

MODELING LONGITUDINAL READING COMPREHENSION IN ADOLESCENCE: PROTECTIVE AND RISK FACTORS - PROJECT SUMMARY/ABSTRACT TODAY'S HIGH SCHOOL STUDENTS ARE REQUIRED TO UNDERSTAND AND SYNTHESIZE INFORMATION FROM INCREASINGLY COMPLEX, DIVERSE TEXTS. THESE ADVANCED READING COMPREHENSION DEMANDS ARE REFLECTED IN CURRENT EDUCATIONAL STANDARDS, SUCH AS THE COMMON CORE STATE STANDARDS, AND IN THE ENGLISH LANGUAGE ARTS CURRICULA ADOPTED BY HIGH SCHOOLS. STUDENTS ARE EXPECTED TO `INTEGRATE AND INTERPRET' AND TO `REFLECT AND EVALUATE' INFORMATION ACROSS TEXT TYPES, CONTENT AREAS, AND PRESENTATION MEDIA. THE PROBLEM IS THAT WE DO NOT HAVE EMPIRICALLY VALIDATED THEORETICAL MODELS THAT REFLECT THE TEXT AND TASK COMPLEXITIES ENCOUNTERED BY HIGH SCHOOL STUDENTS. FURTHER, EXTANT MODELS DO NOT PROVIDE AN EXPLANATORY FRAMEWORK FOR THE ADVANTAGE FOR MONOLINGUAL OVER BILINGUAL OR FEMALE OVER MALE STUDENTS. THIS LACK OF EVIDENCED-BASED MODELS OF THE STRUCTURE OF READING COMPREHENSION CONSTITUTES A CRITICAL GAP IN READING SCIENCE THAT LIMITS OUR ABILITY TO ADDRESS THE WELL-DOCUMENTED READING DEFICITS OF HIGH SCHOOL STUDENTS IN THE U.S. A SECOND CRITICAL GAP IS THE LACK OF COMPREHENSIVE PREDICTOR MODELS THAT GO BEYOND THE SIMPLE VIEW OF READING (SVR) AND CONSIDER ADDITIONAL COGNITIVE INFLUENCES ON READING COMPREHENSION, SUCH AS EXECUTIVE FUNCTION, AS WELL AS PSYCHOLOGICAL AND ECOLOGICAL FACTORS, SUCH AS MOTIVATION AND THE SCHOOL ENVIRONMENT, WHICH MAY BECOME MORE INFLUENTIAL AS THEY CONSOLIDATE OR CHANGE DURING ADOLESCENCE. A THIRD CRITICAL GAP IS THE LACK OF LONGITUDINAL STUDIES FROM MIDDLE TO HIGH SCHOOL THAT CAN IDENTIFY UNIQUE FACTORS OPERATING OVER TIME THAT MAY PROTECT ADOLESCENTS FROM, OR PLACE THEM AT HIGHER RISK OF, POOR READING COMPREHENSION. THESE MAY DIFFER IN THEIR STRENGTH OF INFLUENCE FROM THOSE AFFECTING READING COMPREHENSION IN ELEMENTARY SCHOOL STUDENTS. OUR PROJECT - MODELLING LONGITUDINAL READING COMPREHENSION IN ADOLESCENCE: PROTECTIVE AND RISK FACTORS - BRINGS TOGETHER MULTIDISCIPLINARY RESEARCHERS TO ADDRESS THESE KNOWLEDGE GAPS AND ADVANCE UNDERSTANDING OF READING COMPREHENSION IN HIGH- SCHOOL STUDENTS. OUR PRINCIPAL GOALS ARE TO DETERMINE THE STRUCTURE OF READING COMPREHENSION IN 11TH GRADE, CLARIFY KEY PREDICTORS OF READING COMPREHENSION WITHIN AND ACROSS ADOLESCENCE, AND TO IDENTIFY PROTECTIVE AND RISK FACTORS FOR GOOD AND POOR READING COMPREHENSION. WE BUILD ON OUR RESEARCH CONDUCTED AS THE LANGUAGE AND READING RESEARCH CONSORTIUM (LARRC) AND THE MONOLINGUAL AND BILINGUAL READING COMPREHENSION (MBRC) PROJECT. THIS IS A UNIQUE OPPORTUNITY TO CONTINUE OUR LARRC LONGITUDINAL STUDY OF STUDENTS WHO ENTERED PRESCHOOL AS MONOLINGUAL ENGLISH SPEAKERS OR AS SPANISH-ENGLISH BILINGUAL SPEAKERS. THESE TWO LONGITUDINAL GROUPS ARE NOW IN 9TH GRADE. ADDITIONAL LONGITUDINAL PARTICIPANTS FROM MBRC (MONOLINGUAL, BILINGUAL) ASSESSED IN 6TH GRADE WILL CONTINUE IN 9TH AND 11TH GRADES. WE WILL ASSESS THESE FOUR LONGITUDINAL SAMPLES IN 11TH GRADE, AND A NEW CROSS-SECTIONAL SAMPLE OF 11TH GRADERS.

ANTIOXIDANT IMAGING MARKER OF INVESTIGATING GAINS IN NEUROCOGNITION IN AN INTERVENTION TRIAL OF EXERCISE (AIM-IGNITE)

ASTHMA IN OLDER ADULTS: IDENTIFYING PHENOTYPES AND FACTORS IMPACTING OUTCOMES

REGULATION OF RENAL RESPONSE TO VASOPRESSIN BY GLYCOGEN SYNTHASE

MECHANISMS FOR GENERATING CARGO SPECIFICITY IN INFLAMMASOME-MEDIATED EXOSOME SECRETION

ANTI-COAGULATION FACTORS AND PLACENTATION

MULTISENSORY DYSFUNCTION PHENOTYPES AS PREDICTORS OF COGNITIVE IMPAIRMENT AND TRAJECTORY AFTER TRAUMATICBRAIN INJURY

NOVEL DUAL NOTCH/PXR TARGETING FOR COLON CANCER THERAPY

A VIRTUAL REALITY INTERVENTION (SECOND LIFE) TO IMPROVE WEIGHT MAINTENANCE

ROLE OF CLAUDIN-2 IN CALCIUM HOMEOSTASIS AND KIDNEY STONE DISEASE

STAYING STRONG AND HEALTHY DURING ANDROGEN DEPRIVATION THERAPY FOR LATINO MEN

CARGO, BIOGENESIS AND FUNCTIONS OF EXTRACELLULAR VESICLES RELEASED DURING HSV-1 INFECTION - FOLLOWING PRODUCTIVE, LYTIC INFECTION IN MUCOSAL EPITHELIAL CELLS LOCATED AT THE PORTAL OF ENTRY IN THE BODY, HERPES SIMPLEX VIRUS-1 (HSV-1) ESTABLISHES A LIFELONG, SILENT INFECTION IN SENSORY NEURONS. THE VIRUS IS OCCASIONALLY REACTIVATED DUE TO WEAKENED IMMUNE RESPONSE OR STRESS CAUSING DISEASES THAT RANGE IN SEVERITY FROM BENIGN COLD SORES TO ENCEPHALITIS. HSV-1 CONTRIBUTES TO EXACERBATION OF NEURODEGENERATIVE DISEASES SUCH AS ALZHEIMER'S AND FACILITATES INFECTION BY OTHER PATHOGENS SUCH AS HIV-1. EXTRACELLULAR VESICLES (EVS) ARE RELEASED BY ALL TYPES OF CELLS, AS THEY CONSTITUTE A MAJOR MECHANISM OF INTERCELLULAR COMMUNICATION, AND THEY CAN INFLUENCE RECIPIENT CELL FUNCTIONS. DURING HSV-1 INFECTION TWO POPULATIONS OF EVS ARE READILY DETECTABLE. THE FIRST POPULATION IS PRODUCED THROUGH A TETRASPANINS BIOGENESIS PATHWAY. THESE ARE THE MOST ABUNDANT EVS RELEASED FROM HSV-1 INFECTED CELLS, WHICH ARE ENRICHED IN CD63 TETRASPANIN AND CARRY HOST FACTORS SUCH AS THE STIMULATOR OF INTERFERON GENES (STING), A SENSOR OF DNA IN THE CYTOSOL. THESE CD63+ EVS CAN ACTIVATE INNATE IMMUNE RESPONSES IN UNINFECTED RECIPIENT CELLS AND SUPPRESS A SUBSEQUENT HSV-1 INFECTION. THE SECOND POPULATION OF EVS IS PRODUCED THROUGH THE ENDOSOMAL SORTING COMPLEX REQUIRED FOR THE TRANSPORT (ESCRT) PATHWAY, THUS WE NAMED THEM ESCRT+ EVS. THESE EVS CARRY ESCRT COMPONENTS ALONG WITH SELECTED VIRAL TEGUMENT AND ENVELOPE PROTEIN AND THEY APPEAR TO HAVE A PROVIRAL ROLE. IN ADDITION TO THESE TWO POPULATION OF EVS, EARLIER STUDIES HAVE REPORTED THE PRODUCTION OF CAPSIDLESS PARTICLES DURING HSV-1 INFECTION COMPOSED OF TEGUMENT AND ENVELOPE PROTEINS BUT LACKING VIRAL GENOME. THESE PARTICLES ARE LIGHTER THAN HSV-1 VIRIONS AND ARE KNOWN AS L-PARTICLES. L-PARTICLES RESEMBLE THE ESCRT+ EVS IN THAT THEY CARRY VIRAL PROTEINS AND HAVE A PROVIRAL EFFECT BUT ARE DENSER THAN ESCRT+ EVS AND ENRICHED IN VIRAL PROTEINS. WE HYPOTHESIZE THAT DISTINCT POPULATIONS OF EVS ARE RELEASED DURING HSV- 1 INFECTION WITH DIFFERENT EFFECTS ON THE INFECTION. TO TEST OUR HYPOTHESIS, WE HAVE FORMULATED THREE AIMS. IN AIM 1, WE PROPOSE TO COMPARE THE CARGO OF ESCRT+ EVS AND CD63+ EVS WITH L-PARTICLES PRODUCED DURING HSV-1 INFECTION USING A MASS SPECTROMETRY APPROACH. THE RESULTS OF THIS ANALYSIS WILL GENERATE IMPORTANT INFORMATION ABOUT MESSAGES COMMUNICATED BY INFECTED CELLS. IN AIM 2, WE PROPOSE TO DETERMINE EV BIOGENESIS PATHWAYS INVOLVED IN THE PRODUCTION OF ESCRT+ EVS, CD63+ EVS AND L-PARTICLES DURING HSV-1 INFECTION. FOR THIS, WE WILL USE A GENE SILENCING APPROACH TO COMPROMISE SELECTED EV BIOGENESIS PATHWAYS OR WE WILL USE MUTANT VIRUSES TO DETERMINE THE IMPACT OF SELECTED VIRAL GENES ON EV BIOGENESIS. IN AIM 3, WE PROPOSE TO DETERMINE THE TYPE OF RESPONSES THAT CD63+ EVS, ESCRT+ EVS AND L-PARTICLES TRIGGER IN RECIPIENT CELLS AND DETERMINE THE CONSEQUENCES TO THE INFECTION. THESE STUDIES WILL PROVIDE IMPORTANT INFORMATION ON THE BIOGENESIS, CARGO, AND FUNCTIONS OF EVS RELEASED BY HSV-1 INFECTED CELLS, WHICH ARE ESSENTIAL TO DETERMINE THEIR IMPACT ON HSV-1 PATHOGENESIS.

HEARTLAND INSTITUTE FOR CLINICAL AND TRANSLATIONAL RESEARCH

ROLE OF SPECC1L CYTOSKELETAL PROTEIN IN PALATE ELEVATION DYNAMICS - PROJECT SUMMARY OROFACIAL CLEFTS INVOLVING THE LIP AND PALATE ARE THE MOST COMMON CONGENITAL CRANIOFACIAL MALFORMATION THAT OCCUR AS PART OF >400 SYNDROMES OR AS AN ISOLATED PHENOTYPE IN ~1/700 LIVE-BIRTHS. NON-SYNDROMIC CLEFT PALATE ONLY BY ITSELF AFFLICTS 1/1700 CHILDREN WITH A 2:1 INCREASED INCIDENCE IN FEMALES. THE LIFETIME COST FOR MEDICAL TREATMENT, EDUCATIONAL SERVICES, AND LOST PRODUCTIVITY AVERAGES MORE THAN $100,000 PER AFFECTED PERSON. EMBRYONIC PALATOGENESIS INVOLVES BILATERAL VERTICAL OUTGROWTH OF SHELVES FROM THE MAXILLA THAT ELEVATE HORIZONTALLY AND FUSE ABOVE THE TONGUE. WHILE PALATOGENESIS HAS BEEN STUDIED FOR MORE THAN A CENTURY, IT IS NOT CLEAR HOW PALATAL SHELVES REORIENT FROM THE VERTICAL TO HORIZONTAL DIRECTION DURING ELEVATION. ONE REASON FOR THIS KNOWLEDGE GAP IS THAT THIS PROCESS IS RAPID AND THEREFORE HARD TO TIME AND CAPTURE. ANOTHER IS A LACK OF METHODOLOGIES TO ASSESS PALATE ELEVATION AND OF MOUSE MODELS WITH A WELL-CHARACTERIZED PALATE ELEVATION DELAY. OUR STUDIES SHOW THAT PALATAL SHELVES ELEVATE IN LESS THAN 3 HOURS IN UTERO AND THAT THERE IS A DEFINED EMBRYONIC WINDOW OF TIME FOR ELEVATION. WE HAVE ALSO ASSESSED THE DYNAMIC INTERPLAY OF CELL PROLIFERATION, CELL ORIENTATION AND ACTOMYOSIN CONTRACTION THAT UNDERLIES NORMAL PALATAL SHELF ELEVATION. WE HAVE ESTABLISHED NOVEL METHODOLOGIES TO USE MRI FOR IN UTERO IMAGING AND TO USE FINITE ELEMENT ANALYSIS TO MODEL PALATAL SHELF ELEVATION. IN ADDITION, WE HAVE BEEN STUDYING THE ROLE OF CYTOSKELETAL SCAFFOLDING PROTEIN SPECC1L IN PALATOGENESIS. WE IDENTIFIED THE FIRST DE NOVO AUTOSOMAL DOMINANT SPECC1L MUTATIONS IN PATIENTS WITH OROFACIAL CLEFTS. WE AND OTHERS HAVE NOW SHOWN THAT PATIENTS WITH SPECC1L MUTATIONS CLUSTERED IN THE SECOND COIL ED COIL DOMAIN (CCD2) OR CALPONIN HOMOLOGY DOMAIN (CHD) COMMONLY MANIFEST HYPERTELORISM, CLEFT PALATE AND OMPHALOCELE AMONG OTHER PHENOTYPES. USING MULTIPLE SPECC1L MOUSE ALLELES, WE HAVE ESTABLISHED THAT LOSS OF SPECC1L LEADS TO A DELAY IN PALATAL SHELF ELEVATION. INTERESTINGLY, IN-FRAME CCD2 SPECIFIC MUTATIONS (DELETIONS, POINT MUTATIONS) IN MICE RESULT IN A MORE SEVERE PALATAL SHELF ELEVATION DELAY, INDICATING A GAIN-OF-FUNCTION. AT THE CELLULAR LEVEL, CCD2 LEADS TO PERINUCLEAR MISLOCALIZATION OF SPECC1L ALONG WITH A DISRUPTION OF CYTOPLASMIC FILAMENTOUS ACTIN AND NON-MUSCLE MYOSIN II. LASTLY, OUR PRELIMINARY DATA SHOW THAT CLEFT PALATE IN CCD2 MUTANTS IS RESCUED UPON MATERNAL FOLIC ACID SUPPLEMENTATION. IN AIM 1, WE WILL STUDY THE CELL AND TISSUE MECHANICS UNDERLYING BOTH NORMAL AND ABNORMAL PALATE ELEVATION IN CCD2 ALLELES USING EX VIVO AND IN VIVO MAGNETIC RESONANCE IMAGING AND COMPUTATIONAL MODELING. IN AIM 2, WE WILL INVESTIGATE THE CELLULAR AND MOLECULAR MECHANISMS UNDERLYING THE GAIN-OF-FUNCTION IN CCD2 MUTANT CELLS USING STATE-OF-THE-ART PROTEOMIC ANALYSES. IN AIM 3, WE WILL DETERMINE HOW MATERNAL FOLATE SUPPLEMENTATION RESCUES PALATE ELEVATION DEFECTS IN CCD2 MUTANTS. SUCCESSFUL COMPLETION OF THESE STUDIES WILL PROVIDE CRITICAL INSIGHTS INTO TISSUE DYNAMICS AND CELL SIGNALING DURING NORMAL AND ABNORMAL PALATAL SHELF ELEVATION, AS WELL AS INTO THE EFFECT OF MATERNAL FOLIC ACID SUPPLEMENTATION, WHICH WILL PROVIDE TARGETS FOR FUTURE TRANSLATIONAL STRATEGIES AGAINST OROFACIAL CLEFTING.

ACUTE EXERCISE AND THE CEREBRAL METABOLIC RESPONSE IN AGING AND ALZHEIMER'S DISEASE

TELEHEALTH TECHNOLOGY-ENABLED LEARNING PROGRAM

LOCALIZED MHEALTH APPROACH TO BOOSTING COVID-19 TESTING AND VACCINE LITERACY, ACCESS, AND UPTAKE AMONG WOMEN WITH CRIMINAL LEGAL SYSTEM INVOLVEMENT - ABSTRACT PEOPLE WITH CRIMINAL LEGAL SYSTEM INVOLVEMENT (CLSI) HAVE EXPERIENCED FIVE TIMES AS MANY COVID-19 INFECTIONS AND HAVE THREE TIMES THE RISK OF DEATH COMPARED TO GENERAL POPULATION IN THE U.S. HEAVILY IMPACTED BY COVID-19 AND SQUARELY WITHIN NIH HEALTH DISPARITIES POPULATIONS, PEOPLE WITH CLSI ARE OFTEN POOR AND DISPROPORTIONATELY FROM RACIAL AND ETHNIC MINORITY GROUPS. DESPITE THE INCREASED RISK OF COVID-19, WE EXPECT THAT ONLY ONE-HALF OF PEOPLE WITH CLSI WILL GET VACCINATED. ONGOING COVID-19 TESTING IN COMMUNITIES AND AMONG GROUPS THAT ARE NOT VACCINATED WILL BE KEY TO CONTAINING THE PANDEMIC. THE MESSAGING THAT COVID-19 TESTING WILL STILL BE IMPORTANT MAY NOT BE GETTING THROUGH TO PEOPLE WHO ARE AT RISK – A CRITICAL DRIVER OF DISPARITIES. OUR TEAM HAS A UNIQUE OPPORTUNITY TO BOOST TESTING LITERACY, ACCESS, AND UPTAKE USING MOBILE HEALTH (MHEALTH) TECHNOLOGIES (TEXT AND WEB) TO REACH WOMEN WITH CLSI IN COMMUNITY SETTINGS WHO ARE PART OF THE EXISTING TRI-CITY COHORT DRAWN FROM GEOGRAPHICALLY AND SOCIO-POLITICALLY DIVERSE CITIES: BIRMINGHAM, AL, KANSAS CITY, MO/KS, AND OAKLAND, CA. THIS APPLICATION IS HIGHLY RESPONSIVE TO THE RADX-UP PHASE II CALL FOR RESEARCH THAT TESTS INTERVENTIONS TO REDUCE COVID-19 DISPARITIES AMONG UNDERSERVED POPULATIONS. OUR TEAM IS POSITIONED TO EMBED THE PROPOSED STUDY INTO AN EXISTING WEB-BASED WOMEN’S HEALTH LITERACY INTERVENTION PLATFORM (WWW.SHEWOMEN.ORG, 2R01CA181047) FOR WOMEN LEAVING JAIL. WE ARE ALSO ABLE TO IMMEDIATELY PUSH THE MHEALTH COVID-19 TESTING LITERACY INTERVENTION TO 508 WOMEN WE HAVE ALREADY RECRUITED TO A THREE-CITY CERVICAL HEALTH STUDY OF WOMEN WITH CLSI (R01CA226838), AND TO PROMPTLY MAKE THIS SCALABLE INTERVENTION WIDELY AVAILABLE TO PEOPLE WITH CLSI. WE WILL ENGAGE THE WOMEN AS STAKEHOLDERS TO STUDY REGIONAL AND INDIVIDUAL DIFFERENCES IN COVID-19 TESTING AND VACCINE LITERACY, ACCESS, AND UPTAKE. WE WILL USE FINDINGS TO RAPIDLY DEVELOP AN MHEALTH INTERVENTION FOCUSED ON COVID-19 LITERACY, AND THEN PUSH THE INTERVENTION TO CLSI WOMEN IN THE THREE CITIES TO BOOST COVID-19 LITERACY, TESTING, ACCESS, AND UPTAKE, AND VACCINATION. FINDINGS WILL BE USED TO DEVELOP DISSEMINATION STRATEGIES WITH STAKEHOLDERS TO PUSH THE MHEALTH INTERVENTION TO THE TWO MILLION WOMEN AND 11 MILLION MEN WHO INTERFACE WITH THE CRIMINAL LEGAL SYSTEM ANNUALLY IN THE U.S.

KANSAS POLYCYSTIC KIDNEY IMAGING PROGRAM (CRISPII)

ROBUST PRECISION MAPPING OF CORTICAL AND SUBCORTICAL BRAIN METABOLIC SIGNATURES IN AD - PROJECT SUMMARY/ABSTRACT TREATING AND CARING FOR THE MORE THAN 6.5 MILLION OLDER ADULTS IN THE U.S. LIVING WITH ALZHEIMER’S DISEASE (AD) PRESENTS THE LARGEST BURDEN FROM A SINGLE DISEASE ON THE HEALTHCARE SYSTEM, WITH COSTS EXCEEDING $320 BILLION PER YEAR FOR AD AND RELATED DEMENTIAS (AD/ADRD). WHILE DEATHS DUE TO MAJOR DISEASES (E.G., STROKE, HEART DISEASE, AND CANCERS) HAVE DECLINED, AD AND AD-RELATED DEATHS HAVE INCREASED SUBSTANTIALLY, WITH A PROJECTED COST OF ABOUT $1 TRILLION PER YEAR TO THE US ECONOMY BY 2050. ALTHOUGH AD IS CURRENTLY IRREVERSIBLE, NEW THERAPEUTIC APPROACHES AND PREVENTION STRATEGIES ARE UNDER EXTENSIVE INVESTIGATION. OVER 50% OF THE PHARMACOLOGIC AGENTS CURRENTLY BEING TESTED FOR AD TARGET ABERRANT BRAIN METABOLISM. THUS, IT IS ESSENTIAL TO ESTABLISH A CONCRETE RELATIONSHIP BETWEEN METABOLIC DYSFUNCTION AND PATHOLOGIC FEATURES OF AD BRAINS. HOWEVER, COMPREHENSIVE WHOLE-BRAIN METABOLIC MAPPING, INCLUDING CORTICAL AND SUBCORTICAL BRAIN REGIONS THAT ARE HIGHLY RELEVANT TO AD PATHOLOGY, HAS NOT BEEN ACHIEVED, DUE TO SUBSTANTIAL TECHNICAL CHALLENGES IN ACQUIRING HIGH-QUALITY MAGNETIC RESONANCE (MR) SPECTROSCOPIC IMAGING DATA WITH SUFFICIENT SPATIAL RESOLUTION ACROSS THE ENTIRE BRAIN IN CLINICALLY ACCEPTABLE SCAN TIME. IN THIS REGARD, WE PROPOSE TO GENERATE A ROBUST AND RELIABLE METABOLIC MAPPING OF THE WHOLE BRAIN, INCLUDING THE CORTICAL REGIONS, BY ESTABLISHING TECHNICAL CAPABILITIES FOR THREE-DIMENSIONAL ECHO-PLANAR SPECTROSCOPIC IMAGING (3D-EPSI). BUILDING ON OUR TEAM’S PIONEERING WORK IN MR TECHNICAL DEVELOPMENT AND AN EXISTING COLLABORATION, WE ARE IDEALLY POSITIONED TO MAKE INTEGRATIVE TECHNICAL ADVANCES IN NUISANCE SIGNAL REDUCTION, IMPROVED SPATIAL ENCODING, AND REAL-TIME MOTION AND B0 CORRECTION, TO CREATE A STATE-OF-THE-ART METABOLIC IMAGING APPROACH. ACCURATE ANATOMY-BASED REGIONAL DATA ANALYSIS TOOLS (NAMELY METASURFER) WILL ALSO BE DEVELOPED TO PROVIDE A NOVEL SURFACE-BASED APPROACH TO PROCESSING WHOLE BRAIN METABOLIC IMAGING DATA. THUS, THIS PROJECT OFFERS COMPREHENSIVE WHOLE-BRAIN METABOLIC IMAGING PACKAGES FOR A FULL END-TO-END SOLUTION FROM ROBUST DATA ACQUISITION TO NOVEL DATA ANALYSIS. USING THE DEVELOPED PACKAGES, WE WILL CREATE POPULATION-AVERAGED NORMATIVE WHOLE-BRAIN METABOLIC ATLASES IN THE AGING POPULATION AFTER STRATIFYING AMYLOID STATUS (ASS- AND ASS+), WHICH WILL PROVIDE A STATISTICAL BASIS FOR ASSESSING METABOLIC ALTERATIONS IN AD. IN OUR PILOT CLINICAL STUDY OF EARLY AD, WE WILL INVESTIGATE THE RELATIONSHIP BETWEEN BRAIN METABOLIC IMAGING OUTCOMES AND MOLECULAR, GENETIC, MORPHOLOGICAL, CLINICAL, AND COGNITIVE MEASURES IN PEOPLE WITH EARLY AD, LEVERAGING THE AVAILABLE DATA FROM NIA AD RESEARCH CENTER (ADRC) RESOURCES AND ONGOING AD CLINICAL STUDIES. THIS STUDY WILL PROVIDE CRITICAL DATA FOR FUTURE LARGE-SCALE CLINICAL TRIALS EVALUATING NEW AD-TREATMENT STRATEGIES AS A PART OF THE EMERGING FIELD OF METABOLIC AND BIOENERGETIC MEDICINE FOR AD/ADRD.

VIRAL AND HOST DETERMINANTS OF PARVOVIRUS REPLICATION

MECHANISMS REGULATING AUTOPHAGY IN ALCOHOL-INDUCED LIVER INJURY

HF GROUP APPOINTMENTS REHOSPITALIZATION PREVENTION

EHS 2009 ARRA EXPANSION

HEALTH CAREERS OPPORTUNITY PROGRAM

THE MOLECULAR ACTIONS OF IMATINIB MESYLATE IN GISTS

ADPKD: UNDERSTANDING MECHANISMS, DISCOVERING TREATMENTS.

MOTOR OUTCOMES TO VALIDATE EVALUATIONS IN PEDIATRIC FSHD (MOVE PEDS) - THE PRIMARY GOAL OF THIS PROPOSAL IS TO HASTEN THERAPEUTIC DEVELOPMENT BY VALIDATING OUTCOMES AND REFINING CLINICAL TRIAL STRATEGIES FOR PEDIATRIC-ONSET FSHD. CROSS SECTIONAL STUDIES HAVE SUGGESTED AN ASSOCIATION BETWEEN A YOUNGER AGE OF ONSET AND GREATER CLINICAL SEVERITY. THEY ALSO SHOW THAT HAVING 1-3 D4Z4 REPEATS IS ASSOCIATED WITH EXTRA-MUSCULAR COMPLICATIONS IN PEDIATRIC FSHD. PROSPECTIVE STUDIES IN EARLY-ONSET FSHD TO DATE HAVE BEEN LIMITED BY SMALL NUMBER OF SITES AND LOW ABILITY TO RECRUIT AND FOLLOW PATIENTS. RATIONALE: FSHD IS CAUSED BY THE ABERRANT EXPRESSION OF A NORMALLY SILENCED GENE, DUX4, WHICH CAUSES A TOXIC GAIN-OF-FUNCTION AND MAY BE A TARGET FOR THERAPY. THE KEY ABNORMALITY IN FSHD IS PARTICULARLY AMENABLE TO MOLECULAR KNOCK- DOWN OR SILENCING OF DUX4, MAKING STRATEGIES LIKE THE USE OF ANTISENSE OLIGONUCLEOTIDE OR RNA INTERFERENCE POSSIBLE. SEVERAL PHARMACEUTICAL COMPANIES HAVE ACTIVE PROGRAMS FOR TARGETED TREATMENTS IN ADULT FSHD, AND MANY MORE ARE PLANNED AND ON THE HORIZON OVER THE NEXT FIVE YEARS. EARLY-ONSET PEDIATRIC FSHD IS A POPULATION OF HIGH INTEREST TO DRUG COMPANIES FOR THE FOLLOWING REASONS: 1) EARLY-ONSET PEDIATRIC FSHD RESULTS IN MORE SIGNIFICANT DISEASE BURDEN THAN IN ADULTS; 2) TREATING FSHD AT EARLIER AGES MAY HAVE A MORE LASTING AND PROFOUND EFFECTS; AND 3) SMALLER BODY SIZE AND FASTER RATES OF PROGRESSION MAY MAKE AAV DELIVERED GENE THERAPIES MORE FEASIBLE. THE FSHD CLINICAL TRIALS RESEARCH NETWORK (CTRN) WILL BE UTILIZED AND IS COMPRISED OF INTERNATIONAL ACADEMIC CENTERS, WHICH HAS LEVERAGED SUPPORT FROM KEY STAKEHOLDERS TO CREATE INFRASTRUCTURE FOR STUDY COORDINATION, EVALUATOR TRAINING, AND DATA MANAGEMENT/STATISTICAL SUPPORT. THE STUDY WILL BE A PROSPECTIVE 24-MONTH STUDY OF 80 PEDIATRIC FSHD PARTICIPANTS (AT LEAST HALF MEETING CRITERIA FOR EARLY-ONSET FSHD) AND WILL VALIDATE THE PEDIATRIC FSHD COMPOSITE FUNCTIONAL MEASURE (FSHD-COM PEDS), REACHABLE WORKSPACE (RWS), AND QUANTITATIVE MRI (QMRI) MEASURES INTRA-MUSCULAR FAT CONTENT, WHICH HAVE SHOWN TO BE RESPONSIVE TO DISEASE PROGRESSION OR TREATMENT IN ADULTS WITH FSHD AND CORRELATED TO PERFORMANCE. THE STUDY PROPOSES THE FOLLOWING AIMS. AIM 1 WILL DETERMINE THE VALIDITY OF THE PEDIATRIC FSHD COM AND RWS AS A PRIMARY CLINICAL OUTCOME ASSESSMENT (COA) FOR FSHD CLINICAL TRIALS. ALSO, WILL DETERMINE MULTICENTER TEST-RETEST RELIABILITY, CROSS SECTIONAL ASSOCIATIONS TO OTHER FSHD DISEASE MEASURES, RESPONSIVENESS TO FSHD DISEASE PROGRESSION, PREDICTIVE BASELINE CLINICAL CHARACTERISTICS FOR TRIAL PLANNING, AND MINIMAL CLINICALLY IMPORTANT CHANGES. AIM 2 WILL DETERMINE THE VALIDITY OF QMRI AS A PROGNOSTIC OR MONITORING BIOMARKER FOR FSHD CLINICAL TRIALS. SIMILAR TO AIM 1, THIS DETERMINES THE CONVERGENT VALIDITY, RESPONSIVENESS TO DISEASE PROGRESSION, AND BASELINE CUT OFFS USEFUL FOR TRIAL PLANNING. AT THE COMPLETION OF THIS STUDY, THE FSHD-COM PEDS, RWS, AND QMRI WILL BE VALIDATED FOR USE IN PEDIATRIC FSHD CLINICAL TRIALS AND WILL INVESTIGATE DIFFERENCES BETWEEN THE EARLY-ONSET AND CHILDHOOD AND ADOLESCENT ONSET FSHD FOR TRIAL PLANNING PURPOSES.

ADDRESSING FOOD INSECURITY IN TRANSPLANT AND CELLULAR THERAPY PATIENTS WITH HEALTHCARE-COMMUNITY PARTNERSHIPS - ABSTRACT FOOD INSECURITY (FI), DEFINED AS A LACK OF CONSISTENT ACCESS TO ENOUGH FOOD FOR EVERY PERSON IN A HOUSEHOLD TO LIVE AN ACTIVE, HEALTHY LIFE DUE TO INSUFFICIENT MONEY OR OTHER RESOURCES, AFFECTS 17 MILLION (12.8%) OF AMERICAN HOUSEHOLDS. FI IS EXACERBATED IN PATIENTS WITH COMPLEX MEDICAL CONDITIONS, AND IT IS ASSOCIATED WITH WORSE HEALTH OUTCOMES AND INCREASED HEALTHCARE UTILIZATION AND COSTS. STRATEGIES TO ADDRESS FI SUCH AS HOME-DELIVERED MEALS OR FOOD ASSISTANCE PROGRAMS LIKE THE SUPPLEMENTAL NUTRITION ASSISTANCE PROGRAM (SNAP) AND FOOD BANKS/PANTRIES/PHARMACIES MAY IMPROVE HEALTHCARE OUTCOMES. HOWEVER, HOME-DELIVERED MEALS ARE ASSOCIATED WITH HIGHER COSTS DUE TO INDIVIDUALIZED DELIVERY WHILE FOOD ASSISTANCE PROGRAMS HAVE SEVERAL BARRIERS TO PARTICIPATION. WE PROPOSE TO LEVERAGE THE STRENGTHS OF BOTH THOSE APPROACHES IN A NOVEL HEALTHCARE-COMMUNITY PARTNERSHIP BETWEEN CANCER CENTERS AND FOOD BANKS CALLED NUTRITION OUTREACH IN SYSTEMS OF HEALTHCARE (NOURISH), TO DIRECTLY DELIVER FOOD TO PATIENTS IN CLINIC. PATIENTS, CAREGIVERS, DIETITIANS, SOCIAL WORKERS, NURSES, PHYSICIANS, FOOD BANK STAFF, AND COMMUNITY MEMBERS WILL WORK TOGETHER TO DETERMINE MEDICALLY TAILORED OPTIONS FOR THE PATIENT POPULATION; FOOD BANKS WILL OVERSEE SOURCING AND PREPARING BAGS OF FOOD; AND HEALTHCARE PROVIDERS WILL DISTRIBUTE BAGS TO PATIENTS IN CLINIC AFTER THEIR APPOINTMENTS. BECAUSE NOURISH DOES NOT REQUIRE PATIENTS TO MAKE AN EXTRA TRIP AND BAGS ARE DISTRIBUTED DISCREETLY TO AVOID STIGMA, IT INCREASES ADOPTION; BECAUSE FOOD IS HANDED OUT IN CLINIC, IT LOWERS COSTS. WE PROPOSE TO EVALUATE NOURISH IN A MULTICENTER RANDOMIZED CONTROLLED TRIAL IN FI PATIENTS WITH HEMATOLOGIC MALIGNANCIES RECEIVING TRANSPLANT AND CELLULAR THERAPY (TCT). WE CHOSE THIS POPULATION FOR THREE REASONS: (1) TCT PATIENTS ARE IN GREAT NEED AS APPROXIMATELY 75% WILL RELOCATE TO LIVE NEAR A QUATERNARY CANCER CENTER (QCC) FOR A MONTH OR MORE WHILE RECEIVING TCT, REMOVING THEM FROM THEIR NORMAL SOURCES OF SUPPORT; (2) TCT PATIENTS ARE AT HIGH RISK FOR MALNUTRITION AND OTHER ADVERSE OUTCOMES, OFTEN STRUGGLING WITH NAUSEA, ANOREXIA, AND OTHER SIDE EFFECTS THAT CAN BE EXACERBATED BY FI; (3) TCT MAY BE A MODEL FOR SUSTAINING CARE: WHILE OTHER FOOD IS MEDICINE INITIATIVES HAVE SHOWN ECONOMIC BENEFITS, BECAUSE COST SAVINGS DO NOT FLOW TO HEALTHCARE SYSTEMS, THERE IS LITTLE INCENTIVE FOR IMPLEMENTATION. IN CONTRAST, TCT IS AMONG THE MOST EXPENSIVE MEDICAL PROCEDURES, AND HEALTHCARE SYSTEMS ARE TYPICALLY REIMBURSED THROUGH BUNDLED PAYMENTS. AS A RESULT, QCCS HAVE AN INCENTIVE TO PURSUE STRATEGIES THAT MAY LOWER COSTS AND IMPROVE OUTCOMES. FOR EXAMPLE, MANY TCT PATIENTS WITH FI WILL RECEIVE TOTAL PARENTERAL NUTRITION, AT SIGNIFICANT COST. NOURISH MAY PREVENT MALNUTRITION AND THE NEED FOR INTRAVENOUS NUTRITION THROUGH MUCH CHEAPER FOOD ASSISTANCE. THE SUCCESS OF OUR RANDOMIZED CONTROLLED TRIAL WILL PROVIDE A COMPELLING RATIONALE FOR QCCS TO CONTINUE TO FUND FOOD BANKS IN THEIR COMMUNITIES, PROVIDING MUCH-NEEDED FINANCIAL SUPPORT TO SUSTAIN THESE PARTNERSHIPS WHILE IMPROVING ACCESS AND OUTCOMES FOR PATIENTS. FURTHERMORE, POSITIVE EXPERIENCES IN TCT MAY LEAD TO THE EXPANSION OF THESE HEALTHCARE- COMMUNITY PARTNERSHIPS TO THE BROADER CANCER POPULATION AND BEYOND.

HIPPO SIGNALING EFFECTOR AND PLACENTATION

BETA-CELL RESPONSES TO OXIDATIVE STRESS AND TYPE 1 DIABETES - TYPE 1 DIABETES (T1D) IS AN AUTOIMMUNE DISEASE RESULTING IN PANCREATIC SS-CELL DESTRUCTION DUE TO THE GENERATION OF REACTIVE OXYGEN SPECIES (ROS), PROINFLAMMATORY CYTOKINES/CHEMOKINES, AND T CELL EFFECTOR MOLECULES. RECENT EVIDENCE HAS SHOWN THAT SS-CELL DYSFUNCTION IS ALSO AN ACTIVATE PARTICIPANT IN T1D PATHOGENESIS. WE WILL COMPARE PANCREATIC SS-CELL FUNCTIONAL IDENTITY CHANGES THAT OCCUR WITH T1D-PRONE NON-OBESE DIABETIC (NOD) MICE WITH T1D-RESISTANT NOD.NCF1M1J MICE UNABLE TO GENERATE NADPH OXIDASE (NOX)-DERIVED SUPEROXIDE. WE WILL EXAMINE HOW THE ABSENCE OF ROS IN NOD.NCF1M1J MICE CAN REGULATE SS-CELL FUNCTIONAL IDENTITY, INTERACTIONS WITH IMMUNE CELLS, AND DELAY IN T1D. TO CORROBORATE OUR GENETIC MOUSE MODELS, WE WILL EXAMINE PANCREATIC SS-CELL RESPONSES FOLLOWING TREATMENT WITH A PHARMACOLOGICAL MANGANESE METALLOPORPHYRIN ANTIOXIDANT WITH HUMAN ISLETS. OUR OVERARCHING HYPOTHESIS IS THAT ROS REDUCTION WILL PRESERVE OR ENHANCE SS-CELL FUNCTIONAL IDENTITY, AS DEFINED BY TRANSCRIPTIONAL SIGNATURES AND INSULIN SECRETION IN T1D-PRONE NOD MICE AND HUMAN ISLETS. TO ADDRESS THIS HYPOTHESIS, THE FOLLOWING INDEPENDENT AND INTERRELATED AIMS WILL BE DEFINED: (1) DEFINE HOW GENETIC ABLATION OF ROS PRESERVES SS-CELL FUNCTIONAL IDENTITY. (2) DETERMINE WHETHER THE ABSENCE OF ROS CAN DECREASE PANCREATIC SS-CELL-MEDIATED INFLAMMATORY RESPONSES. (3) DETERMINE WHETHER ANTIOXIDANT TREATMENT PRESERVES THE FUNCTION OF MOUSE AND HUMAN SS-CELLS. THE INSIGHTS GAINED FROM OUR STUDIES WILL INCREASE OUR UNDERSTANDING OF DIABETES ETIOLOGY AND MAY ALSO POINT TO FUTURE STRATEGIES EMPLOYING ANTIOXIDANT COMPOUNDS TO PRESERVE AND/OR REPLACE THE FUNCTION OF PANCREATIC SS-CELLS.

DESIGN OF A NOVEL NANOCARRIER TECHNOLOGY TO DRUG-LOAD CAR T CELLS - PROJECT SUMMARY: CURRENT TREATMENT FOR GLIOBLASTOMA MULTIFORME (GBM), THE MOST COMMON MALIGNANT BRAIN TUMOR IN ADULTS, INVOLVES MAXIMAL SAFE RESECTION, FOLLOWED BY ADJUVANT CHEMORADIATION. ALTHOUGH THIS TREATMENT IS LIFE PROLONGING, IT IS NEVER CURATIVE. FIVE YEAR SURVIVAL IS LESS THAN 7 %1 AND IMPROVED THERAPIES ARE URGENTLY NEEDED. IN THIS PROPOSAL, WE AIM TO DEVELOP A NEW TARGETED THERAPY WITH REDUCED TOXICITY AND INCREASED EFFICACY FOR GBM PATIENTS BY LEVERAGING NANOTECHNOLOGY DISCOVERIES IN OUR LABORATORY TO IMPROVE ADOPTIVE CELL THERAPY. CHIMERIC ANTIGEN RECEPTOR (CAR) T CELLS COMBINE THE CYTOLYTIC POTENCY OF A T CELL WITH THE TUMOR SPECIFICITY OF AN ANTIBODY. RECENT CLINICAL TRIAL EXPERIENCES OF CAR T CELLS IN SOLID TUMORS HAVE IDENTIFIED THE IMMUNE-SUPPRESSIVE TUMOR MICROENVIRONMENT (TME) AS A MAJOR BARRIER TO CLINICAL SUCCESS2-4. ONE IMMUNE-SUPPRESSIVE ENDOGENOUS NEGATIVE REGULATOR IN GBM TME IS TGFSS, WHICH HAS BEEN IDENTIFIED AS BARRIER TO CAR T TUMOR ERADICATION. SMALL MOLECULE INHIBITORS OF THE TGFSS RECEPTOR AS WELL AS TGFSS RESISTANT CAR T CELLS HAVE BEEN DEVELOPED AND TESTED CLINICALLY, HOWEVER THEY ARE LIMITED DUE TO SYSTEMIC TOXICITY. HEREIN WE PROPOSE DEVELOPING A PLATFORM TECHNOLOGY TO DRUG-LOAD CAR T CELLS WITH NANOCARRIERS, THUS ENHANCING THE THERAPEUTIC WINDOW OF CAR T CELLS, AND ADDRESSING ONE OF THE MAJOR OBSTACLES TO CAR T CELLS IN BRAIN TUMORS.

TROPHOBLAST-GUIDED UTERINE TRANSFORMATION IN THE ESTABLISHMENT OF PREGNANCY - PROJECT SUMMARY/ABSTRACT TROPHOBLAST CELL DERIVATIVES OF THE EMBRYO CONTRIBUTE TO RESTRUCTURING THE UTERINE ENVIRONMENT, AN EVENT REQUIRED FOR THE ESTABLISHMENT OF A SUCCESSFUL PREGNANCY. THE RAT AND HUMAN EACH POSSESS A UTERINE- PLACENTAL INTERFACE THAT IS CHARACTERIZED BY DEEP INTRAUTERINE INFILTRATION OF TROPHOBLAST CELLS, WHICH CONTRIBUTE TO DYNAMIC CHANGES IN UTERINE IMMUNE CELL, ENDOTHELIAL CELL, SMOOTH MUSCLE CELL, AND STROMAL CELL CONSTITUENTS. THIS IMPORTANT DEVELOPMENTAL PROCESS IS DIRECTED BY SPECIALIZED TROPHOBLAST CELLS POSSESSING INVASIVE PROPERTIES WITH THE POTENTIAL OF TARGETING MATERNAL CELLS WITHIN THE UTERINE COMPARTMENT. IN THE HUMAN, THESE INVASIVE TROPHOBLAST CELLS ARE REFERRED TO AS EXTRAVILLOUS TROPHOBLAST (EVT). DISRUPTIONS IN DIFFERENTIATION OF THE INVASIVE TROPHOBLAST/EVT CELL LINEAGE, INTRAUTERINE TROPHOBLAST CELL INVASION, AND/OR TROPHOBLAST CELL-DIRECTED UTERINE CELL MODULATION CONTRIBUTE TO EARLY PREGNANCY LOSS, PLACENTAL DYSFUNCTION, PREGNANCY-RELATED DISEASES, AND A RANGE OF POSTNATAL HEALTH ISSUES. THE PROJECT FOCUSES ON PLACENTA SPECIFIC 1 (PLAC1), AN INTRINSIC REGULATOR OF PLACENTATION. OUR LONG-TERM GOAL IS TO ELUCIDATE REGULATORY PROCESSES CONTROLLING DEVELOPMENT OF THE INVASIVE TROPHOBLAST/EVT CELL LINEAGE AND ITS ROLE IN ESTABLISHING THE UTERINE-PLACENTAL INTERFACE. IN THIS PROJECT, OUR EFFORTS ARE FOCUSED ON TWO AIMS. IN AIM 1, WE DISSECT THE ACTIONS OF PLAC1 IN THE ESTABLISHMENT OF THE INVASIVE TROPHOBLAST CELL LINEAGE. IN AIM 2 WE INVESTIGATE TROPHOBLAST CELL-UTERINE CELL CROSSTALK AND PLASTICITY AT THE UTERINE-PLACENTAL INTERFACE. EXPERIMENTATION UTILIZES GENETICALLY MANIPULATED LOSS-OF-FUNCTION RAT MODELS, TROPHOBLAST STEM CELLS, AND GENOME-WIDE ANALYSES OF TRANSCRIPTOMES AND CHROMATIN LANDSCAPES. EXECUTION OF THIS RESEARCH PROJECT WILL FACILITATE ELUCIDATION OF MOLECULAR PATHWAYS CONTROLLING TROPHOBLAST-GUIDED TRANSFORMATION OF THE UTERINE ENVIRONMENT AND WILL CREATE A PLATFORM FOR UNDERSTANDING THE PATHOGENESIS OF EARLY PREGNANCY LOSS AND PLACENTAL ANOMALIES LEADING TO PREGNANCY DISORDERS.

AEROBIC FITNESS, MITOCHONDRIAL FUNCTION, AND FATTY LIVER DISEASE.

KANSURVIVE: TESTING A MODEL FOR IMPROVING CANCER SURVIVORSHIP CARE IN RURAL PRACTICE

WASHINGTON UNIVERSITY'S PRECISION BIOLOGIC INTERVENTIONS FOR SEVERE EXACERBATION PRONE ASTHMA (PRECISE) CLINICAL CENTER

IMPACT OF POST-STROKE REHABILITATION ON NEUROPHYSIOLOGICAL DYNAMICS - SUMMARY/ABSTRACT THE LONG-TERM GOAL OF THIS PROJECT IS TO DEVELOP A NOVEL MECHANISTIC FRAMEWORK TO UNDERSTAND HOW POST-STROKE REHABILITATIVE TRAINING MODULATES NEURAL REORGANIZATION IN SENSORIMOTOR BRAIN REGIONS, AND WHETHER SUCH REORGANIZATION IS ASSOCIATED WITH RECOVERY OF MOTOR FUNCTION. IN A NON-HUMAN PRIMATE MODEL OF CAPSULAR STROKE, WE WILL DESCRIBE THE TIME COURSE OF CHANGES IN TASK-RELATED MOTOR ENCODING AND MESOSCALE CORTICO-CORTICAL CONNECTIVITY THAT OCCUR IN SENSORIMOTOR BRAIN REGIONS, AND THE TIME COURSE OF THESE CHANGES IN RELATION TO MOTOR RECOVERY. THESE NEUROPHYSIOLOGICAL CHANGES WILL BE COMPARED TO THOSE OCCURRING IN ANIMALS UNDERGOING INTENSIVE REHABILITATION INITIATED IN THE SUB-ACUTE STAGE AFTER INJURY. POST-STROKE NEURAL PLASTICITY HAS BEEN DEMONSTRATED REPEATEDLY IN PRE-CLINICAL AND CLINICAL STUDIES. ANIMAL STUDIES HAVE PROVIDED KEY INFORMATION REGARDING THE MOLECULAR MECHANISMS OF SYNAPTIC PLASTICITY, AND FOCAL CORTICAL STROKE MODELS HAVE DEMONSTRATED THAT ALTERATIONS IN NEURONAL CONNECTIVITY ARE CORRELATED WITH FUNCTIONAL RECOVERY. HOWEVER, MOST STUDIES ARE CROSS- SECTIONAL AND CANNOT ADDRESS THE COMPLEX TEMPORAL RELATIONSHIPS BETWEEN NEURAL PLASTICITY AND BEHAVIORAL RECOVERY; CONCLUSIONS ABOUT THE IMPACT OF REHABILITATION ON RECOVERY MECHANISMS, AND ULTIMATELY ON CLINICAL RECOVERY, ARE LARGELY CORRELATIVE. AS A RESULT, IT IS CURRENTLY UNKNOWN WHETHER PLASTICITY MECHANISMS DEMONSTRATED IN MOST CLINICAL AND PRECLINICAL STUDIES ARE ASSOCIATED WITH THE INITIATION OF RECOVERY PROCESSES OR ARE THE RESULT OF BEHAVIORAL RECOVERY. FURTHER, WHEN LONGITUDINAL STUDIES IN CLINICAL POPULATIONS HAVE BEEN DONE, RELATIONSHIPS BETWEEN PLASTICITY AND MOTOR RECOVERY HAVE BEEN EQUIVOCAL, IN PART BECAUSE FMRI-BASED APPROACHES LACK THE TEMPORAL SPECIFICITY TO RESOLVE THE INTRICATE PATTERNS OF COMMUNICATION AMONG BRAIN REGIONS THAT ARE ESSENTIAL FOR NORMAL SENSORIMOTOR FUNCTION. USING CHRONIC MICROELECTRODE ARRAYS IN A LONGITUDINAL EXPERIMENTAL DESIGN, WE WILL ADDRESS THREE SPECIFIC AIMS THAT EXAMINE NEURAL ACTIVITY (EXTRACELLULAR SPIKES) SIMULTANEOUSLY RECORDED FROM MULTIPLE CORTICAL SENSORIMOTOR AREAS AND MOTOR THALAMUS BEFORE AND AFTER CAPSULAR INFARCT. THIS WILL ALLOW US TO EXAMINE HOW STROKE-LIKE INJURIES DISRUPT TASK-RELATED MOTOR ENCODING IN SOMATOSENSORY AND MOTOR CORTICAL AREAS USING TRADITIONAL DYNAMICAL STRUCTURE MODELS (AIM 1). FURTHER, WE WILL CHARACTERIZE THE IMPACT OF CAPSULAR INFARCTS ON MESOSCALE EFFECTIVE CONNECTIVITY USING A NOVEL NEUROPHYSIOLOGICAL APPROACH THAT WE RECENTLY DEVELOPED (AIM 2). FINALLY, WE WILL DETERMINE WHETHER REHABILITATIVE TRAINING PROCEDURES INITIATED IN THE SUB-ACUTE PERIOD AFTER NEURAL INJURY INFLUENCE RECOVERY BY MODULATING TASK-RELATED ACTIVITY, ALTERING EFFECTIVE CONNECTIVITY, OR BOTH (AIM 3). THE NOVELTY AND POTENTIAL IMPACT OF THIS PROJECT STEMS FROM THE UNIQUE LONGITUDINAL DESIGN, PROVIDING US WITH THE ABILITY TO PLOT THE PRECISE TEMPORAL PROFILE OF LOCAL AND NETWORKED CHANGES TO DETERMINE IF A PARTICULAR BIOMARKER PRECEDES REHABILITATION-AIDED RECOVERY, AND THUS, IS MORE LIKELY TO HAVE A DIRECT CAUSAL RELATIONSHIP WITH FUNCTIONAL RESTORATION. ACHIEVING THESE GOALS ULTIMATELY WILL INFORM CLINICAL STUDIES AIMED AT PERSONALIZING POST-STROKE REHABILITATION BASED ON NEUROPHYSIOLOGICAL BIOMARKERS OF RECOVERY POTENTIAL.

EXTRACELLULAR VESICLES AND AND HIV/COCAINE ASSOCIATED CARDIOPULMONARY DYSFUNCTION

GERIATRIC EDUCATION CENTERS

THE SAFETY AND EFFICACY OF MEGESTEROL AS PART OF AN OUTPATIENT FEEDING PROTOCOL FOR CHILDREN WITH CHRONIC MEDICAL CONDITIONS

CENTERS OF EXCELLENCE

SUBUNIT INTERACTIONS OF PHOSPHORYLASE KINASE

EQUIVALENT WEIGHT LOSS FOR PHONE AND CLINIC WEIGHT MANAGEMENT PROGRAMS

HISTONE DEMETHYLASES AND TROPHOBLAST DIFFERENTIATIONT - ABSTRACT PLACENTAL DYSFUNCTION LEADS TO PREGNANCY-ASSOCIATED DISORDERS, INCLUDING INTRAUTERINE GROWTH RESTRICTION (IUGR) AND PREECLAMPSIA, AND ALSO SERVES AS A DEVELOPMENTAL CAUSE FOR POSTNATAL AND ADULT DISEASES. OFTEN, THE CAUSAL ALTERATIONS IN THE PLACENTATION PROCESS, WHICH LEAD TO DEFECTIVE PREGNANCIES, OCCUR EARLY IN GESTATION. DEFECTIVE DEVELOPMENT AND DIFFERENTIATION OF TROPHOBLAST PROGENITORS ARE LEADING CAUSES FOR PATHOLOGICAL PREGNANCIES. HOWEVER, WE HAVE A POOR UNDERSTANDING OF MOLECULAR MECHANISMS THAT REGULATE TROPHOBLAST PROGENITOR SELF-RENEWAL, DIFFERENTIATION AND FUNCTION IN POSTIMPLANTATION EMBRYOS. STUDIES ON MUTANT MOUSE MODELS AND MOUSE TROPHOBLAST STEM CELLS (MOUSE TSCS) IMPLICATED LYSINE-SPECIFIC DEMETHYLASE 1 (LSD1), THE FIRST IDENTIFIED HISTONE DEMETHYLAS, AS A CRITICAL REGULATOR TO PREVENT PREMATURE DIFFERENTIATION OF MOUSE TSCS. HOWEVER, THE IMPORTANCE OF LSD1 IN THE CONTEXT OF DIFFERENTIATED TROPHOBLAST CELLS OF A MATURED PLACENTA IS YET TO BE DEFINED. ALSO, THE IMPORTANCE OF LSD1 IN HUMAN TROPHOBLAST DEVELOPMENT HAS NEVER BEEN TESTED. OUR PRELIMINARY FINDINGS ESTABLISH THAT LSD1 EXPRESSION IS CONSERVED IN TROPHOBLAST PROGENITORS ACROSS MAMMALIAN SPECIES, INCLUDING HUMANS. THUS, IN THIS PROPOSAL WE WILL INVESTIGATE IMPORTANCE OF LSD1 IN THE DEVELOPMENT OF SPECIALIZED TROPHOBLAST CELLS, NAMELY SYNCYTIOTROPHOBLASTS (SYNTBS) AND INVASIVE TROPHOBLASTS, AT THE MATERNAL- FETAL INTERFACE. WE WILL ALSO DEFINE IMPORTANCE OF LSD1 IN HUMAN TROPHOBLAST DIFFERENTIATION AND INTERROGATE LSD1 FUNCTION. TWO SPECIFIC AIMS ARE PROPOSED. AIM 1 WILL STUDY LSD1 CONDITIONAL KNOCKOUT MOUSE MODEL TO TEST THE HYPOTHESIS THAT CELL-AUTONOMOUS FUNCTION OF LSD1 IN LINEAGE-SPECIFIC TROPHOBLAST PROGENITORS ENSURES ESTABLISHMENT OF DIFFERENTIATED SYNTBS AND INVASIVE TROPHOBLAST CELLS AT THE MATERNAL-FETAL INTERFACE. IN AIM 2, USING CTB-DERIVED HUMAN TROPHOBLAST STEM CELLS, WE WILL TEST THE HYPOTHESIS THAT LSD1 ESTABLISHES A CONSERVED GENE EXPRESSION PROGRAM IN MOUSE AND HUMAN TROPHOBLAST PROGENITORS AND IMPAIRMENT OF LSD1-DEPENDENT TRANSCRIPTIONAL PROGRAM WILL IMPAIR SELF-RENEWAL AND DIFFERENTIATION POTENTIAL OF HUMAN TROPHOBLAST PROGENITORS. IN ADDITION, WE WILL ALSO INTERROGATE SIGNIFICANCE OF LSD1-DEPENDENT MECHANISMS IN THE CONTEXT OF PATHOLOGICAL PREGNANCIES.

ROLE OF TRANSLATIONAL FIDELITY IN CELLULAR PHYSIOLOGY OF ORAL STREPTOCOCCI - ABSTRACT RIBOSOMES ARE COMPOSED OF RIBONUCLEOPROTEINS AND ARE ESSENTIAL FOR PROTEIN BIOSYNTHESIS, WHICH IS ONE OF THE MOST COMPLEX BIOLOGICAL PROCESSES IN THE CELL. IN PROKARYOTES, MATURE RIBOSOMES CONTAIN PROTEINS (R- PROTEINS) AND RNA (RRNA) THAT ARE ASSEMBLED INTO THE MATURE 70S RIBOSOME. THE 70S RIBOSOMES ARE MADE BY TWO SUBUNITS, DESIGNATED AS THE 30S (SMALL) AND THE 50S RIBOSOME (LARGE) SUBUNITS. THE SMALL SUBUNIT IS COMPOSED OF THE 16S RIBOSOMAL RNA (RRNA) AND OVER 20 CORE R-PROTEINS WHILE THE LARGE SUBUNIT IS COMPOSED OF 23S AND 5S RRNAS, AND MORE THAN 30 CORE R-PROTEINS. RIBOSOME IS NOT A STATIONARY ENTITY, RATHER IT IS ADAPTED TO CHANGING ENVIRONMENTS GIVING RISE TO RIBOSOME HETEROGENEITY. ADDITIONALLY, SEVERAL SMALL ACCESSORY PROTEINS MODULATE THE BIOGENESIS, RECYCLING, AND FUNCTION OF THE RIBOSOME; MANY OF THESE PROTEINS AND THEIR MOLECULAR FUNCTIONS REMAIN TO BE DISCOVERED. DURING PROTEIN SYNTHESIS, TRANSLATIONAL FIDELITY IS MAINTAINED WITH HIGH ACCURACY. HOWEVER, THE AVERAGE TRANSLATION ERROR RATE IS RELATIVELY HIGHER (10-4 TO 10-3 PER CODON) COMPARED TO TRANSCRIPTION OR REPLICATION ERROR RATES. MAINTAINING PROPER TRANSLATIONAL FIDELITY REQUIRES COGNATE PAIRING OF AMINO ACIDS AND TRNAS BY AMINOACYL-TRNA (AA-TRNA) SYNTHETASE AND ACCURATE DECODING OF MRNA CODONS BY THE CORRESPONDING AA- TRNAS ON THE RIBOSOME. SEVERAL CORE AND ACCESSORY R-PROTEINS DRIVE THE CORRECT DECODING OF THE CODONS TO MAINTAIN THE TRANSLATIONAL FIDELITY. VARIOUS STRESS CONDITIONS SUCH AS NUTRITIONAL AND OXIDATIVE STRESSES OFTEN LEAD TO MISTRANSLATION AND GROWTH DEFECTS IN BACTERIA. WE HAVE RECENTLY IDENTIFIED SEVERAL FACTORS INCLUDING A CONSERVED NOVEL PROTEIN, SPRV (90 AMINO ACIDS), IN STREPTOCOCCUS MUTANS (AN ORAL PATHOGEN) THAT IS REQUIRED FOR TRANSLATIONAL FIDELITY, STRESS TOLERANCE AND ADAPTATION. THE MAJOR GOAL OF THIS STUDY IS TO UNDERSTAND AT THE MOLECULAR LEVEL HOW SPRV AND OTHER ACCESSORY PROTEINS SUCH AS L9 (R-PROTEIN) AND EF-P MODULATE TRANSLATIONAL FIDELITY TO ALTER PHYSIOLOGY AND BIOLOGICAL FITNESS OF ORAL STREPTOCOCCI.

DEFINING THE MECHANISM OF MEIOTIC INITIATION THROUGH AUTOPHAGY PATHWAY

TAILORED TOUCHSCREEN COLORECTAL CANCER PREVENTION IN AMERICAN INDIAN COMMUNITIES

MONOLINGUAL AND BILINGUAL READING COMPREHENSION IN MIDDLE SCHOOL STUDENTS

EXPLOITING BIOLOGICAL NETWORKS TO IMPROVE CLINICAL TREATMENT OF OVARIAN CANCER

REACH FOR EQUITY IN SOUTHWEST KANSAS

FERTILIZATION-INDUCED MATURATION OF CORTICAL ER CLUSTERS IN OOCYTES; IMPACT OF MATERNAL AGE - PROJECT SUMMARY/ABSTRACT CORTICAL ER STRUCTURE IS A KEY ASPECT OF OOCYTE QUALITY AS EXEMPLIFIED IN MAMMALS WHERE UNIQUE `ER CLUSTERS' BECOME POSITIONED IN CLOSE PROXIMITY TO THE PLASMA MEMBRANE (PM). OUR RECENT IN VIVO STUDIES DEMONSTRATE THE PRESENCE OF HERETO UNKNOWN ACTIN FENESTRAE WITHIN CORTICAL ACTIN LAYER, IN ADDITION THE ER CLUSTERS WERE CENTRALLY LOCATED WITHIN THESE FENESTRAE AND SPERM BINDING OCCURRED PREFERENTIALLY OVER THESE FENESTRAE. ANOTHER NOVEL OBSERVATION WAS THAT UPON SPERM FUSION THE OOCYTE ER CLUSTERS UNDERGO A MATURATIONAL EVENT INVOLVING AN INCREASE IN VOLUME, DOCKING TO FENESTRAE IN THE ACTIN LAYER. THIS LED US TO A HYPOTHESIS THAT THE PM OVERLYING ER CLUSTERS IS ENRICHED IN SPERM BINDING PROTEINS THAT PROMOTE CLOSE INTERACTION BETWEEN THE SPERM, OOCYTE PM, AND THE ER CLUSTER. TEMPORAL AND MECHANISTIC STUDIES ARE NECESSARY TO ELUCIDATE THE ROLE OF THE OOCYTE CORTICAL ACTIN FENESTRAE IN THE ESTABLISHMENT OF SPERM BINDING SITES AS WELL AS THE ROLE OF THE SPERM PLC RELEASED FROM THE SPERM HEAD IN MEDIATING THE ER CLUSTER MATURATIONAL CHANGES. THE PRESENCE OF UNIQUE ACTIN FENESTRAE LED TO A SECOND HYPOTHESIS THAT ACTIN REMODELING PROTEINS, RHOA AND CDC42, COULD MODULATE SPERM BINDING SITES, CORTICAL ER CLUSTER FORMATION VIA THE ACTIN FENESTRAE. LASTLY, WE OBSERVED THAT OOCYTES FROM AGED FEMALE MICE EXHIBITED ABNORMAL ER STRUCTURE AND VARIED CONSIDERABLY IN THEIR ABILITY TO FORM ER CLUSTERS IN RESPONSE TO FERTILIZATION. THIS FINDING LED US TO PROPOSE A THIRD HYPOTHESIS WHERE MATERNAL AGING DISRUPTS ACTIN FENESTRAE AND CA2+ OSCILLATIONS, CAUSING DEFECTS IN ER CLUSTER MATURATION AND REDUCED FERTILITY. OUR FINDINGS SUGGEST A NEW PARADIGM WHEREIN THE OOCYTE RESPONDS TO SPERM BINDING/FUSION BY ER CLUSTER MATURATION, THEN ESTABLISHES CLOSE INTERACTION WITH THE SPERM DURING ITS INCORPORATION INTO THE EGG. TESTING OF THE HYPOTHESES PRESENTED IN THIS PROPOSAL WILL LEAD TO AN ENHANCED UNDERSTANDING OF THE FERTILIZATION PROCESS, AND POTENTIAL MECHANISMS FOR IMPROVING ASSISTED REPRODUCTION TECHNOLOGIES SUCH AS ICSI AND PROTOCOLS FOR REPRODUCTIVELY AGED OOCYTES AS WELL AS POTENTIAL NEW CONTRACEPTIVE TARGETS THAT BLOCK FERTILIZATION.

ROLE OF ARGININE METHYLATION IN ALCOHOL PATHOGENESIS

ROLES OF PEROXISOMAL DYSFUNCTION IN ALCOHOL-RELATED LIVER DISEASE - PROJECT SUMMARY / ABSTRACT ALCOHOL-RELATED LIVER DISEASE (ALD) HAS BEEN AMONG THE LEADING CAUSES OF MORBIDITY AND MORTALITY WORLDWIDE. HOWEVER, THE PATHOGENETIC MECHANISMS IN ALD ARE NOT WELL UNDERSTOOD AND, AS SUCH, THERE IS AN ABSENCE OF PROVEN THERAPIES. EMERGING EVIDENCE NOW SUGGESTS THAT BILE ACID ABNORMALITIES PLAY A CAUSATIVE ROLE IN THE PATHOGENESIS OF ALD. PEROXISOMES ARE DYNAMIC ORGANELLES CONTROLLING CELLULAR METABOLIC PROCESSES, INCLUDING BILE ACID SYNTHESIS. ALTHOUGH EARLY STUDIES HAVE IMPLICATED PEROXISOMAL DAMAGE UPON ALCOHOL EXPOSURE, THE SIGNIFICANCE OF PEROXISOMES IN ALD IS STILL BEING UNDERESTIMATED, LEAVING KNOWLEDGE ABOUT THE MOLECULAR MECHANISMS OF PEROXISOMAL PERTURBATION AND ITS METABOLIC CONSEQUENCE, SUCH AS BILE ACID DISORDER, UPON ALCOHOL INTOXICATION REMAIN RUDIMENTARY. THUS, THE OBJECTIVE OF THIS APPLICATION IS TO OVERCOME THIS KNOWLEDGE GAP BY DETERMINING THE LINK BETWEEN PEROXISOMAL DYSFUNCTION, THE CONSEQUENT BILE ACID DISORDER, AND THE DEVELOPMENT OF ALD. OUR PRELIMINARY STUDIES SUGGEST THAT ALCOHOL EXPOSURE DECREASES HEPATIC PEROXISOMAL BIOGENESIS IN A MANNER DEPENDENT ON A KEY PEROXIN, PEX3, IN BOTH ALCOHOL-FED MICE AND PATIENTS WITH ALCOHOLIC HEPATITIS. USING A UNIQUE MOUSE MODEL OF HEPATOCYTE-SPECIFIC PEROXISOME DEFICIENCY (PEX3 KNOCKOUT), WE FOUND THAT PEROXISOMES ARE CRITICAL FOR BILE ACID SYNTHESIS AND THAT PEX3 REDUCTION CAUSES SYSTEMIC ACCUMULATION OF TOXIC BILE ACID INTERMEDIATES AND INCREASED SUSCEPTIBILITY TO ALCOHOL. BY PURSUING THE MOLECULAR MECHANISM THROUGH WHICH PEROXISOMAL DYSFUNCTION CAUSES LIVER DAMAGE, WE FOUND THAT PEROXISOME AFFECTS MITOCHONDRIAL AND ER DYNAMICS, AT LEAST PARTIALLY, THROUGH BILE ACID INTERMEDIATES. MOREOVER, WE FOUND A STRONG INDUCTION OF LIPOCALIN 2 IN ALD PATIENTS AND MICE AS WELL AS IN PEX3 KNOCKOUT MICE. FURTHER KNOCKOUT OF LCN2 IN PEX3 KNOCKOUT MICE AMELIORATES PEX3 DEFICIENCY-INDUCED LIVER INJURY. THESE DATA LED US TO HYPOTHESIZE THAT ALCOHOL EXPOSURE INDUCES PEROXISOMAL DYSFUNCTION AND THE ACCUMULATION OF TOXIC BILE ACID INTERMEDIATES VIA TARGETING PEX3, WHICH IN TURN, PROMOTES THE DEVELOPMENT OF ALD. WE PROPOSE THREE SPECIFIC AIMS TO TEST THE HYPOTHESES. STUDIES IN AIM 1 WILL DETERMINE THE ROLE OF HEPATOCYTE PEX3 REDUCTION IN THE PATHOGENESIS OF ALD USING PEX3 KNOCKOUT AND ALCOHOL INTOXICATION MOUSE MODELS; AIM 2 WILL CHARACTERIZE THE TOXICITY OF BILE ACID INTERMEDIATES IN THE DEVELOPMENT OF ALD AT THE GUT-LIVER AXIS; AIM 3 WILL EXPLORE THE ROLE OF HEPATOCYTE LCN2 IN PEROXISOMAL DYSFUNCTION-INDUCED LIVER DAMAGE IN ALD. KNOWLEDGE OBTAINED FROM THE STUDY WILL REFINE THE IMPORTANCE OF FUNCTIONAL PEROXISOMES IN MAINTAINING BILE ACID HOMEOSTASIS TO COMBAT AGAINST TOXIC STIMULI, SUCH AS ALCOHOL. THE PROJECT IS EXPECTED TO HAVE AN IMPORTANT IMPACT BY DEFINING NEW MOLECULAR TARGETS FOR THE PREVENTION AND/OR TREATMENT OF ALD AND ITS COMPLICATIONS.