Tufts Medical Center Parent Inc

VITAMIN D AND TYPE 2 DIABETES (D2D)

IMPROVING MEDICAL DECISION MAKING FOR OLDER PATIENTS WITH END STAGE RENAL DISEASE

TRIP-PCI: PAR1 PEPDUCIN-BASED INTERVENTIONS IN ARTERIAL THROMBOSIS

PRECISION MEDICINE IN THE DIAGNOSIS OF GENETIC DISORDERS IN NEONATES

THE ROLE OF VASCULAR MR-REGULATED GENES IN VASCULAR FUNCTION AND DISEASE

SMOOTH MUSCLE MINERALOCORTICOID RECEPTORS IN VASCULAR AGING AND HYPERTENSION

POLYCYSTIC KIDNEY DISEASE CLINICAL TRIALS NETWORK

REMOTE TAI CHI FOR KNEE OSTEOARTHRITIS: AN EMBEDDED PRAGMATIC TRIAL - PROJECT SUMMARY/ABSTRACT SYMPTOMATIC OSTEOARTHRITIS (OA) AFFECTS OVER 32.5 MILLION INDIVIDUALS IN THE U.S. AND IS A LEADING CAUSE OF DISABILITY AND INCREASING MEDICAL COSTS. TOXICITIES ASSOCIATED WITH DRUG THERAPIES FOR KNEE OA PAIN HAVE CAUSED THE NUMBER OF RECOMMENDED TREATMENTS TO DECREASE OVER TIME. THERE IS NOW A CRITICAL SHORTAGE OF TREATMENT OPTIONS FOR PEOPLE WITH KNEE OA, ESPECIALLY BECAUSE COMORBIDITIES THAT COMPLICATE TREATMENT SELECTION ARE HIGHLY PREVALENT IN THIS OLDER ADULT POPULATION. TAI CHI, A MULTI-DIMENSIONAL PRACTICE THAT INTEGRATES PHYSICAL, PSYCHOSOCIAL, AND BEHAVIORAL COMPONENTS, HAS EXHIBITED CLINICALLY SIGNIFICANT IMPROVEMENTS IN CHRONIC KNEE OA PAIN CONDITIONS. THE AMERICAN COLLEGE OF RHEUMATOLOGY CLINICAL PRACTICE GUIDELINES STRONGLY RECOMMEND TAI CHI AS AN INTERVENTION FOR KNEE OA. RECENT STUDIES CONDUCTED DURING THE PANDEMIC SUGGEST THAT REMOTELY DELIVERED TAI CHI IS A PROMISING AND SCALABLE STRATEGY FOR KNEE OA PAIN. HOWEVER, CRITICAL GAPS REMAIN AS TO THE REAL-WORLD EFFECTIVENESS OF REMOTE TAI CHI FOR KNEE OA AND ITS IMPLEMENTATION ACROSS MULTIPLE HEALTH CARE SYSTEMS. WE PROPOSE AN EMBEDDED, PRAGMATIC, RANDOMIZED TRIAL THAT WILL COMPARE THE EFFECTS OF A 3-MONTH TWICE WEEKLY REMOTELY DELIVERED WEB-BASED TAI CHI INTERVENTION VERSUS ROUTINE CARE ACROSS FOUR HEALTH CARE SYSTEMS (TUFTS MEDICAL CENTER, BOSTON MEDICAL CENTER, UNIVERSITY OF CALIFORNIA LOS ANGELES HEALTH, AND CLEVELAND CLINIC OHIO AND CLEVELAND CLINIC FLORIDA) IN FOUR GEOGRAPHIC REGIONS (EASTERN MASSACHUSETTS, SOUTHERN CALIFORNIA, NORTHEAST OHIO, SOUTHERN FLORIDA). WE WILL ENROLL 480 PATIENTS WITH A CLINICAL DIAGNOSIS OF KNEE OA. PARTICIPANTS WILL BE EVALUATED AT BASELINE AND 3 MONTHS, WITH ADDITIONAL FOLLOW-UP AT 6 AND 12 MONTHS. WE HYPOTHESIZE THAT IMPLEMENTATION OF REMOTELY DELIVERED TAI CHI IS FEASIBLE ACROSS FOUR HEALTH CARE SYSTEMS AND THAT TAI CHI, COMPARED TO ROUTINE CARE, WILL IMPROVE PHYSICAL HEALTH (INCLUDING KNEE-RELATED PAIN AND FUNCTION) AND MENTAL HEALTH AS WELL AS HEALTHCARE UTILIZATION. OUR INNOVATIVE STUDY IS THE FIRST RIGOROUS MULTI-SITE PRAGMATIC TRIAL OF A REMOTE TAI CHI, IN THE MULTIPLE HEALTH CARE SYSTEMS UTILIZING WEB-BASED TECHNOLOGY. IT IS DESIGNED TO IMPROVE PATIENT CENTERED OUTCOMES OF KNEE OA. THE RESULTS WILL ENABLE WIDESPREAD ADOPTION OF MIND-BODY APPROACHES FOR KNEE OA ACROSS HEALTH CARE SYSTEMS AND LAY THE GROUNDWORK FOR FUTURE TRIALS COMPARING THE EFFECTIVENESS OF DIFFERENT IMPLEMENTATION STRATEGIES.

MEETING THE CHALLENGES OF COVID-19 BY EXPANDING THE REACH OF PALLIATIVE CARE: PROACTIVE ADVANCE CARE PLANNING WITH VIDEOS FOR THE ELDERLY AND ALL PATIENTS WITH DEMENTIA - THE MAJORITY OF PATIENTS AGED 65 OR OVER, AND PATIENTS WITH ALZHEIMER'S DISEASE AND RELATED DEMENTIAS (ADRD), HAVE NEVER COMMUNICATED THEIR PREFERENCES TO CLINICIANS OR COMPLETED ADVANCE CARE PLANNING (ACP) DOCUMENTS. PALLIATIVE CARE HAS THE POTENTIAL TO IMPROVE ADRD CARE, IMPROVE PATIENT-CLINICIAN COMMUNICATION AND PATIENT-CENTERED OUTCOMES, WHILE DECREASING UNWANTED BURDENSOME TREATMENTS AND IMPROVING CARE AT THE END OF LIFE. THE NOVEL CORONAVIRUS DISEASE 2019 (COVID-19) HAS ACUTELY ESCALATED THE IMPORTANCE OF INTEGRATING ACP AND PALLIATIVE CARE SERVICES INTO MEDICAL CARE. THE DEFAULT RESPONSE TO CRITICAL ILLNESS FOR PATIENTS WITH ADRD (AND ALL OTHERS) IS INTUBATION, MECHANICAL VENTILATION, AND AGGRESSIVE CARE DESPITE HAVING NO CHANGE IN MORTALITY OUTCOME. ADRD PATIENTS AND THEIR CAREGIVERS MAY PREFER TO AVOID THESE INTERVENTIONS. TO ADDRESS THESE GAPS, WE HAVE DEVELOPED A COVID-19 ACP EDUCATOR-LED, VIDEO-ASSISTED PALLIATIVE CARE INTERVENTION TO IMPROVE PATIENT-CLINICIAN COMMUNICATION, INCREASE ACP DOCUMENTATION, AND LEAD TO MORE PATIENT-CENTERED CARE AT THE END OF LIFE. WE WILL IDENTIFY ALL HOSPITALIZED PATIENTS AGED 65 AND OLDER, AND ANY PATIENT WITH ADRD, AND THEN AN ACP EDUCATOR WILL PROACTIVELY PROCEED WITH PRIMARY PALLIATIVE CARE SERVICES OF ACP, LEVERAGING CERTIFIED VIDEO DECISION AIDS THAT WE HAVE DEVELOPED. THE ACP EDUCATOR TO BE TESTED IN THIS PROPOSAL REPRESENTS A NEW ROLE AND PROACTIVE FUNCTION FOR THE PALLIATIVE CARE TEAM. THE ACP EDUCATOR, WHO WILL BE A PALLIATIVE CARE NURSE, WILL WORK WITH OLDER PATIENTS OR PATIENTS WITH ADRD AND PROXY DECISION-MAKERS TO LEARN ABOUT AND DOCUMENT PATIENTS' WISHES. THE OVERALL OBJECTIVE IS TO REDUCE THE BURDEN OF COVID-19 BY EXPANDING THE REACH OF INPATIENT PALLIATIVE CARE, ESPECIALLY FOR PATIENTS WITH ADRD. WE PROPOSE TO CONDUCT A STEPPED WEDGE CLUSTER RANDOMIZED TRIAL OF AN ACP EDUCATOR INTERVENTION AMONG HOSPITALIZED PATIENTS AGED 65 AND OVER, OR ANY PATIENT WITH ADRD AND THEIR PROXY DECISION-MAKERS IN THE WARD AND ICU SETTINGS OF TWO MAJOR HOSPITALS: BOSTON MEDICAL CENTER AND NORTH SHORE UNIVERSITY HOSPITAL. PATIENT OUTCOMES WILL BE ABSTRACTED FROM ELECTRONIC HEALTH RECORDS WITH NATURAL LANGUAGE PROCESSING. WE WILL EVALUATE INTERVENTION EFFECTIVENESS BY COMPARING THE FOLLOWING OUTCOMES AMONG 9,000 HOSPITALIZED PATIENTS: ACP DOCUMENTATION; PREFERENCES FOR RESUSCITATION; PALLIATIVE CARE CONSULTS; AND, HOSPICE USE. WE WILL CHARACTERIZE CAREGIVER-CENTERED OUTCOMES OF PATIENTS WITH ADRD, INCLUDING: (1) KNOWLEDGE, (2) CONFIDENCE IN FUTURE CARE, (3) COMMUNICATION SATISFACTION, AND (4) DECISIONAL CERTAINTY IN 600 CAREGIVERS OF PATIENTS WITH ADRD ADMITTED TO THE HOSPITAL. COVID-19 POSES A UNIQUE DILEMMA FOR OLDER AMERICANS AND PATIENTS WITH ADRD AND THEIR CAREGIVERS, WHO MUST BALANCE THEIR DESIRE TO LIVE AGAINST THE RISK OF A LONELY AND POTENTIALLY TRAUMATIC HOSPITAL DEATH. VIDEO DECISION SUPPORT IS A PRACTICAL, EVIDENCE- BASED, AND INNOVATIVE APPROACH TO ASSIST PATIENTS FACING SUCH CHOICES. IF PROVEN EFFECTIVE, THIS INNOVATIVE CARE MODEL CAN BE IMMEDIATELY DEPLOYED ACROSS THE COUNTRY TO IMPROVE THE QUALITY OF CARE FOR MILLIONS OF AMERICANS.

N-GLYCOSYLATION AND OCULAR SURFACE HOMEOSTASIS

I KUA NA'U "LET ME CARRY OUT YOUR LAST WISHES" ADVANCE CARE PLANNING FOR NATIVE HAWAIIAN ELDERS

MULTILEVEL PHYSICAL ACTIVITY INTERVENTION FOR LOW INCOME PUBLIC HOUSING RESIDENTS - PROJECT SUMMARY PHYSICAL ACTIVITY HAS BEEN ASSOCIATED WITH SEVERAL CHRONIC DISEASE MARKERS FOR THE PAST 25 YEARS, AND COUNTLESS STUDIES HAVE TESTED INTERVENTIONS TO IMPROVE PHYSICAL ACTIVITY OF SEDENTARY POPULATIONS. MOST OF THESE INTERVENTION STUDIES HAVE ATTEMPTED TO IMPROVE PHYSICAL ACTIVITY BEHAVIORS BY CHANGING INDIVIDUAL LEVEL DRIVERS OF ACTIVITY, LIKE MOTIVATION, ATTITUDES, AND SELF-EFFICACY FOR BEING ACTIVE. UNFORTUNATELY, THESE EFFORTS TO CHANGE ACTIVITY LEVELS ARE OFTEN NOT SUSTAINED BEYOND THE INITIAL INTERVENTION PERIOD. ONE POSSIBLE CAUSE OF THIS LACK OF SUSTAINABILITY IS THAT INSUFFICIENT ATTENTION WAS PAID TO ENVIRONMENTAL FACTORS THAT FACILITATE PHYSICAL ACTIVITY. THUS, ATTENTION IS SHIFTING TO MORE COMPLEX ENVIRONMENTAL AND SOCIAL CONTRIBUTIONS TO PHYSICAL ACTIVITY, WITH THE AIM OF IDENTIFYING MULTI-LEVEL STRATEGIES TO BETTER TARGET INTERVENTIONS TO GROUPS THAT NEED HELP. VERY FEW TESTS OF CHANGING ENVIRONMENT LEVELS TO INCREASE PHYSICAL ACTIVITY EXIST IN THE LITERATURE. A FOCUS ON INTERVENTIONS AT ENVIRONMENTAL LEVELS, AS CALLED FOR BY RECENT REVIEWS AS WELL AS REPORTS FROM THE INSTITUTE OF MEDICINE, MIGHT PROVIDE THE LONG-TERM SUSTAINABLE CHANGE THAT IS NEEDED TO CHANGE PHYSICAL ACTIVITY IN LOW-INCOME POPULATIONS. THIS PROJECT SEEKS TO TEST A NEW MULTI-LEVEL, MULTI-COMPONENT PACKAGE TO INCREASE MODERATE INTENSITY PHYSICAL ACTIVITY LEVELS OF PEOPLE LIVING IN PUBLIC HOUSING DEVELOPMENTS. OUR AIMS ARE TO EVALUATE THE EFFECTS OF AN INTERVENTION PACKAGE FOCUSED ON THE ENVIRONMENT LEVEL TO PRODUCE CHANGES IN MODERATE PHYSICAL ACTIVITY AMONG PUBLIC HOUSING RESIDENTS. FURTHERMORE, WE WILL EVALUATE THE ADDED EFFECTS OF AN EFFICACY-TESTED INDIVIDUAL-LEVEL EHEALTH PHONE PROGRAM TO PRODUCE FURTHER CHANGES IN MODERATE INTENSITY PHYSICAL ACTIVITY. THE DESIGN OF THIS STUDY IS A PROSPECTIVE, CLUSTER RANDOMIZED CONTROLLED TRIAL, WITH HOUSING DEVELOPMENTS AS THE UNITS OF RANDOMIZATION. IN THIS FOUR GROUP, FACTORIAL, CLUSTER RANDOMIZED CONTROLLED TRIAL, WE WILL COMPARE AN ENVIRONMENTAL INTERVENTION ALONE (E ONLY), AN INDIVIDUAL INTERVENTION ALONE (I ONLY), AN ENVIRONMENTAL PLUS INDIVIDUAL INTERVENTION (E+I), ALL AGAINST A CONTROL GROUP. MEDIATION AND MODERATION OF OUR INTERVENTION WILL BE ASSESSED. LASTLY, WE WILL ASSESS FACTORS FROM THE CONSOLIDATED FRAMEWORK FOR IMPLEMENTATION RESEARCH DOMAINS TO EXAMINE FUTURE IMPLEMENTATION OF A MULTI-LEVEL PHYSICAL ACTIVITY INTERVENTION AMONG KEY INFORMANTS IN PUBLIC HOUSING DEVELOPMENTS.

MODELING MULTI-SOURCE DATA IN HODGKIN LYMPHOMA - ABSTRACT HODGKIN LYMPHOMA (HL) IS ASSOCIATED WITH EXCELLENT CURE RATES. DESPITE EARLY DISEASE CONTROL, THIS SUCCESS COMES AT CONSIDERABLE COST, WITH TREATMENT-INDUCED MORBIDITY (“LATE EFFECTS” [LE]) THAT MANIFESTS AS EARLY AS A YEAR AFTER THERAPY (E.G., 2ND CANCERS, CARDIOVASCULAR [CVD] DISEASE), COMPROMISED HEALTH-RELATED QUALITY OF LIFE (HRQL), AND EARLY MORTALITY. OVER THE PAST 20 YEARS, WHILE IMPORTANT HL CLINICAL TRIALS HAVE BEEN CONDUCTED, THERE HAS BEEN A LACK OF CONSENSUS ABOUT THE PREFERRED APPROACH TO TREATMENT, CONSIDERING BOTH SHORT- AND LONGER TERM OUTCOMES. WHILE CLINICAL TRIALS PROVIDE RICH INFORMATION ABOUT SHORT TERM DISEASE OUTCOMES, THEY DO NOT FOLLOW EFFICACY BEYOND 5 YEARS AND RARELY TRACK POST-THERAPY MORBIDITY. IN CONTRAST, HL REGISTRIES CAPTURE LONGITUDINAL OUTCOMES AND CAN BE LINKED TO OTHER SOURCES INCLUDING HEALTHCARE UTILIZATION VIA ADMINISTRATIVE CLAIMS AND CANCER REGISTRIES TO CHARACTERIZE LE AND SURVIVAL. THIS PROPOSAL REPRESENTS AN UNPRECEDENTED OPPORTUNITY TO DRAW ON THE COLLECTIVE EXPERTISE OF INTERNATIONAL CLINICAL HL ONCOLOGY EXPERTS, EPIDEMIOLOGISTS, IMAGING EXPERTS, AND METHODS & MODELING EXPERTS WITH ACCESS TO INDIVIDUAL PATIENT DATA FROM MODERN HL CLINICAL TRIALS AND REAL-WORLD REGISTRIES FROM ACROSS THE WORLD. IN PREPARATION FOR THE PROJECT, WE HARMONIZED INDIVIDUAL PATIENT DATA (IPD) FOR >12,000 HL PATIENTS FROM 12 CLINICAL TRIALS AND 4 LARGE HL REGISTRIES. BUILDING ON DATA SCIENCE PRINCIPLES, WE ESTABLISHED A COMMON DATA MODEL & UNIFYING DATA DICTIONARY, WHICH ALLOWS US TO EXPAND THE CURRENT DATABASE OVER TIME, INCORPORATING FUTURE DATA AS THEY BECOME AVAILABLE. WE WILL HARNESS THESE MULTI- SOURCE DATA TO FIRST, CREATE A MODERN PREDICTION MODEL VIA PREDICTIVE MODELING OF PRE-TREATMENT CLINICAL FACTORS; SECOND, WE WILL ESTIMATE AND VALIDATE DISEASE PROGRESSION AND EARLY EMERGENT LATE EFFECTS, ENHANCED BY THE ADDITION OF INTERIM PET IMAGING DATA AND ALTERNATIVE TREATMENT OPTIONS VIA MULTI-STATE COX PROPORTIONAL HAZARDS MODELS TO ESTIMATE TRANSITION PROBABILITIES; AND THIRD, WE WILL GENERATE A DYNAMIC DECISION MODEL TO PROJECT PRECALCULATED OUTCOMES OF INTEREST, SUCH AS SHORT TERM AND LONGER TERM OUTCOMES, INCLUDING HRQL, THE AGGREGATED, “STANDARDIZED” PRECALCULATED VISUALIZATIONS/PROJECTIONS (LIFE EXPECTANCE AND QUALITY-ADJUSTED LIFE YEARS) WILL PROVIDE A BASIS FOR COMPARING ALTERNATIVE TREATMENTS FOR A BROAD RANGE OF DISEASE SUBGROUPS AND PATIENT CHARACTERISTICS “ON THE FLY.” FURTHERMORE, BOTH THE RESULTS OF THE STATISTICAL MODELS & PARAMETER ESTIMATES FROM THE SIMULATION MODEL WILL BE VALIDATED AND RE-CALIBRATED AS NEEDED IN LARGE EXTERNAL COHORTS (I.E., GERMAN HODGKIN STUDY GROUP (GHSG) CLINICAL TRIALS DATA AND DUTCH HL REGISTRY). THE SIMULATION MODEL WILL THEN BE CONVERTED TO OPEN SOURCE, WHICH WILL ALLOW LOCAL ANALYSES THAT GO BEYOND OUR PRECALCULATED STANDARD SCENARIOS. OUR THREE-STEP APPROACH (PREDICTIVE MODELING TO MULTI-STATE MODELING TO SIMULATION/DECISION MODELING) WILL BE DESIGNED TO INCORPORATE FUTURE PROSPECTIVE DATA AS NEW/NOVEL TREATMENTS, AND KNOWLEDGE EMERGES OVER TIME. OVERALL, THIS PROJECT’S RESULTS WILL BE SIGNIFICANT AS THEY ARE EXPECTED TO DELINEATE PRECISE OUTCOMES & OPTIMAL THERAPY FOR INDIVIDUAL HL PATIENTS AND INFORM THE DEVELOPMENT OF MODELS AND PARADIGMS FOR OTHER DISEASES.

LIFESTYLE INTERVENTION IN PREPARATION FOR PREGNANCY (LIPP)

DIGITAL HEALTH SUPPORTED WEIGHT MANAGEMENT INTERVENTION DELIVERED BY COMMUNITY HEALTH WORKERS AMONG PUBLIC HOUSING RESIDENTS

IMPROVING PRO INTERPRETATION AT THE INDIVIDUAL LEVEL FOR PATIENTS WITH CANCER USING CONVERSATIONAL AGENTS AND DATA VISUALIZATION - THERE IS INCREASING RECOGNITION OF THE IMPORTANCE OF PATIENT-REPORTED OUTCOMES (PROS) FOR ASSESSMENT OF HEALTH- RELATED QUALITY OF LIFE IN BOTH RESEARCH AND CLINICAL SETTINGS. PROS ARE ESPECIALLY IMPORTANT FOR INHERENTLY SUBJECTIVE BUT CRUCIAL CLINICAL PHENOMENA SUCH AS PAIN, MOOD, AND FATIGUE. DESPITE MUCH RESEARCH IN PROS, CONCERNS ABOUT RELIABILITY AND VALIDITY PERSIST, ESPECIALLY WHEN USED AT THE INDIVIDUAL LEVEL, PARTICULARLY AMONG PATIENTS WHO MAY STRUGGLE TO UNDERSTAND PRO QUESTIONS, SUCH AS THOSE WITH LOW HEALTH LITERACY OR UNDETECTED COGNITIVE IMPAIRMENT. OVER THE PAST DECADE, WE HAVE DEVELOPED AND TESTED A TOOL WITH THE POTENTIAL TO ENHANCE PROS AT THE INDIVIDUAL LEVEL – EMBODIED CONVERSATIONAL AGENTS (ECA), WHICH ARE COMPUTER CHARACTERS THAT SIMULATE FACE- TO-FACE CONVERSATION USING VOICE, HAND GESTURES, GAZE CUES AND OTHER NONVERBAL BEHAVIOR. WE HAVE SUCCESSFULLY USED THEM IN BEHAVIORAL INTERVENTIONS FOR POPULATIONS WITH LIMITED HEALTH LITERACY, ELDERLY PATIENTS, AND PATIENTS WITH CANCER. FACE-TO-FACE ENCOUNTERS, IN CONJUNCTION WITH WRITTEN INSTRUCTIONS SUPPORTED BY PICTURES, REMAINS ONE OF THE BEST METHODS FOR COMMUNICATING INFORMATION IN GENERAL, BUT IS PARTICULARLY EFFECTIVE FOR INDIVIDUALS WITH LIMITED HEALTH LITERACY. WE HAVE ALSO DEMONSTRATED THAT ECAS CAN BE USED AS VALID ALTERNATIVES TO STANDARD PAPER-BASED SURVEYS FOR SUBSTANCE USE SCREENING, AND THAT THE DISPLAY OF EMPATHY FOR PATIENTS AND OTHER RELATIONAL BEHAVIOR BY ECAS LEADS TO INCREASED ENGAGEMENT BY PATIENTS OVER TIME. WE WILL ADAPT OUR PRIOR WORK ON ECAS TO PRODUCE ECA-PRO, A FRAMEWORK FOR ADMINISTERING PROS OVER TIME USING AN ECA ON PATIENTS’ SMARTPHONES IN ENGLISH AND SPANISH. THE ECA-PRO SYSTEM WILL INCLUDE NOVEL USER INTERFACES TO OPTIMALLY COMMUNICATE THE RESULTS TO PATIENTS AND CLINICIANS USING CLEAR VISUALIZATIONS. TO DEMONSTRATE THE GENERALIZABILITY OF ECA-PRO, WE WILL FOCUS ON TWO CLINICAL SCENARIOS: 1) LONGITUDINAL MONITORING OF SYMPTOMS AND QUALITY OF LIFE IN PATIENTS UNDERGOING CANCER TREATMENT, AND 2) MONITORING OF MEDICATION ADHERENCE IN PATIENTS TAKING LONG-TERM ORAL ANTI-CANCER DRUGS. WE HYPOTHESIZE THAT THE ECA-PRO SYSTEM, DESIGNED FOR INDIVIDUAL-PATIENT-LEVEL INTERACTIONS AND DATA COLLECTION, WILL IMPROVE THE RELIABILITY, VALIDITY, AND OVERALL CLINICAL RELEVANCE OF PROS COLLECTED DURING CANCER TREATMENT. WE WILL DEVELOP AND EVALUATE A PRO SYSTEM THAT ENGAGES PATIENTS WITH INTERACTIVE COMMUNICATION AND EMPATHY, WHILE DELIVERING STANDARD PROS IN A WAY THAT MINIMIZES MISSING DATA AND ENABLES USER-FRIENDLY VISUAL SHARING OF RESULTS. THE ECA-PRO SYSTEM WILL CREATE A STRONG FOUNDATION FOR PRO-BASED CLINICAL DECISION-MAKING. IF SUCCESSFUL, THESE TOOLS CAN BE RAPIDLY AND BROADLY DISSEMINATED.

NEW APPROACHES TO MITIGATE LEFT VENTRICULAR INJURY WITH VA-ECMO IN ACUTE MYOCARDIAL INFARCTION - THIS NEW RO1 PROPOSAL EXPLORES NOVEL MECHANISMS OF CARDIOPROTECTION INVOLVING VENO-ARTERIAL MEMBRANE OXYGENATION (VA-ECMO) AS A PLATFORM TO REDUCE MYOCARDIAL DAMAGE AFTER ACUTE MYOCARDIAL INFARCTION (AMI). USE OF VA-ECMO HAS GROWN EXPONENTIALLY IN AMI OVER THE PAST DECADE, HOWEVER THE IMPACT OF VA-ECMO ON MYOCARDIAL INJURY HAS NOT BEEN RIGOROUSLY STUDIED. NEW MECHANISTIC INSIGHT INTO THE EFFECT OF VA-ECMO ON REPERFUSION INJURY IS NEEDED. WE RECENTLY REPORTED THE CRITICAL OBSERVATION THAT VA-ECMO INCREASES INFARCT SIZE IN SWINE MODELS OF AMI AND IN NEW DATA HAVE NOW IDENTIFIED A NOVEL PARADIGM WHEREBY VA-ECMO DEPLETES CRITICAL REGULATORS OF MITOCHONDRIAL FUNCTION AND WORSENS HEART DAMAGE IN AMI. BY EMPLOYING HIGHLY TRANSLATIONAL LARGE ANIMAL MODELS AND CLINICALLY RELEVANT INTERVENTIONAL APPROACHES, WE WILL NOW EXPLORE NEW MECHANISMS INVOLVING VA-ECMO AND MYOCARDIAL REPERFUSION INJURY, PROVIDE PENETRATING INSIGHT INTO CARDIOPROTECTION, AND GENERATE PROOF OF CONCEPT DATA FOR THE DEVELOPMENT OF NEW THERAPEUTIC APPROACHES TO LIMIT LEFT VENTRICULAR (LV) INJURY IN AMI. THE PI IS AN INTERVENTIONAL CARDIOLOGIST AND ADVANCED HEART FAILURE SPECIALIST WHO STUDIES MOLECULAR MECHANISMS OF CARDIAC REMODELING, REPERFUSION INJURY, AND THE HEMODYNAMIC EFFECTS OF CIRCULATORY SUPPORT PUMPS. THE CURRENT PROPOSAL INTEGRATES EXPERTISE IN CORONARY AND VENTRICULAR PHYSIOLOGY, MECHANICAL CIRCULATORY SUPPORT, MOLECULAR BIOLOGY, AND INTERVENTIONAL CARDIOLOGY TO THE FIELD OF MYOCARDIAL REPERFUSION INJURY, FOR WHICH NO SPECIFIC THERAPY CURRENTLY EXISTS. WE WILL TEST THE NOVEL HYPOTHESIS THAT VA-ECMO PROMOTES MYOCARDIAL DAMAGE BY WORSENING MYOCARDIAL OXYGEN SUPPLY-DEMAND MISMATCH THROUGH INCREASED LV WALL STRESS AND HYPEROXEMIA-MEDIATED INJURY RESULTING IN LOSS OF MITOCHONDRIAL INTEGRITY AND FURTHER THAT TARGETING THESE MECHANISMS WILL REDUCE INFARCT SIZE IN AMI. EXCITING NEW PRELIMINARY DATA SHOW THAT LV DECOMPRESSION OR TARGETING NORMAL ARTERIAL OXYGEN TENSION DURING VA-ECMO SUPPORT CAN MITIGATE LV INJURY BY REDUCING MYOCARDIAL OXYGEN DEMAND AND INCREASING CORONARY BLOOD FLOW. WE OBSERVED FOR THE FIRST TIME THAT VA-ECMO DECREASES LEVELS OF TAFAZZIN, A KEY ENZYME CONTROLLING MATURATION OF CARDIOLIPIN (CL), A MASTER REGULATOR OF MITOCHONDRIAL INTEGRITY. IN EXCITING NEW FINDINGS, TREATMENT WITH ELAMIPRETIDE, A CL-STABILIZING COMPOUND, BEFORE INITIATION OF VA- ECMO SIGNIFICANTLY REDUCED INFARCT SIZE COMPARED TO REPERFUSION ALONE. THESE PIONEERING APPROACHES ADDRESS MAJOR KNOWLEDGE GAPS BY STUDYING THE EFFECT OF VA-ECMO ON VENTRICULAR LOAD, CORONARY BLOOD FLOW AND OVERCOME CRITICAL BARRIERS ASSOCIATED WITH CARDIOPROTECTION IN AMI. TO TEST OUR HYPOTHESIS WE WILL EMPLOY TRANSLATIONAL STUDIES IN SWINE MODELS TO DETERMINE THE IMPACT OF VA-ECMO ON MYOCARDIAL BLOOD FLOW (SA1), MITOCHONDRIAL INTEGRITY (SA2), AND TO TEST THE THERAPEUTIC UTILITY OF A COMBINED DRUG-DEVICE APPROACH (SA3) TO LIMIT ADVERSE CARDIAC REMODELING AFTER AMI. THIS PROPOSAL HAS TREMENDOUS POTENTIAL TO IMPACT OUR UNDERSTANDING OF CORONARY AND VENTRICULAR PHYSIOLOGY, CIRCULATORY SUPPORT, AND CARDIOPROTECTION WITH IMPORTANT IMPLICATIONS FOR AMI PATIENTS AND FOR ECMO USE IN CARDIAC OR RESPIRATORY FAILURE.

ENABLING COMPARATIVE EFFECTIVENESS RESEARCH IN SILENT BRAIN INFARCTION THROUGH NATURAL LANGUAGE PROCESSING AND BIG DATA

VITAMIN D AND CALCIUM HOMEOSTASIS IN RELATION TO TYPE 2 DIABETES

EFFECT OF INTRA-ARTICULAR STEROIDS ON STRUCTURAL PROGRESSION OF KNEE OA: AN RCT

UNDERSTANDING AND ELIMINATING ONCOGENIC EGFR SIGNALING IN MALIGNANT GLIOMA

CONVERSATIONAL AGENT TO IMPROVE GUIDELINE CONCORDANT CARE FOR PEOPLE WITH CERVICAL CANCER SCREENING ABNORMALITIES - PROJECT SUMMARY / ABSTRACT CERVICAL CANCER IS ALMOST ENTIRELY PREVENTABLE WITH APPROPRIATE SCREENING AND MANAGEMENT OF ABNORMAL RESULTS, YET IN THE US, OVER 14,000 INDIVIDUALS WERE DIAGNOSED WITH CERVICAL CANCER IN 2023, AND OVER 4,000 DIED. BLACK, HISPANIC, AND LOW-INCOME INDIVIDUALS HAVE HIGHER CERVICAL CANCER INCIDENCE AND MORTALITY. OVER 20% OF THOSE DIAGNOSED WITH CERVICAL CANCER DID NOT RECEIVE APPROPRIATE DIAGNOSIS AND TREATMENT AFTER AN ABNORMAL RESULT. THE FDA APPROVED HPV SELF-COLLECTION, A NEW FORM OF SCREENING, IN MAY 2024. SELF-COLLECTION WILL EXPAND ACCESS TO SCREENING, BUT INCREASES BY NEARLY TWOFOLD THE NUMBER OF PATIENTS REQUIRING IMMEDIATE FOLLOW-UP AFTER AN ABNORMAL RESULT. FEAR OF CANCER, POOR COMMUNICATION, AND DIFFICULTY SCHEDULING FOLLOW-UP APPOINTMENTS WERE KEY BARRIERS. EMBODIED CONVERSATIONAL AGENTS (ECAS) ARE ANIMATED COMPUTER CHARACTERS THAT SIMULATE FACE-TO-FACE CONVERSATION BETWEEN A PATIENT AND A CAREGIVER, USING BOTH VERBAL AND NONVERBAL CONVERSATIONAL BEHAVIOR, TO PROVIDE A NATURAL AND INTUITIVE COMPUTER INTERFACE THAT IS ACCESSIBLE TO PATIENTS OF ALL LEVELS OF HEALTH AND COMPUTER LITERACY. WE HAVE SUCCESSFULLY DEVELOPED AND EVALUATED THIS INTERFACE IN SEVERAL CLINICAL TRIALS TO MOTIVATE HEALTH BEHAVIOR CHANGE FOR A WIDE RANGE OF POPULATIONS, INCLUDING A PILOT EVALUATION OF AN ECA THAT PROMOTES HPV VACCINATION FOR THE FAMILIES OF PATIENTS WITH CERVICAL PRE-CANCER AND CANCER. IN THIS PROJECT WE WILL ADAPT THIS TECHNOLOGY TO PRODUCE ENGLISH AND SPANISH SMARTPHONE ECAS FOR FOLLOW-UP OF ABNORMAL CERVICAL CANCER SCREENING RESULTS (ECA-CCSA). THE ECA WILL PROVIDE FOLLOW-UP RECOMMENDATIONS AND MOTIVATIONAL INTERVIEWING TO PATIENTS WITH ABNORMAL SCREENING TEST RESULTS AND WILL FACILITATE COMMUNICATION WITH CLINIC STAFF. FOLLOW-UP PROMOTION OVER TIME CAN LEAD TO COMPLETION OF NEEDED TESTING AMONG THOSE WITH BARRIERS, AND THE ECA CAN CONDUCT REPEATED CONVERSATIONS WITH PATIENTS BOTH PRIOR TO AND FOLLOWING CLINIC VISITS. WE WILL EVALUATE ECA-CCSA IN A RANDOMIZED CONTROLLED TRIAL FOR PATIENTS AGED 21 AND OLDER WITH ABNORMAL SCREENING TEST RESULTS TO EVALUATE ECA-CCSA, COMPARING USUAL CARE (UC) VERSUS USUAL CARE PLUS THE ECA (UC + ECA-CCSA). THE RESEARCH TEAM IS NATIONALLY RECOGNIZED AS LEADERS IN CERVICAL CANCER PREVENTION, HEALTH LITERACY, AND INNOVATIVE TECHNOLOGIES TO IMPROVE HEALTH. THIS STUDY WILL ADVANCE OUR RESEARCH ON THE DEVELOPMENT OF EASY-TO-USE TECHNOLOGIES TO EMPOWER PATIENTS. THIS SCALABLE APPROACH HAS SIGNIFICANT POTENTIAL TO INCREASE FOLLOW-UP AFTER AN ABNORMAL SCREENING TEST RESULT, WHICH IS TIMELY AS CLINICAL SETTINGS ARE CURRENTLY ADOPTING HPV SELF-COLLECTION TECHNOLOGIES. IF SUCCESSFUL, OUR TEAM WILL PROMOTE THE ECA-CCSA THROUGH NATIONAL NETWORKS FOR BROAD IMPLEMENTATION AND WORK TO ADAPT ECA-CCSA TO OTHER LANGUAGES AND SETTINGS.

USE OF DROPLETTE MICROMIST TECHNOLOGY DEVICE (DMTD) FOR DEEP TISSUE TREATMENT OF PRESSURE ULCERS

COMPARATIVE EFFECTIVENESS OF DEVELOPMENTAL-BEHAVIORAL SCREENING INSTRUMENTS

INVESTIGATING MIXED LINEAGE KINASE 3 AS A BLOOD PRESSURE-INDEPENDENT PROTEIN KINASE G1 EFFECTOR IN HEART FAILURE - THE CGMP-DEPENDENT PROTEIN KINASE 1 ALPHA (PKG1A) OPPOSES PATHOLOGICAL LEFT VENTRICULAR (LV) HYPERTROPHY AND REMODELING VIA ROLES IN THE CARDIAC MYOCYTE (CM) AND REGULATES BLOOD PRESSURE BY PROMOTING VASCULAR SMOOTH MUSCLE CELL (VSMC) RELAXATION AND VASODILATION. DRUGS WHICH ACTIVATE PKG1, INCLUDING NITRATES, SACUBITRIL/VALSARTAN, VERICIGUAT, AND OTHERS HAVE IMPROVED MORTALITY IN HEART FAILURE WITH REDUCED LV EJECTION FRACTION (HFREF) AND THUS REPRESENT A CENTRAL ADVANCE IN HFREF TREATMENT. HOWEVER, THESE THERAPIES REMAIN LIMITED BY INCOMPLETE EFFICACY IN HFREF. FURTHERMORE, HYPOTENSION FROM PKG1-INDUCED VASODILATION HAS SEVERELY LIMITED THE PRACTICAL USE OF THESE AGENTS. THE OVERARCHING HYPOTHESIS OF THIS PROGRAM IS THAT IDENTIFYING DOWNSTREAM PKG1A ANTI-REMODELING SUBSTRATES IN THE LV CAN REVEAL NOVEL THERAPEUTIC CANDIDATES TO OVERCOME THESE CRITICAL LIMITATIONS OF CURRENT PKG1-ACTIVATING DRUGS. WE HAVE IDENTIFIED MIXED LINEAGE KINASE 3 (MLK3) AS A NOVEL PKG1A-INTERACTING PROTEIN AND ANTI-REMODELING MOLECULE. WE PROPOSE TO EXPLORE THE FOLLOWING EXCITING FINDINGS WHICH IDENTIFY MLK3 AS A TRANSLATIONALLY RELEVANT MOLECULE IN HFREF. 1) PKG1A-MLK3 INTERACTION DECLINES IN THE FAILING LV, AND MLK3 IS REQUIRED FOR PKG1A-MEDIATED THERAPEUTIC EFFECTS OF SILDENAFIL ON LV FUNCTION AFTER PRESSURE OVERLOAD, THUS IDENTIFYING DISRUPTION OF MYOCARDIAL MLK3 REGULATION BY PKG AS PROMOTING LV REMODELING AND DECREASING THE EFFICACY OF PKG1-ACTIVATING DRUGS IN HF. 2) MLK3 KINASE FUNCTION OPPOSES PATHOLOGICAL CM AND LV DYSFUNCTION AND REMODELING BUT DOES NOT AFFECT BLOOD PRESSURE IN VIVO. 3) MLK3 DELETION PROMOTES HYPERTENSION IN VIVO, BUT MLK3 REGULATION OF BLOOD PRESSURE OCCURS THROUGH MLK3 KINASE INDEPENDENT MECHANISMS AND INDEPENDENTLY OF SIGNALING BY PKG1A. WE PROPOSE TO TEST A TWO-PART NOVEL MODEL IN WHICH 1) PKG1A ACTIVATION OF MLK3 PROMOTES LV COMPENSATION TO PRESSURE OVERLOAD THROUGH MLK3 KINASE-DEPENDENT MECHANISMS IN THE CM; AND 2) MLK3 OPPOSES HYPERTENSION THROUGH KINASE-INDEPENDENT EFFECTS ON VASCULAR STIFFNESS THROUGH A ROLE IN THE VSMC. SA1 WILL USE NOVEL MLK3 CELL-SPECIFIC DELETION MODELS DEVELOPED IN OUR LAB TO DETERMINE THE CM AND SMC-SPECIFIC ROLES OF MLK3 IN BASAL REGULATION OF LV FUNCTION AND BLOOD PRESSURE AND IN THE CHRONIC LV RESPONSE TO PRESSURE OVERLOAD OR MYOCARDIAL INFARCTION. SA2 WILL DETERMINE THE KINASE DEPENDENT VERSUS KINASE INDEPENDENT EFFECTS OF MLK3 ON LV FUNCTION AND BLOOD PRESSURE. SA3 WILL DETERMINE THE TRANSLATIONAL RELEVANCE OF MLK3 TO HF TREATMENT BY TESTING THE REQUIREMENT OF MLK3 FOR LV THERAPEUTIC EFFECTS VERSUS BLOOD PRESSURE EFFECTS OF CURRENTLY AVAILABLE PKG1-ACTIVATING DRUGS. THESE STUDIES WILL DEFINE NOVEL MECHANISMS THROUGH WHICH MLK3 REGULATES BLOOD PRESSURE AND THROUGH WHICH MLK3 BLOOD PRESSURE- INDEPENDENT FUNCTIONS MEDIATE THE THERAPEUTIC EFFECT OF CURRENT PKG1-ACTIVATING DRUGS. THESE STUDIES HAVE THE POTENTIAL TO IDENTIFY MLK3 KINASE ACTIVATION AS A NOVEL THERAPEUTIC STRATEGY TO PROMOTE PKG1 THERAPEUTIC EFFECTS ON LV FUNCTION AND REMODELING BUT AVOID UNDESIRED HYPOTENSION WHICH HAS LIMITED PKG1 ACTIVATING DRUGS.

CREDENTIALING A CROSS-SPECIES PLATFORM TO INVESTIGATE CANCER THERAPY-ASSOCIATED CARDIOVASCULAR TOXICITY

IMMUNE RESPONSE TO CRYPTOSPORIDIOSIS IN A BIRTH COHOROT OF CHILDREN OF SOUTH INDI

COVERT CEREBROVASCULAR DISEASE DETECTED BY ARTIFICIAL INTELLIGENCE (C2D2AI): A PLATFORM FOR PRAGMATIC EVIDENCE GENERATION FOR STROKE AND DEMENTIA PREVENTION - PROJECT SUMMARY IT IS A COMMON CLINICAL OCCURRENCE THAT NEUROIMAGING SCANS OBTAINED IN THE COURSE OF ROUTINE CLINICAL CARE DISCOVER COVERT CEREBROVASCULAR DISEASE (CCD), COMPRISING COVERT BRAIN INFARCTION (CBI) AND WHITE MATTER DISEASE (WMD), IN PATIENTS WITH NO HISTORY OF STROKE OR TRANSIENT ISCHEMIC ATTACK. INDEED, EPIDEMIOLOGIC STUDIES INDICATE THAT COVERT CBI ARE FAR MORE COMMON THAN CLINICALLY-EVIDENT STROKES AND THESE IMAGING FINDINGS ARE STRONG, INDEPENDENT RISK FACTORS FOR FUTURE STROKE AND DEMENTIA. HOWEVER, THERE ARE NO PROVEN PREVENTIVE TREATMENTS OR GUIDELINES FOR INITIATING RISK FACTOR-MODIFYING THERAPY. WHILE THERE IS STRONG EVIDENCE THAT ANTIPLATELET THERAPY AND STATIN THERAPY ARE EFFECTIVE IN PREVENTING RECURRENT STROKE IN PATIENTS WITH PRIOR STROKE, IT IS UNCLEAR THE DEGREE TO WHICH THESE RESULTS APPLY TO PATIENTS WITH CCD. ADDITIONALLY, PATIENTS AND PROVIDERS ARE RARELY AWARE OF THESE FINDINGS, EVEN WHEN THEY ARE DETECTED. AS PART OF OUR PREVIOUS GRANT (R01-NS102233), WE DEVELOPED A NATURAL LANGUAGE PROCESSING (NLP) ALGORITHM TO IDENTIFY INCIDENTALLY DISCOVERED (ID-) CCD FROM NEUROIMAGING REPORTS, WHICH WE PORTED INTO A LARGE INTEGRATED HEALTHCARE SYSTEM. WE IDENTIFIED A COHORT OF ALMOST A QUARTER MILLION PATIENTS OVER AGE 50 WHO RECEIVED EITHER A HEAD CT OR MRI AND WERE STROKE- AND DEMENTIA- FREE AT THE TIME OF THE INDEX SCAN. KEY FINDINGS OF OUR ANALYSES INCLUDE: NLP CAN IDENTIFY ID-CBI AND ID-WBD FROM NEUROIMAGE REPORTS AS WELL AS HUMAN READERS; THAT ID-CCD IS PRESENT IN ABOUT ONE-THIRD OF THESE SCANS IN AN AGE- AND VASCULAR RISK FACTOR DEPENDENT MANNER; THAT ID-CCD INCREASES THE RISK OF FUTURE STROKE AND FUTURE DEMENTIA BY APPROXIMATELY 2- TO 3-FOLD; THAT NLP IS ABLE TO EXTRACT ADDITIONAL IMPORTANT PROGNOSTIC INFORMATION ON WMD SEVERITY FROM ROUTINELY OBTAINED IMAGING REPORTS; AND FINALLY, THESE PATIENTS ARE GENERALLY NOT GIVEN RISK FACTOR MODIFYING TREATMENT FOLLOWING THE DISCOVERY OF ID-CCD. GIVEN THE DIFFICULTY OF RECRUITING THIS AT RISK POPULATION, WE NOW PROPOSE TO LEVERAGE THIS NLP SYSTEM AS A PLATFORM TO PLAN AND CONDUCT PROSPECTIVE RANDOMIZED COMPARATIVE EFFECTIVENESS STUDIES TO IDENTIFY OPTIMAL TREATMENT STRATEGIES FOR ID-CCD. THUS, OUR AIMS ARE: AIM 1: TO INFORM THE ENROLLMENT CRITERIA OF PREVENTION CLINICAL TRIALS AND ENSURE CONSISTENCY OF FINDINGS, WE WILL EXPAND THE COHORT TO KAISER PERMANENTE NORTHERN CALIFORNIA AND FURTHER CHARACTERIZE PATIENTS WITH ID-CCD REGARDING THEIR FUTURE STROKE AND DEMENTIA RISK. AIM 2: TO DETERMINE OPTIMAL TREATMENT ALGORITHMS, WE WILL LEVERAGE ESTABLISHED SIMULATION MODELS TO ESTIMATE THE TREATMENT EFFECTS OF DIFFERENT RISK FACTOR MODIFICATION ALGORITHMS IN PATIENTS WITH ID-CCD ON FUTURE STROKE AND DEMENTIA. AIM 3: TO DETERMINE OPTIMAL RECRUITMENT STRATEGIES IN DEMOGRAPHICALLY DIVERSE POPULATIONS, WE WILL EXAMINE THE FEASIBILITY OF RECRUITING THIS NOVEL POPULATION BASED ON NLP-IDENTIFIED FINDINGS BOTH PROSPECTIVELY (I.E. CONCURRENT WITH CLINICAL IDENTIFICATION) AND RETROSPECTIVELY (AS IDENTIFIED FROM PRE-EXISTING SCANS). AIM 4: BASED ON THE ABOVE FINDINGS WE WILL PLAN A MULTICENTER CLINICAL TRIAL FOR THE PREVENTION OF STROKE AND DEMENTIA IN THIS POPULATION WITH CCD.

MIR-409-3P REGULATES ANGIOGENESIS, BROWN FAT ADIPOSITY, AND INSULIN RESISTANCE

MECHANICAL UNLOADING AND DELAYED REPERFUSION PROMOTES MYOCARDIAL RECOVERY AFTER ACUTE MYOCARDIAL INFARCTION

IMPROVING KIDNEY FUNCTION ASSESSMENT IN HEALTH AND DISEASE - ACCURATE ASSESSMENT OF KIDNEY FUNCTION IS FUNDAMENTAL TO THE CARE OF ALL PATIENTS, BUT CURRENT METHODS TO ESTIMATE GFR HAVE ERROR RATES OF 35-60% IN IMPORTANT POPULATIONS AS WELL AS VARIABLE ACCURACY ACROSS RACE, ETHNICITY AND GEOGRAPHY, LEADING TO ERRORS IN CRITICAL DECISIONS, DRUG DOSING, AND DETERMINATION OF PROGNOSIS. CURRENT GFR ESTIMATES INCLUDE A COEFFICIENT FOR BLACK VS NON-BLACK WHICH MAY RESTRICT ACCESS TO CARE. AS A RESULT, THERE ARE CRITICAL KNOWLEDGE GAPS IN EVALUATION AND MANAGEMENT OF GFR IN HEALTH AND DISEASE. OUR GOAL IS TO DEVELOP A VALID AND ROBUST GFR ESTIMATE OPTIMIZED FOR AN INDIVIDUAL PERSON THAT MEETS THE CRITICAL UNMET NEED FOR A CONFIRMATORY TEST. THE CONFIRMATORY TEST WILL USE A PANEL OF ENDOGENOUS FILTRATION MARKERS TO ESTIMATE GFR (PEGFR) FROM A SINGLE BLOOD SAMPLE USING AN EQUATION THAT DOES NOT REQUIRE SERUM CREATININE OR DEMOGRAPHIC CHARACTERISTICS. OUR RESEARCH TEAM HAS EXTENSIVE EXPERIENCE IN BIOMARKER EVALUATION, GFR ESTIMATION, EPIDEMIOLOGY, LABORATORY SCIENCE AND METABOLOMICS. OUR PRELIMINARY DATA PROVIDE PROOF OF CONCEPT THAT A PANEL OF NOVEL METABOLITES THAT DOES NOT INCLUDE SERUM CREATININE OR DEMOGRAPHICS CAN ELIMINATE BIAS AND GREATLY IMPROVE PRECISION OF GFR ESTIMATES IN PATIENTS WITH HEART FAILURE AND REDUCED MUSCLE MASS; AND THAT NOVEL TECHNIQUES CAN BE USED TO PRODUCE A HIGH-ACCURACY AND PARSIMONIOUS PREDICTION MODEL. AIM 1 USING GLOBAL METABOLOMIC DISCOVERY (~1000+ METABOLITES) ON FIVE COHORTS (N=2583), WE WILL SELECT CANDIDATE METABOLITES BASED ON MAXIMAL JOINT ASSOCIATION WITH MGFR AS WELL AS BIOLOGICAL AND PHYSIOLOGICAL ASSESSMENT OF THEIR PROPERTIES AS FILTRATION MARKERS. MARKERS THAT SHOW ACCEPTABLE ANALYTICAL PROPERTIES IN INITIAL TESTING WILL BE INCORPORATED INTO A LIQUID CHROMATOGRAPHY TANDEM MASS SPECTROMETER (LC-MS/MS) MULTIPLEX ASSAY. AIM 2: WE PROPOSE TO USE A SPECTRUM OF NOVEL APPROACHES, SUCH AS MARGINALIZING PREDICTIONS TO DOWN- WEIGHT OUTLIER METABOLITES AND KERNEL NEAREST NEIGHBOR WEIGHTED AVERAGE PREDICTIONS, TO MAXIMIZE PRECISION AS WELL AS ROBUSTNESS ACROSS MULTIPLE DIVERSE POPULATIONS AND TO COMPARE THESE APPROACHES TO A BENCHMARK MODEL DEVELOPED USING SUPERLEARNER ENSEMBLE MODELING TECHNIQUES. DEVELOPMENT AND EXTERNAL VALIDATION IN ~3036 AND ~3465 PARTICIPANTS ACROSS 8 AND 12 STUDIES, RESPECTIVELY. AIM 3: WE PROPOSE TO EVALUATE THE IMPACT OF PANEL EGFR IN PATIENTS WITH HEART AND LIVER FAILURE (N=1796) ON CLINICAL DECISIONS AND OUTCOMES. THE EXPECTED OUTCOME IS DEVELOPMENT OF PANEL EGFR THAT CAN BE USED AS A CONFIRMATORY TEST AND ULTIMATELY INCORPORATED INTO CLINICAL PRACTICE GUIDELINES. THE PROPOSAL IS HIGHLY INNOVATIVE AS IT IS COMPREHENSIVE SPANNING DISCOVERY, VALIDATION, ASSESSMENT OF CLINICAL UTILITY IN POPULATIONS NOT PREVIOUSLY BEEN STUDIED AND USE OF NOVEL STATISTICAL METHODS TO COMPUTE INDIVIDUALIZED GFR ESTIMATES. THE PROPOSAL IS SIGNIFICANT BECAUSE IT WILL ENABLE GENERALIZABLE AND ACCURATE INDIVIDUALIZED GFR ESTIMATES IN HEALTH AND DISEASE, PARTICULARLY DISEASES WITH UNACCEPTABLY GFR ESTIMATION HIGH ERROR RATES AND DIVERSE RACIAL, ETHNIC AND GEOGRAPHIC GROUPS.

TAI CHI AND FIBROMYALGIA

CLUSTERIN AT THE OCULAR SURFACE

TRAINING PROGRAM IN CARDIOVASCULAR RESEARCH

MATRIX METALLOPROTEASE-PAR1 REGULATION OF ATHEROSCLEROSIS

PROTEIN SIGNATURES OF APOE2 AND COGNITIVE AGING

THE SEXUALLY DIMORPHIC ROLE OF SMOOTH MUSCLE CELL ESTROGEN RECEPTOR ALPHA IN VASCULAR AGING - AGING IS ASSOCIATED WITH RISING ARTERIAL STIFFNESS (AS), AN INDEPENDENT RISK FACTOR FOR CARDIOVASCULAR DISEASE (CVD) THAT LEADS TO HYPERTENSION, HEART ATTACK, STROKE, AND END ORGAN DAMAGE. THE DEVELOPMENT OF AGING-ASSOCIATED AS FOLLOWS A SEXUALLY DIMORPHIC PATTERN OF DEVELOPMENT WITH WOMEN DEVELOPING AS LATER IN LIFE AND WOMEN HAVE HIGHER RATES OF ARTERIAL STIFFNESS-ASSOCIATED CVD SUCH AS ISOLATED SYSTOLIC HYPERTENSION AND HEART FAILURE WITH PRESERVED EJECTION FRACTION. THE MOLECULAR MECHANISMS THAT CONTRIBUTE TO SEX DIFFERENCES IN THE DEVELOPMENT OF AGING-ASSOCIATED AS ARE UNCLEAR. DETERMINATION OF THESE MECHANISMS IS AN UNMET MEDICAL NEED WITH SIGNIFICANT PUBLIC HEALTH IMPLICATIONS. WE HAVE SHOWN THAT AGING MICE FOLLOW A SIMILAR PATTERN OF DEVELOPMENT OF AS, WITH FEMALE MICE EXPERIENCING A LATE ONSET OF AS COMPARED TO MALES. ESTROGEN AND ESTROGEN RECEPTOR ALPHA (ERA) ARE PROTECTIVE IN THE PREMENOPAUSAL STATE, YET THE ROLE THAT ESTROGEN/ERA PLAYS IN VASCULAR AGING HAS NOT BEEN DEFINED. RECENT STUDIES HAVE SUGGESTED THAT UNLIGANDED ERA (ERA WITHOUT THE PRESENCE OF ESTROGEN) MAY BE DETRIMENTAL TO VASCULAR HEALTH AND DUE TO THE DECLINING LEVELS OF ESTROGEN IN FEMALES WITH AGE. FURTHER STUDIES SUPPORT THAT ERA/ESTROGEN NEGATIVELY REGULATE POLY (ADP-RIBOSE) POLYMERASE-1 (PARP1) AND THAT PARP1 TRANSCRIPTIONALLY REPRESSES THE ANGIOTENSIN II TYPE 2 RECEPTOR (AT2R), A PROTECTIVE ARM OF THE RENIN-ANGIOTENSIN- ALDOSTERONE SYSTEM. OUR PRELIMINARY DATA DEMONSTRATE THAT: 1) AGING FEMALE MICE DEVELOP INCREASED AS LATER IN LIFE THAN MALES; 2) VASCULAR ERA EXPRESSION RISES WITH AGE IN FEMALES, 3) ESTROGEN REDUCES THE BINDING OF PARP1 TO THE AT2R PROMOTER IN FEMALE SMC; 4) ELDERLY FEMALES HAVE ENHANCED INTRINSIC VASCULAR SMOOTH MUSCLE CELL STIFFNESS MEASURED BY ATOMIC FORCE MICROSCOPY COMPARED TO ELDERLY MALES; 5) IN A NOVEL MOUSE MODEL WITH ERA DELETED FROM SMOOTH MUSCLE CELL (SMC-ERA-KO), AS IS PREVENTED IN OLD FEMALES AND CIRCULATING ESTROGEN DECLINES, SUPPORTING A ROLE FOR UNLIGANDED ERA IN ARTERIAL STIFFENING AND 6) SMC-ERA-KO MICE ARE PROTECTED FROM THE AGING-ASSOCIATED INCREASE IN AORTIC PARP1 AND DECREASE IN AT2R. WE HAVE PROPOSED THREE SPECIFIC AIMS TO TEST THE NOVEL HYPOTHESIS THAT YOUNG FEMALES ARE PROTECTED FROM CVD BY ESTROGEN--MEDIATED INHIBITION OF PARP1, RESULTING IN ENHANCED AT2R ACTIVITY AND THAT WITH ADVANCING AGE, UNLIGANDED SMC-ERA CONTRIBUTES TO THE DEVELOPMENT OF ARTERIAL STIFFENING VIA THE PROMOTION OF PARP1 AND CONSEQUENTIAL INHIBITION OF AT2R EXPRESSION AND SIGNALING. SA1 WILL TEST THE HYPOTHESIS IN VITRO THAT SMC-ERA REGULATES THE PARP-1/AT2R PATHWAY IN HUMAN AORTIC SMC. SA2 WILL TEST THE IN VIVO HYPOTHESIS THAT SMC-ERA REGULATION OF PARP-1/AT2R CONTRIBUTES TO SEX DIFFERENCES IN AS IN AGING MICE BY UTILIZING OUR NOVEL SMC-ERA-KO MICE IN ADDITION TO DETERMINING THE ROLE OF SMC-PARP1 IN AGING-ASSOCIATED AS WITH OUR NOVEL SMC-PARP1-KO MICE. SA3 WILL TEST THE THERAPEUTIC POTENTIAL OF CHRONIC AT2R ACTIVATION AND PARP1 INHIBITION TO AMELIORATE AGING-ASSOCIATED AS IN MALE AND FEMALE MICE. THE LONG-TERM GOAL IS TO IDENTIFY SEX-SPECIFIC THERAPEUTIC TARGETS TO AID IN IMPROVING ARTERIAL STIFFNESS AND THE ASSOCIATED CVD OUTCOMES IN THE AGING POPULATION.

IMPROVING OUTCOME IN NEONATAL ABSTINENCE SYNDROME

DIMENSIONS OF KIDNEY TUBULE HEALTH AND ATHEROSCLEROTIC CARDIOVASCULAR DISEASE AND HEART FAILURE IN MIDDLE-AGED AND OLDER ADULTS - ABSTRACT TWO CLINICAL MEASURES ARE CURRENTLY USED TO STAGE CHRONIC KIDNEY DISEASE (CKD), THE ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) AND URINE ALBUMIN-TO-CREATININE RATIO (ACR). THE ELEVATED MORBIDITY AND MORTALITY RISK THAT IS EXPERIENCED BY PERSONS WITH CKD IS OVERWHELMINGLY A RESULT OF PROGRESSIVE ATHEROSCLEROTIC CARDIOVASCULAR DISEASE (ASCVD) AND HEART FAILURE (HF) RATHER THAN KIDNEY FAILURE. UNFORTUNATELY, EGFR AND ACR INADEQUATELY DEPICT THE KIDNEY’S COMPLEXITY BECAUSE THEY REPRESENT GLOMERULAR FUNCTION AND INJURY RESPECTIVELY; YET THE KIDNEY IS PREDOMINANTLY COMPRISED OF TUBULES, AND THE KIDNEY TUBULES ARE RESPONSIBLE FOR MYRIAD HOMEOSTATIC FUNCTIONS THAT LIKELY HAVE MORE DIRECT INFLUENCE ON THE CARDIOVASCULAR SYSTEM THAN DOES DAMAGE TO THE GLOMERULUS. MOREOVER, PATHOLOGY STUDIES HAVE CONVINCINGLY DEMONSTRATED THAT TUBULE DAMAGE IS MORE PROGNOSTIC FOR LOSS OF KIDNEY FUNCTION THAN GLOMERULAR SCARRING. NOVEL URINE MEASURES THAT QUANTIFY THE HEALTH OF THE KIDNEY TUBULES HAVE RECENTLY ALLOWED US TO DEFINE FOUR ADDITIONAL DIMENSIONS OF KIDNEY HEALTH THAT INDEPENDENTLY INFLUENCE RISK FOR PROGRESSIVE CKD: PROXIMAL TUBULE INJURY, PROXIMAL TUBULE FUNCTION, TUBULE FIBROSIS AND REPAIR, AND TUBULE SYNTHETIC FUNCTION. OUR TEAM HAS SELECTED EIGHT DISTINCT URINE MEASURES THAT CAPTURE EACH OF THESE FOUR DIMENSIONS AND COMPRISE THE KIDNEY TUBULE HEALTH PANEL (KTHP). IN SPECIFIC, HIGH-RISK POPULATIONS, THE KTHP DIMENSIONS ARE STRONGLY ASSOCIATED WITH RISK FOR ASCVD, HF AND MORTALITY; BUT NO STUDIES HAVE EVALUATED THE CONTRIBUTIONS OF KIDNEY TUBULE HEALTH TO THE DEVELOPMENT OF ASCVD AND HF IN THE GENERAL POPULATION. OUR GLOBAL HYPOTHESIS IS THAT KIDNEY TUBULE DAMAGE AND DYSFUNCTION ARE RELATED TO THE ONSET AND PROGRESSION OF ASCVD AND HF. WITHIN TWO WELL-ESTABLISHED, GENERAL POPULATION COHORTS, CARDIA AND MESA, THIS PROPOSAL WILL ADDRESS THE FOLLOWING RESEARCH QUESTIONS THAT ARE CRITICAL TO UNDERSTANDING THE DEVELOPMENT OF EACH DIMENSION OF KIDNEY TUBULE DISEASE AND THEIR ROLE IN PROMOTING ASCVD AND HF: 1) DOES KIDNEY TUBULE DISEASE DEVELOP EARLIER AND PROGRESS FASTER WITH ADVANCING AGE THAN ACR AND EGFR? 2) IS KIDNEY TUBULE DISEASE MORE SEVERE IN BLACK AND HISPANIC PERSONS COMPARED WITH WHITE PERSONS? 3) WHICH ATHEROSCLEROTIC RISK FACTORS HAVE THE STRONGEST ASSOCIATIONS WITH EACH DIMENSION OF KIDNEY TUBULE DISEASE? 4) HOW STRONGLY ASSOCIATED IS KIDNEY TUBULE DISEASE WITH SEVERAL SUBCLINICAL CVD MEASURES? 5) HOW STRONGLY ASSOCIATED ARE KIDNEY TUBULE DISEASE MARKERS WITH ASCVD AND HF, AND DO THEY IMPROVE PREDICTION OF THESE ENDPOINTS? IF THESE AIMS ARE SUCCESSFUL, THESE EASILY MEASURED, NON-INVASIVE INDICES OF KIDNEY TUBULE HEALTH MAY HAVE VALUE FOR POPULATION SCREENING, TO PROVIDE INSIGHTS INTO RACE/ETHNIC DIFFERENCES IN KIDNEY AND CARDIOVASCULAR DISEASE, AND TO IDENTIFYING PATHWAYS FOR NOVEL THERAPEUTICS THAT TARGET KIDNEY TUBULES, SUCH AS THE SGLT2 INHIBITORS AND THE NON-STEROIDAL ALDOSTERONE ANTAGONISTS, THAT REDUCE RISK FOR BOTH KIDNEY AND CARDIOVASCULAR ADVERSE OUTCOMES.

A ROLE OF PKG1A AND INHIBITORS OF CGMP PHOSPHODIESTERASE IN POST MI VT IN MOUSE MODELS FOR TYPE II DIABETES AND METABOLIC SYNDROME

NOVEL STRATEGIES TO UNDERSTAND, PREDICT, AND PREVENT VASCULAR TOXICITY OF TARGETED CML THERAPIES - MOLECULARLY TARGETED CANCER THERAPIES, SUCH AS ABL-TARGETED TYROSINE KINASE INHIBITORS (TKIS), HAVE CONVERTING MANY TERMINAL CANCERS, INCLUDING CHRONIC MYELOID LEUKEMIA (CML), INTO CHRONIC DISEASES. DESPITE THE TARGETED APPROACH, VASCULAR TOXICITIES HAVE EMERGED. SPECIFICALLY, THE FIRST-GENERATION CML TKI IMATINIB IS SAFE, YET NEWER GENERATION TKIS FREQUENTLY USED FOR RESISTANT CML (NILOTINIB, DASATINIB, PONATINIB) CONFER A 2-5 FOLD INCREASED RISK OF ARTERIAL THROMBOSIS CAUSING MI, STROKE, OR LIMB ISCHEMIA. WITH NO VALIDATED MODELS TO TEST FOR VASCULAR TOXICITY PRIOR TO DRUG APPROVAL, THIS SIDE EFFECT WAS IDENTIFIED ONLY WHEN ADVERSE EVENTS ACCRUED AND ONCE RECOGNIZED, THERE ARE NO DATA TO GUIDE CLINICIANS AS TO HOW TO PREVENT THIS OR TO TREAT THESE CANCER SURVIVORS. THIS PROPOSAL ADDRESSES THESE GAPS IN KNOWLEDGE BY LEVERAGING THE CML TKIS, A DRUG CLASS WITH BOTH SAFE AND TOXIC MEMBERS. WE AND OTHERS SHOWED THAT TOXIC CML TKIS DAMAGE ECS IN SOME IN VITRO MODELS AND ENHANCE ATHEROSCLEROSIS IN MICE. AS CML PATIENTS WITH UNDERLYING CV RISK FACTORS ARE PREDISPOSED TO TOXICITY, WE HYPOTHESIZE THAT THE TOXIC CML DRUGS IMPAIR SPECIFIC ENDOTHELIAL CELL (EC) FUNCTIONS THAT LEAD TO PLAQUE DEVELOPMENT, INFLAMMATION, RUPTURE, THROMBOSIS AND ISCHEMIA. AS THESE DRUGS ARE KINASE INHIBITORS, WE FURTHER POSIT THAT THE TOXICITY IS CAUSED BY MODULATION OF THE PHOSPHORYLATION STATE OF SIGNALING PROTEINS IN A MANNER THAT IS DELETERIOUS TO EC FUNCTION AND HAVE SHOWN THIS USING PROTEOMIC APPROACHES. THUS, WE NOW PROPOSE TO TEST THE HYPOTHESIS THAT TOXIC CML TKIS ACT ON ECS TO IMPAIR BARRIER INTEGRITY, ENHANCE LEUKOCYTE TRAFFICKING, SLOW WOUND HEALING, AND INCREASE INTERACTION WITH PLATELETS, THEREBY PROMOTING AN ATHEROSCLEROSIS PHENOTYPE PRONE TO RUPTURE AND THROMBOSIS, AND THAT THE DRUG-INDUCED EC PROTEOMIC PROFILE CAN PREDICT VASCULAR TOXICITY AND IDENTIFY MITIGATING TREATMENTS. WE TEST THIS WITH 2 AIMS USING MULTIPLE INNOVATIVE APPROACHES: SA1 INTERROGATES THE IMPACT OF EACH CML TKI USING HUMAN ENGINEERED MICROVESSELS (HEMVS) TO EXAMINE THE IMPACT ON VASCULAR PERMEABILITY AND PLATELET AGGREGATION AND IN MICE USING INTRAVITAL MICROSCOPY TO QUANTIFY LEUKOCYTE-EC INTERACTION, CAROTID WIRE INJURY TO MEASURE VASCULAR RE- ENDOTHELIALIZATION, AND APO-E-KO MICE WITH FACS TO QUANTIFY VASCULAR INFLAMMATION IN ATHEROSCLEROSIS. SA2 USES A TARGETED MASS SPECTROMETRY BASED PHOSPHOPROTEOMIC ASSAY TO PROFILE THE EFFECTS OF EMERGING CML TKIS AND A BROAD RANGE OF DRUGS APPROVED FOR CV DISEASE IN HUMAN ECS TO DETERMINE IF THIS CAN PREDICT TOXICITY OF NEW TKIS AND IDENTIFY MITIGATING THERAPIES. PREDICTED TOXICITIES AND “ANTIDOTES” THAT OPPOSE THE TOXIC PROTEOMIC SIGNATURE WILL BE TESTED USING THE IN VITRO AND IN VIVO MODELS DESCRIBED IN SA1. COMPLETION OF THE AIMS WILL TRANSFORM CARDIOONCOLOGY BY VALIDATING PRECLINICAL MODELS TO PREDICT VASCULAR SAFETY OF CML TKIS AND IDENTIFY POTENTIAL TREATMENTS FOR VASCULAR TOXICITY THAT CAN BE RAPIDLY TRANSLATED TO CARDIOONCOLOGY CARE.

INFECTIOUS DISEASE TRAINING-PATHOGENESIS/HOST RESPONSE

CONSTITUTIONAL AND METABOLIC FACTORS ASSOCIATED WITH THE DEVELOPMENT OF HAND OA

VALUE OF PERSONALIZED RISK INFORMATION

PATHOGENESIS OF CARDIOPULMONARY FIBROSIS ASSOCIATED WITH HEART FAILURE IN THE ELDERLY

MECHANISMS FOR SEX DIFFERENCES IN CVD PATHOLOGY AND DEVELOPMENT OF A TARGETED THERAPEUTIC

THE ROLE OF BONE IN OSTEOARTHRITIS PROGRESSION

PLACENTAL LIPID METABOLISM IMPACTS FETAL ADIPOSITY AND IS PROGRAMMED BY THE MATERNAL METABOLIC MILIEU IN EARLY PREGNANCY

ASSESSING DIAGNOSIS AND TREATMENT DELAYS AND HEALTH CARE DISPARITIES BY RACE/ETHNICITY AMONG INDIVIDUALS WITH ALZHEIMER?S DISEASE AND RELATED DEMENTIAS

KIDNEY FUNCTION, AORTIC STIFFNESS AND AGING

DISCOVERY APPROACH TO OCULAR HYPERTENSION

CONTROL OF LETHAL PROSTATE CANCER WITH A BISPECIFIC AV AND A5B1 INTEGRIN ANTIBODY

THE ROLE OF PLASMACYTOID DENDRITIC CELLS IN CORNEAL IMMUNITY

TAI CHI AND KNEE OSTEOARTHRITIS

SCREENING FOR AL AMYLOIDOSIS IN SMOLDERING MULTIPLE MYELOMA - ABSTRACT OUR OBJECTIVE IS TO DEVELOP TOOLS THAT IMPROVE EARLY DIAGNOSIS OF SYSTEMIC LIGHT-CHAIN (AL) AMYLOIDOSIS, A DISEASE THAT CAUSES HEART AND KIDNEY FAILURE AND EARLY DEATH, IN PATIENTS WITH SMOLDERING MULTIPLE MYELOMA, A DISEASE IN WHICH PATIENTS MAKE IMMUNOGLOBULIN FREE LIGHT CHAINS BUT ARE RELATIVELY ASYMPTOMATIC. BASED ON A RETROSPECTIVE STUDY IN MEMBERS OF THE US ARMED FORCES WHO DEVELOPED AL, THERE IS A 10 TO 15 YEAR PRECURSOR PERIOD PRIOR TO PATIENTS PRESENTING AT A MEDIAN AGE OF 63 WITH SYMPTOMS OF AL DUE TO TOXIC FREE LIGHT CHAINS (FLC) AND AMYLOID DEPOSITS. IN SIMILAR STUDIES OF PATIENTS WITH SMOLDERING MYELOMA WE KNOW THAT 2% OF THEM DEVELOP AL, MEANING THAT 2% HAVE FLC THAT ARE MARKEDLY ABNORMAL. OVER HALF OF NEW AL PATIENTS PRESENT WITH HEART INVOLVEMENT AND IT IS THE FAILURE TO DIAGNOSE EARLY THAT UNDERLIES THEIR 20% MORTALITY WITHIN 6 MONTHS. IN THIS APPLICATION, WE SEEK SUPPORT TO SCREEN PATIENTS WITH SMOLDERING MULTIPLE MYELOMA FOR UNDIAGNOSED AL AND RISK OF AL USING A SERIES OF CRITERIA THAT WILL INCREASE OUR KNOWLEDGE OF THE LIKELIHOOD OF HAVING UNDIAGNOSED AL OR OF BEING AT RISK FOR AL. ONLY EFFORTS TO DIAGNOSE AL AND DETERMINE RISK OF AL IN THE PRECURSOR PHASE OF THE DISEASE WILL REDUCE THE EARLY MORTALITY RATE. OUR GOAL IS TO DEVELOP A LIKELIHOOD ALGORITHM FOR UNDIAGNOSED AL AND RISK OF AL IN SMOLDERING MYELOMA PATIENTS AND OUR AIMS IN THIS APPLICATION ARE TO CREATE A NETWORK TO ENROLL 340 PATIENTS WITH SMOLDERING MULTIPLE MYELOMA (SMM) ON A COLLABORATIVE STUDY REQUIRING MARROW AND BLOOD SPECIMENS AND COLLECTION OF DATA FOR A TRAINING SET OF LIKELIHOOD STATISTICS AND TO PLAN THE FUTURE VALIDATION STUDY AND TO VALIDATE AN NEXT GENERATION SEQUENCE (NGS) ASSAY THAT IDENTIFIES IGVL GENES IN CLONAL PLASMA CELLS. THE CLONAL Κ AND Λ IGVL GENES IN AL CASES ARE RESTRICTED AL-RELATED SETS OF GENES. THE LIKELIHOOD ALGORITHM WILL EMPLOY 5 PARAMETERS: (1) THE PRESENCE OF SMM; (2) A DIFFERENCE BETWEEN INVOLVED (PATHOLOGIC) AND UNINVOLVED FLC > 23MG/L; (3) CLONAL PLASMA CELL CYTOGENETICS SHOWING T(11;14) OR GAIN 1Q, (4) AL-RELATED Κ OR Λ IGVL GENES BY NGS, AND (5) NT-PROBNP > 332PG/ML. ALL SUBJECTS WILL HAVE THEIR CLONAL IGVL GENES IDENTIFIED BY NGS ENABLING THE CREATION AND VALIDATION OF A LABORATORY DEVELOPED TEST IN A PRECISION MEDICINE LABORATORY THAT IS CERTIFIED UNDER REGULATIONS OF THE CLINICAL LABORATORY IMPROVEMENT AMENDMENTS OF 1988 (CLIA). OUR LONG-TERM GOAL IS TO OVERCOME THE CURRENT INABILITY IN PATIENTS WITH SMM TO EFFECTIVELY ASSESS FOR THE PRESENCE OF OCCULT AL OR TO ESTIMATE THE LIKELIHOOD OF DEVELOPING AL. BY DETERMINING THE VALUES OF THE 5 PARAMETERS WE WILL CREATE THE TRAINING SET FOR AN ALGORITHM TO ESTIMATE THE LIKELIHOOD OF HAVING OR PROGRESSING TO AL AND WILL BE ABLE TO DESIGN THE VALIDATION STUDY. WE HAVE ASSEMBLED A COLLABORATIVE TEAM OF INVESTIGATORS AT CENTERS ACROSS THE USA TO PURSUE OUR AIMS AND AN EXPERT SUPPORT GROUP TO ADDRESS THE OPPORTUNITIES, CHALLENGES AND PATIENT CARE ISSUES THAT WILL ARISE. WE HAVE PUT TOGETHER A TEAM OF EXPERT COLLABORATORS FROM OVER A DOZEN ACADEMIC CENTERS AND EXPERT CONSULTANTS IN MYELOMA, AL AMYLOIDOSIS, MOLECULAR BIOLOGY AND PROTEIN BIOLOGY, IN ORDER TO PURSUE THESE AIMS, REALIZING THE COMPLEXITY OF THE ENDEAVOR AND THE DEMANDS OF EACH AIM.

COVERT CEREBROVASCULAR DISEASE DETECTED BY ARTIFICIAL INTELLIGENCE (C2D2AI): PRAGMATIC NEUROIMAGING BIOMARKERS FOR FUTURE STROKE AND DEMENTIA RISK - PROJECT SUMMARY COVERT CEREBROVASCULAR DISEASE (CCD), COMPRISING COVERT BRAIN INFARCTION (CBI) AND WHITE MATTER DISEASE (WMD), IS COMMONLY FOUND INCIDENTALLY ON NEUROIMAGING SCANS OBTAINED IN ROUTINE CLINICAL CARE. CBI IS BELIEVED TO BE PATHOPHYSIOLOGICALLY SIMILAR TO CLINICALLY-EVIDENT STROKE, BUT WITH INFARCT LOCATIONS IN CLINICALLY LESS ARTICULATE PARTS OF THE BRAIN. EPIDEMIOLOGIC STUDIES BASED ON MRI-SCREENED COHORTS INDICATE THAT CBI IS FAR MORE COMMON THAN CLINICALLY-EVIDENT STROKE, AND WMD IS EVEN MORE COMMON. BOTH TYPES OF CCD ARE STRONG, INDEPENDENT RISK FACTORS FOR FUTURE STROKE AND DEMENTIA. THE AMERICAN HEART ASSOCIATION/AMERICAN STROKE ASSOCIATION HAS IDENTIFIED CCD AS A MAJOR PRIORITY FOR NEW STUDIES ON STROKE PREVENTION. IDENTIFYING HIGH-RISK INDIVIDUALS PRIOR TO THE ONSET OF SEVERE COGNITIVE DECLINE IS A CENTRAL GOAL IN DEMENTIA PREVENTION RESEARCH. HOWEVER, APPLICATION OF INSIGHTS FROM STUDIES OF MRI-SCREENED COHORTS TO PATIENTS WITH INCIDENTALLY-DISCOVERED CCD IS NOT STRAIGHTFORWARD. PATIENTS ARE NOT SCREENED BUT ARE SELECTED FOR CLINICALLY-INDICATED NEUROIMAGING; REAL-WORLD IMAGING IS DOMINATED BY CT SCANS; NEUROIMAGING INTERPRETATION AND REPORTING ARE HETEROGENEOUS AND POORLY STANDARDIZED. ADDITIONALLY, THERE ARE NO ICD-9 CODES FOR CBI OR WMD, WHICH ALSO DO NOT GENERALLY APPEAR IN A PATIENT’S PROBLEM LIST OR IN STRUCTURED FIELDS OF ELECTRONIC HEALTH RECORDS. INDEED, BOTH PATIENTS AND THEIR PROVIDERS ARE OFTEN UNAWARE OF THESE FINDINGS EVEN AFTER THEY ARE DETECTED. OUR TEAM HAS PERFORMED THE FIRST LARGE-SCALE STUDY OF THE PREVALENCE AND PROGNOSTIC IMPORTANCE OF INCIDENTALLY-DISCOVERED (ID)-CCD USING NATURAL LANGUAGE PROCESSING (NLP) ALGORITHMS AND CREATED A REAL-WORLD COHORT COMPRISING APPROXIMATELY 250,000 STROKE- AND DEMENTIA-FREE PATIENTS OVER AGE 50 WHO RECEIVED EITHER HEAD CT OR MRI, APPROXIMATELY 30% OF WHOM HAVE ID-CCD. THESE NLP-IDENTIFIED ID-CBI AND ID-WMD ARE BOTH STRONG PREDICTORS OF FUTURE CLINICALLY-EVIDENT STROKE AND DEMENTIA. WHILE THIS COHORT HAS YIELDED IMPORTANT INSIGHTS, THERE ARE SUBSTANTIAL LIMITATIONS. EXTRACTABLE INFORMATION ON WMD SEVERITY IS FREQUENTLY MISSING. EVEN WHEN PRESENT IN TEXT REPORTS, ONLY RELATIVELY CRUDE INFORMATION ON WMD BURDEN CAN BE OBTAINED. FURTHER, OTHER EVIDENCE OF CCD—INCLUDING MICROBLEEDS, MICROINFARCTS, PROMINENT PERIVASCULAR SPACES—MAY ALSO BE PROGNOSTICALLY IMPORTANT. FINALLY, DIRECT IMAGE ANALYSIS MAY DISCOVER NEW RADIOMIC BIOMARKERS PREDICTIVE OF FUTURE STROKE AND DEMENTIA THAT ARE NOT CAPTURED OR UNKNOWN. THE AMBITIOUS GOAL OF THIS PROJECT IS TO DEVELOP A CLINICALLY USEFUL ALGORITHM THAT CAN DIRECTLY READ ROUTINELY OBTAINED NEUROIMAGING SCANS AT SCALE AND RELATE FINDINGS TO STROKE AND DEMENTIA OUTCOMES THROUGH THE FOLLOWING SPECIFIC AIMS: AIM 1: DEVELOP A DEEP LEARNING MODEL TO IDENTIFY AND CHARACTERIZE COVERT ID-CCD FROM ROUTINELY OBTAINED CT AND MRI NEUROIMAGES AND USE THESE FEATURES, AND OTHER DEEP RADIOMIC BIOMARKERS, TO PREDICT THE DEVELOPMENT OF FUTURE STROKE AND DEMENTIA. AIM 2: TEST THE DEEP LEARNING ALGORITHMS DEVELOPED IN AIM 1 ON A LARGE COHORT OF PATIENTS FROM AN INTEGRATED HEALTH SYSTEM FOR THE PREDICTION OF FUTURE STROKE AND DEMENTIA TO EVALUATE THEIR INCREMENTAL PROGNOSTIC VALUE.

EPIDEMIOLOGY, CLINICAL TRIALS, AND OUTCOMES RESEARCH

MONITORING AUTOPHAGY IN THE HEART AND IN TUMORS TREATED WITH POTENTIALLY CARDIOTOXIC CHEMOTHERAPY - THE TREATMENT OF CANCER HAS BEEN REVOLUTIONIZED BY THE DEVELOPMENT OF TARGETED AND IMMUNE-BASED THERAPIES. HOWEVER, MANY OF THESE NEW THERAPIES, AS WELL AS ESTABLISHED ONES SUCH AS DOXORUBICIN, CAN DAMAGE THE HEART AND CAUSE SEVERE HEART FAILURE. A GROWING BODY OF EVIDENCE SUGGESTS THAT PERTURBATIONS IN CARDIOMYOCYTE AUTOPHAGY MAY PLAY A CENTRAL ROLE IN CHEMOTHERAPY-INDUCED HEART FAILURE, AND THE ABILITY TO IMAGE THIS PROCESS IN VIVO COULD PROVIDE IMPORTANT INSIGHTS. WE HAVE RECENTLY DEVELOPED AN AUTOPHAGY-DETECTING NANOPARTICLE (ADN) AND HAVE USED THIS AGENT TO IMAGE AUTOPHAGY IN THE HEART DURING CHEMOTHERAPY WITH DOXORUBICIN AND DASATANIB. THE CORE OF THE AGENT CONSISTS OF FERUMOXYTOL, AN MRI-DETECTABLE NANOPARTICLE, TO WHICH SEVERAL POLYARGININE- CY5.5 MOIETIES ARE ATTACHED. THE POLYARGININE PEPTIDES FACILITATE THE TRANSLOCATION OF THE AGENT INTO THE CELL, WHERE IT IS TAKEN UP BY AUTOPHAGOSOMES AND TRAFFICKED TO THE LYSOSOMES. FOLDING OF THE POLYARGININE PEPTIDES ALSO RESULTS IN STACKING AND QUENCHING OF THE CY5.5 FLUOROCHROMES UNTIL THE PEPTIDES ARE CLEAVED BY CATHEPSINS IN THE AUTOPHAGOLYSOSOMES. WE HAVE SHOWN USING CHEMICAL INHIBITORS/STIMULATORS OF AUTOPHAGY, AND CELLS WITH GENETIC DELETION OF THE KEY AUTOPHAGY PROTEINS ATG5 AND ATG7, THAT THE ACTIVATION OF ADN IS SPECIFIC FOR AUTOPHAGY. LIKEWISE, USING A TRANSGENIC MOUSE WITH OVEREXPRESSION OF THE DDIT4L TRANSCRIPTION FACTOR IN THE HEART AND THE CANONICAL AUTOPHAGY MODEL OF INTERMITTENT FASTING, WE HAVE SHOWN THAT ADN CAN DETECT AUTOPHAGY IN VIVO WITH A HIGH DEGREE OF SENSITIVITY AND SPECIFICITY. IN THIS PROPOSAL WE WILL USE ADN TO INTERROGATE CHANGES IN AUTOPHAGY IN BOTH THE HEART AND CANCER. WHILE THE UPREGULATION OF AUTOPHAGY IN THE HEART IS PROTECTIVE, IT HAS THE POTENTIAL TO EITHER PROTECT OR HARM TUMORS UNDERGOING CHEMOTHERAPY. WE HYPOTHESIZE THAT THE IMAGING OF AUTOPHAGY WITH ADN WILL ALLOW CONDITIONS AND STRATEGIES TO BE IDENTIFIED WHERE THE UPREGULATION OF AUTOPHAGY IS CARDIOPROTECTIVE BUT DOES NOT ATTENUATE THE EFFECT OF THE CHEMOTHERAPY ON THE TUMOR. IN AIM 1 OF THE PROPOSAL, WE WILL MAKE A SMALL CHEMICAL MODIFICATION TO THE PROBE, ENABLING IT TO BE DETECTED BEFORE AND AFTER ITS ACTIVATION, AND USE CONFOCAL/SUPER-RESOLUTION MICROSCOPY OF LIVE CELLS TO DEVELOP A DETAILED KINETIC MODEL OF AUTOPHAGY. IPSC-DERIVED CARDIOMYOCYTES AND RELEVANT TUMOR CELL LINES WILL BE STUDIED. IN AIM 2 WE WILL ASSESS THE IMPACT OF AUTOPHAGY UPREGULATION ON A LIBRARY OF TUMOR CELL LINES EXPOSED TO A LARGE PANEL OF CHEMOTHERAPIES, MANY KNOWN TO CAUSE HEART FAILURE. IN AIM 3 WE WILL USE A MULTISPECTRAL FLUORESCENCE APPROACH TO IMAGE AUTOPHAGY, APOPTOSIS AND INFLAMMATION IN THE HEART AND IN TUMORS IN MICE IN VIVO. THE IMPACT OF AUTOPHAGY UPREGULATION WILL BE ASSESSED AND A DETAILED KINETIC MODEL OF AUTOPHAGY IN THE HEART AND IN TUMORS WILL BE DERIVED. EXECUTION OF THE PROPOSED AIMS WILL PROVIDE IMPORTANT INSIGHTS INTO THE ROLE OF AUTOPHAGY IN THE HEART AND CANCER, AND PROVIDE A PLATFORM TO IDENTIFY SAFE AND EFFECTIVE AUTOPHAGY REGULATING STRATEGIES TO PROTECT THE HEART DURING CHEMOTHERAPY.

ENDOGLIN: A NEW TARGET OF THERAPY FOR HEART FAILURE

PREVENTING MID- AND LATER-LIFE WORK LIMITATIONS: COMMUNITY-BASED DEPRESSION CARE

THE RISK OF PARADOXICAL EMBOLISM (ROPE) STUDY

MOLECULAR MECHANISMS OF VASCULAR RELAXATION

NOVEL PROTEIN KINASE GI SUBSTRATES IN CARDIAC REMODELING AND BLOOD PRESSURE CONTROL

NATIONAL CENTER FOR EDUCATION RESEARCH

CDK6 AS A NOVEL THERAPEUTIC TARGET FOR TYPE II DIABETES

DISCOVERY OF THE BIOMARKER SIGNATURE FOR NEUROPATHIC CORNEAL PAIN

SEX DEPENDENT REGULATION OF RETINAL DEGENERATION

VASCULAR ESTROGEN RECEPTOR SIGNALING PATHWAYS

VASCULAR SURGERY - ESTROGEN AND THE INJURY RESPONSE

MOLECULAR PATHOGENESIS & THERAPY OF JAK2 V617F-INDUCED MYELOPROLIFERATIVE DISEASE

HELMINTHIC PROTECTION FROM IBD

POSTDOCTORAL FELLOWSHIPS IN HEALTH SERVICES RESEARCH

FETO-MATERNAL DNA/RNA TRAFFICKING:BIOLOGY & APPLICATIONS

ROLE OF STEROLS & INSULIN IN CARDIAC AUTONOMIC RESPONSE

HSCT-CHESS TO ENHANCE HEMATOPOIETIC TRANSPLANT RECOVERY

THE ROLE OF PLASMACYTOID DENDRITIC CELLS IN OCULAR ANGIOGENESIS

PLACENTAL MRNA PROFILES ASSOCIATED WITH MATERNAL INSULIN RESISTANCE AND FETAL ADIPOSITY: MATERNAL-PLACENTAL CROSSTALK

TREATMENT FOR BIPOLAR DEPRESSION: ACUTE & PROPHYLACTIC EFFICACY WITH CITALOPRAM

THE MECHANISM OF ANGIOGENIN-INDUCED ANGIOGENESIS

SMOOTH MUSCLE CELL PROTEIN SEROTONYLATION AND PULMONARY HYPERTENSION

ESTIMATING GFR FROM A PANEL OF ENDOGENOUS FILTRATION MARKERS (PANEL EGFR)

PLACENTAL MIRNAS PARACRINE AND ENDOCRINE ROLES IN INSULIN SENSITIVITY IN PREGNANCY - PROJECT ABSTRACT THE PHYSIOLOGICAL DECREASE IN MATERNAL INSULIN SENSITIVITY DURING PREGNANCY IS NECESSARY TO INCREASE NUTRIENT AVAILABILITY FOR PLACENTAL UPTAKE AND FETAL DELIVERY. WHEN THE DECREASE IN INSULIN SENSITIVITY IS EXCESSIVE, IT RESULTS IN ADVERSE PREGNANCY OUTCOMES SUCH AS GESTATIONAL DIABETES LEADING TO FETAL MACROSOMIA AND HYPOGLYCEMIA AT DELIVERY, AND LONG-TERM RISK FOR DEVELOPMENT OF DIABETES IN MOTHER AND OFFSPRING. THE MECHANISMS REGULATING INSULIN SIGNALING DURING PREGNANCY ARE UNKNOWN. MATERNAL INSULIN SENSITIVITY IMPROVES 120% WITHIN HOURS FOLLOWING DELIVERY OF THE PLACENTA, SUGGESTING A PLACENTAL FACTOR MAY REGULATE INSULIN SIGNALING DURING PREGNANCY. WE HAVE IDENTIFIED MICRORNAS (MIRNAS) PRODUCED IN THE PLACENTA THAT ARE ASSOCIATED WITH MATERNAL INSULIN SENSITIVITY INDEX IN LATE PREGNANCY. WE DETECTED SOME OF THESE PLACENTA-EXPRESSED MIRNAS IN MATERNAL CIRCULATION AS EARLY AS 8-12 WEEKS OF GESTATION, SUGGESTING THEY MAY BE INVOLVED IN THE PHYSIOLOGICAL ADAPTATIONS OF MATERNAL GLUCOSE METABOLISM BEGINNING EARLY IN PREGNANCY. THE OVERALL GOAL OF THIS STUDY IS TO INVESTIGATE MECHANISMS BY WHICH SELECTED CANDIDATE PLACENTAL MIRNA PARTICIPATE IN THE INTERPLAY BETWEEN PLACENTA AND GLUCOSE-INSULIN REGULATION DURING PREGNANCY. WE HYPOTHESIZE THAT MIRNA PRODUCED IN THE PLACENTA AND REGULATED BY MATERNAL GLYCEMIA, ACT LOCALLY AND PERIPHERALLY TO MANIPULATE MATERNAL INSULIN SENSITIVITY DURING PREGNANCY. TO TEST THIS HYPOTHESIS, WE WILL LEVERAGE OUR EXISTING PERINATAL COHORTS WHICH INCLUDE LONGITUDINAL PROSPECTIVELY COLLECTED PLASMA SAMPLES AND INSULIN SENSITIVITY INDEX (ISI) DATA DERIVED FROM ORAL GLUCOSE TOLERANCE TESTS IN THE FIRST, SECOND AND THIRD TRIMESTERS OF PREGNANCY. WE WILL ALSO UTILIZE IN VITRO HUMAN PRIMARY CELLULAR MODELS TO DIRECTLY TEST THE FUNCTION OF PLACENTA-DERIVED MIRNA LOCALLY (PARACRINE ACTIONS IN PLACENTA) AND IN INSULIN-SENSITIVE PERIPHERAL TISSUES (ENDOCRINE ACTIONS). UPON COMPLETION OF THE PROPOSED STUDIES WE WILL HAVE DETERMINED: 1) THE LOCAL EFFECT OF PLACENTAL MIRNA RELATED TO MATERNAL INSULIN SENSITIVITY ON PLACENTAL GENE EXPRESSION AND FUNCTION; 2) THE PERIPHERAL EFFECT OF PLACENTAL MIRNA RELATED TO MATERNAL INSULIN SENSITIVITY ON SKELETAL MYOCYTES, ADIPOCYTES AND HEPATOCYTES IN VITRO; 3) THE REGULATORY ROLE OF HYPERGLYCEMIA ON PLACENTAL MIRNA EXPRESSION AND RELEASE. A DETAILED UNDERSTANDING OF THE FUNCTION AND REGULATION OF THESE PLACENTAL MIRNA MAY PROVIDE US WITH NOVEL TARGETS FOR TREATMENT OF PATHOPHYSIOLOGICAL DECREASES IN INSULIN SENSITIVITY.

A PEDIATRICS-BASED INTERVENTION FOR YOUNG CHILDREN AT RISK FOR ADHD OR ODD

PERIARTICULAR BONE DENSITY AS A BIOMARKER FOR EARLY KNEE OA

ANGIOGENIN IN ALS PATHOBIOLOGY AND THERAPY

INSURANCE INSTABILITY AND DISPARITIES IN CHRONIC DISEASE OUTCOMES

PROTECTION AND MITIGATION OF BONE MARROW FAILURE BY ANGIOGENIN

TUBERIN AND HAMARTIN IN RAPAMYCIN-SENSITIVE & RAPAMYCIN-INSENSITIVE SMOOTH MUSCLE

MENTORING AND RESEARCH IN PATIENT-ORIENTED INTEGRATIVE MEDICINE

METABOLIC REPROGRAMMING BY PROTEASE-ACTIVATED RECEPTOR 2 - EXCESSIVE SUGAR AND FAT CONSUMPTION CAN LEAD TO A RANGE OF METABOLIC ABNORMALITIES INCLUDING NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD), HYPERCHOLESTEROLEMIA, DYSLIPIDEMIA, OBESITY, AND INSULIN RESISTANCE. EMERGING EVIDENCE POINTS TO A NEW MECHANISM LINKING CARBON METABOLISM AND FATTY LIVER DISEASE TO THE G PROTEIN-COUPLED PROTEASE ACTIVATED RECEPTOR-2 (PAR2), A RECEPTOR PREVIOUSLY KNOWN TO BE INVOLVED IN INFLAMMATION. TO PROVIDE KEY SUPPORT FOR THE POTENTIAL IMPORTANCE OF HEPATIC PAR2 IN HUMANS, IN A CROSS-SECTIONAL STUDY OF LIVER SPECIMENS AND CLINICAL DATA FROM 108 NAFLD PATIENTS AND CONTROLS, WE FOUND THAT PAR2 PROTEIN EXPRESSION IN HEPATOCYTES WAS LOW IN CONTROL LIVERS AND PROGRESSIVELY INCREASED IN PATIENTS WITH MILD NAFLD FIBROSIS AND IN NAFLD WITH HIGHER STAGES OF FIBROSIS. THE HIGH PAR2-EXPRESSING NAFLD PATIENT COHORT HAD SIGNIFICANTLY ELEVATED PLASMA LDL CHOLESTEROL AS COMPARED TO THE LOW PAR2-EXPRESSING COHORT. HOWEVER, A DEFINITIVE ROLE FOR PAR2 IN METABOLISM, CHOLESTEROL HOMEOSTASIS, AND LIVER PATHOLOGY REMAINS UNKNOWN. THE OVERARCHING GOAL OF THIS GRANT PROPOSAL IS TO EXAMINE THE ROLE OF PAR2 SIGNALING IN THE ETIOLOGY AND PATHOGENESIS OF FATTY LIVER DISEASE TO TEST OUR CENTRAL HYPOTHESIS THAT HEPATIC PAR2 IS A NOVEL CONTRIBUTOR OF HYPERTRIGLYCERIDEMIA, OBESITY, AND INSULIN RESISTANCE. PAR2 IS EXPRESSED BY MANY TISSUES AND CELL TYPES AND A CONVENTIONAL MOUSE WHOLE-BODY KNOCKOUT (KO) HAS BEEN USED TO DATE. THEREFORE, IT IS UNCLEAR HOW MUCH OF THE KO PHENOTYPE OR EFFECTS OF PAR2 INHIBITION ON STEATOSIS, LIPID METABOLISM, AND WEIGHT LOSS IS MEDIATED ONLY AT THE LEVEL OF THE HEPATOCYTE AND HOW MUCH IS DUE TO LOSS OF PAR2 AT OTHER SITES OF EXPRESSION. WE WILL USE OUR NEW HEPATOCYTE-SPECIFIC PAR2-KO, PAR2HEP MICE TO DEFINE AND VALIDATE THE SPECIFIC INVOLVEMENT OF LIVER PAR2 IN THESE PROFOUND METABOLIC EFFECTS IN AIMS 1-3. IT IS UNCLEAR HOW PAR2 PROMOTES INSULIN RESISTANCE IN DIET-INDUCED OBESITY MODELS. AIM 2 WILL EXPLORE A NOVEL MECHANISM WHEREBY PAR2 ACTIVATES A GQ-PLC PATHWAY TO STIMULATE CALCIUM FLUX AND CAMKK2 TO INTERFERE IN INSULIN ACTIVATION OF AKT-GLUCOSE SIGNALING. TO EXPLAIN OUR PRELIMINARY DATA THAT GLOBAL PAR2-DEFICIENCY LOWERS BASAL PLASMA GLUCOSE, BUT INCREASES LIVER GLUCOSE AND GLYCOGEN IN BOTH LEAN AND OBESE MOUSE MODELS, AIM 3 WILL TEST THE HYPOTHESIS THAT HEPATOCYTE PAR2 SUPPRESSES THE MAJOR LIVER GLUCOSE TRANSPORTER GLUT2 THROUGH A MECHANISM POTENTIALLY INVOLVING GQ-MAPK-FOXA3. AIMS 1-3 WILL UTILIZE OUR PEPDUCIN TECHNOLOGY DEVELOPED TO ALLOSTERICALLY TARGET G-PROTEIN COUPLED RECEPTORS ON THE INSIDE SURFACE OF THE PLASMA MEMBRANE TO HELP DELINEATE SPECIFIC PAR2-EFFECTOR SIGNALING PATHWAYS IN ABERRANT LIVER METABOLISM AND INSULIN RESISTANCE IN VITRO AND IN VIVO.

INNATE IMMUNOMODULATION OF RETINAL VASCULAR DEVELOPMENT - PROJECT SUMMARY RETINAL BLOOD VESSEL FORMATION IS A HIGHLY REGULATED PROCESS THAT REQUIRES MULTI-CELLULAR CROSSTALK AND INTERACTIONS. DUE TO THE COMPLEXITY OF RETINAL VASCULAR DEVELOPMENT, THERE ARE SEVERAL CRITICAL KNOWLEDGE GAPS THAT NEED TO BE ADDRESSED. FOR EXAMPLE, THE KEY GLIAL CELL TYPE THAT REGULATE RETINAL VASCULAR DEVELOPMENT ARE ASTROCYTES, WHICH LAY A TEMPLATE FOR BLOOD VESSEL FORMATION. ENDOTHELIAL CELLS MIGRATE OVER THE SPATIALLY ORGANIZED ASTROCYTIC TEMPLATE TO FORM SUPERFICIAL BLOOD VESSELS THAT GIVE RISE TO THREE INTERCONNECTED VASCULAR LAYERS IN THE MATURE RETINA. DISRUPTION OF THE ASTROCYTIC TEMPLATE DURING DEVELOPMENT OR LOSS OF ASTROCYTE ASSOCIATION WITH BLOOD VESSELS IN ADULTHOOD CAN BE DETRIMENTAL TO VASCULAR GROWTH, INTEGRITY, AND FUNCTION. THE UNDERLYING CELLULAR AND MOLECULAR SIGNALING MECHANISMS THAT REGULATE ASTROCYTE SPATIAL PATTERNING AND SUBSEQUENT ORGANIZED BLOOD VESSEL FORMATION DURING DEVELOPMENT REMAIN INCOMPLETELY UNDERSTOOD. ELUCIDATING THE MOLECULAR MECHANISMS THAT GOVERN BLOOD VESSEL DEVELOPMENT AND FUNCTION IS NECESSARY TO IDENTIFY MORE TARGETED THERAPEUTIC STRATEGIES FOR BLINDING RETINAL VASCULAR PATHOLOGIES, AND TO IDENTIFY WHICH CRITICAL DEVELOPMENTAL PROCESSES SHOULD NOT BE TARGETED IN SOME CONTEXTS, FOR EXAMPLE RETINOPATHY OF PREMATURITY. OUR MAJOR GOAL IS TO DELINEATE THE SIGNALING MECHANISMS THAT REGULATE ASTROCYTE TEMPLATE SPATIAL ARRANGEMENT AND VASCULAR NETWORK FORMATION. OUR PRELIMINARY FINDINGS STRONGLY SUPPORT THE RATIONALE FOR THE PRESENT STUDY. OUR RNA-SEQ DATA REVEAL THAT SPECIFIC CHEMOKINE AND COMPLEMENT GENE EXPRESSION LEVELS ARE ELEVATED DURING RETINAL VASCULAR DEVELOPMENT. INTRIGUINGLY, DELETION OF ONE OF THE AFFECTED CHEMOKINE RECEPTORS DISRUPTS ASTROCYTE TEMPLATE FORMATION AND MICROGLIAL RECRUITMENT AND DISTRIBUTION. ON THE OTHER HAND, DELETION OF COMPLEMENT COMPONENTS RESULTS IN AN ABERRANTLY DENSE ASTROCYTIC TEMPLATE AND DYSMORPHIC EXCESSIVE TIP CELL FORMATION. BASED ON THESE NOVEL FINDINGS, WE HYPOTHESIZE THAT MICROGLIAL CHEMOKINE SIGNALING AND COMPLEMENT ACTIVATION ARE CRITICAL FOR NORMAL RETINAL VASCULAR DEVELOPMENT. WE WILL REFUTE OR VALIDATE OUR HYPOTHESIS IN THE FOLLOWING TWO SPECIFIC AIMS: AIM 1: TO DETERMINE IF CHEMOKINE SIGNALING RECRUITS MICROGLIA TO MODULATE ASTROCYTE TEMPLATE ASSEMBLY. AIM 2: TO DEFINE THE ROLE OF COMPLEMENT RECEPTORS IN ASTROCYTE TEMPLATE AND VASCULAR NETWORK FORMATION. WE WILL UTILIZE INNOVATIVE MULTIPLEX RNA/PROTEIN BASED ASSAYS, NOVEL EX VIVO MIGRATION ASSAYS, UNIQUE REPORTER MICE, AND CRE/LOX ANIMALS FOR CELL-SPECIFIC DELETION. WE EXPECT THAT SUCCESSFUL COMPLETION OF THE PROPOSED STUDIES WILL IDENTIFY NOVEL ROLES FOR THE INNATE IMMUNE SYSTEM IN REGULATING HIGHLY COMPLEX RETINAL VASCULAR DEVELOPMENTAL PROCESSES. MOREOVER, FURTHER ELUCIDATING PHYSIOLOGICAL REGULATORY MECHANISMS OF VASCULAR DEVELOPMENT, WILL ALSO IDENTIFY FUTURE PUTATIVE THERAPEUTIC STRATEGIES FOR RETINAL VASCULAR PATHOLOGIES.

THE MECHANISMS RESPONSIBLE FOR ACUTE BILIARY PANCREATITIS

AN ANIMAL MODEL OF DIABETIC AUTONOMIC NEUROPATHY: STUDY OF MECHANISM AND THERAPY

CTRIP: MMP1-PAR1-BASED INTERVENTIONS IN ARTERIAL THROMBOSIS

CLIP R-59: A NOVEL REGULATOR OF AKT SIGNALING

RESEARCH TRAINING IN ONCOLOGY

CDK6 IN T CELL DEVELOPMENT AND CANCER

BEYOND THE GLOMERULUS: NOVEL CLINICAL MARKERS OF KIDNEY HEALTH AND PROGNOSIS

CYCLIN D1 FUNCTION IN TUMORIGENESIS AND DIFFERENTIATION

GALECTIN-3 AND CORNEAL NERVE REGENERATION - PROJECT SUMMARY/ABSTRACT THE AVASCULAR CORNEA IS INNERVATED BY A DENSE NETWORK OF SENSORY PROCESSES DERIVED FROM THE OPHTHALMIC AND MAXILLARY REGIONS OF THE TRIGEMINAL GANGLION. CORNEAL NERVES PROVIDE NOT ONLY MECHANICAL, CHEMICAL, AND THERMAL SENSITIVITY TO THE FRONT OF THE EYE BUT ALSO RELEASE NUTRIENTS AND TROPHIC FACTORS THAT SUPPLY THE CORNEA. STRUCTURAL AND FUNCTIONAL NERVE ABNORMALITIES ARE THE HALLMARKS OF NEUROTROPHIC KERATOPATHY, A DEGENERATIVE DISEASE ASSOCIATED WITH IMPAIRED CORNEAL HEALING AND ULCERATION. THESE ABNORMATILIES CAN ALSO BE OBSERVED IN OTHER CONDITIONS KNOWN TO CAUSE CORNEAL DAMAGE, SUCH AS DRY EYE. MOST THERAPEUTIC APPROACHES AIMED TO PROMOTE CORNEAL NERVE REGENERATION FOCUS ON PROVIDING NEUROTROPHIC SUPPORT. RECENTLY, THE U.S. FOOD AND DRUG ADMINISTRATION HAS APPROVED THE USE OF RECOMBINANT NERVE GROWTH FACTOR EYE DROPS FOR THE TREATMENT OF NEUROTROPHIC KERATOPATHY, BUT ITS USE HAS BEEN ASSOCIATED WITH SEVERAL ADVERSE EFFECTS AND LIMITATIONS. THIS PROPOSAL CENTERS ON A MAJOR GAP IN OUR UNDERSTANDING OF THE INHIBITORY MECHANISMS HAMPERING CORNEAL NERVE REGENERATION, WHICH COULD PROVE IMPORTANT TO DEVELOP NEW STRATEGIES TO PROMOTE FUNCTIONAL REINNERVATION. RESEARCH DURING THE LAST DECADE HAS CONSISTENTLY FOUND INCREASED LEVELS OF THE CARBOHYDRATE-BINDING PROTEIN GALECTIN-3 IN THE TEAR FLUID AND CORNEAL EPITHELIUM OF PATIENTS WITH OCULAR SURFACE DISEASE. IMPORTANTLY, THE AREAS WHERE INCREASED GALECTIN-3 EXPRESSION HAS BEEN OBSERVED COINCIDE WITH THE LOCATION OF INTRAEPITHELIAL NERVE TERMINALS AND THE BASAL NERVE PLEXUS. IT IS BECOME INCREASINGLY CLEAR THAT MULTIMERIZATION OF GALECTIN-3 LEADS TO CROSS-LINKING OF CARBOHYDRATE LIGANDS AND THE FORMATION OF LATTICE-LIKE STRUCTURES ON PLASMA MEMBRANES ESSENTIAL FOR REGULATING CELL SURVIVAL OR DEGENERATION. WE HYPOTHESIZE THAT OVERABUNDANCE OF GALECTIN-3 PROMOTES DEGENERATIVE SIGNALING BY INTERACTING WITH SPECIFIC SURFACE RECEPTORS IN PERIPHERAL SENSORY NEURONS AND MAY CONSTITUTE AN IMPORTANT THERAPEUTIC TARGET FOR THE FULL RECOVERY OF NERVE SENSATION IN CORNEAL DISEASE. THE FOLLOWING SPECIFIC AIMS WILL ADDRESS THIS OBJECTIVE: (1) TO EXAMINE THE ROLE OF GALECTIN-3 IN MODULATING NEUROTROPHIC SIGNALING, (2) TO DETERMINE THE IMPACT OF GALECTIN-3 ON THE NEURAL MECHANISMS UNDERLYING CORNEAL DISEASE, AND (3) TO INVESTIGATE WHETHER WHETHER THERAPEUTIC INHIBITION OF GALECTIN-3 IMPROVES CORNEAL NERVE REGENERATION AND SENSATION. IT IS ANTICIPATED THAT THE SUCCESSFUL CONCLUSION OF THIS PROJECT WILL REVEAL A NOVEL MECHANISM BY WHICH GALECTIN-3 REGULATES NEUROTROPHIC SIGNALING IN CORNEAL NERVES. RESULTS COULD POTENTIALLY ADVANCE THE FIELD OF CORNEAL NERVE REGENERATION BY TARGETING THE PATHOLOGICAL ACTIONS OF GALECTIN-3 AND LEAD TO THE DEVELOPMENT OF NOVEL THERAPIES TO PROMOTE FUNCTIONAL INNERVATION.

THROMBIN RECEPTOR-G PROTEIN SIGNALING MECHANISMS

MITOCHONDRIA AND MUSTARD DAMAGE AT THE OCULAR SURFACE - PROJECT SUMMARY OCULAR SURFACE (OCS) EXPOSURE TO THE CHEMICAL WARFARE VESICANT SULFUR MUSTARD (SM), OR ITS ANALOGUE NITROGEN MUSTARD (NM), CAUSES IMMEDIATE TISSUE DAMAGE AND LONG-TERM PATHOLOGY. CURRENT MEDICAL COUNTERMEASURES (MCMS) FREQUENTLY RESULT IN INCOMPLETE OR TRANSIENT EFFICACY. EXCESSIVE ACCUMULATION OF REACTIVE OXYGEN SPECIES (ROS) INDUCES OXIDATIVE STRESS (OXS), WHICH PLAYS PROMINENTLY IN OCS EPITHELIAL DAMAGE FROM A VARIETY OF CAUSES, INCLUDING EXPOSURE TO SM AND ANALOGUES. ROS ARE PRODUCED BY MITOCHONDRIA. IT IS KNOWN THAT MITOCHONDRIA ARE DAMAGED BY EXPOSURE TO SM ANALOGUES, BUT MECHANISMS LEADING TO OXS ARE UNDER- EXPLORED. RECENTLY, THE PROJECT TEAM MADE THE UNEXPECTED DISCOVERY THAT DYNASORE AND DYNGO-4A, SMALL MOLECULES THAT TARGET DYNAMIN FAMILY PROTEINS INVOLVED IN MITOCHONDRIAL HOMEOSTASIS, ARE REMARKABLY PROTECTIVE AGAINST OXS DUE TO HYDROGEN PEROXIDE (HP) EXPOSURE IN AN OCS EPITHELIAL CELL CULTURE MODEL. IN A FOLLOW-UP STUDY, THEY IDENTIFIED A NOVEL PATHWAY WHEREBY DYNASORE PROTECTS BY INHIBITING CA2+ INFLUX, SHIFTING ACTIVITY OF THE UNFOLDED PROTEIN RESPONSE (UPR) TOWARDS HOMEOSTASIS AND INHIBITING MITOCHONDRIAL TRANSITION PORE (MPTP) OPENING. IN PRELIMINARY DATA PRESENTED HEREIN, THEY NOW SHOW THAT NM EXPOSURE ALSO INDUCES THE UPR IN THE CELL CULTURE MODEL, BUT DYNASORE IS NOT PROTECTIVE. INTERESTINGLY, ANOTHER SMALL MOLECULE INHIBITOR OF DYNAMINS IS PROTECTIVE: MDIVI-1. SIGNFICANTLY, MDIVI-1 DID NOT SHIFT THE UPR TOWARDS HOMEOSTASIS IN NM-EXPOSED CELLS AND DID NOT PROTECT AGAINST HP EXPOSURE. THESE RESULTS INDICATE THAT MECHANISMS LEADING TO OXS AFTER EXPOSURE TO HP OR NM MUST BE DIFFERENT, AND THAT ELUCIDATING THE MECHANISM OF MDIVI-1 COUNTERACTION MAY PROVIDE IMPORTANT INSIGHT INTO HOW NM DAMAGES CELLS. MDIVI-1 HAS BEEN WIDELY CONSIDERED TO BE A SPECIFIC INHIBITOR OF THE MITOCHONDRIAL-LOCALIZED DYNAMIN DRP1. HOWEVER, IT WAS RECENTLY REPORTED THAT MDIVI-1 ALSO DIRECTLY TARGETS MITOCHONDRIAL ENERGETICS. THE OBJECTIVE OF THIS PROJECT IS TO INVESTIGATE MITOCHONDRIAL MECHANISMS IN OCS EXPOSURE TO NM, THE RELATIONSHIP TO HP EXPOSURE, AND MECHANISMS OF OCS PROTECTION BY MDIVI-1. THE TEAM WILL EMPLOY A WELL-ESTABLISHED HUMAN CORNEAL EPITHELIAL CELL CULTURE MODEL. TO ENSURE SCIENTIFIC RIGOR, PRIMARY HUMAN CORNEAL EPITHELIAL CELLS WILL BE USED TO VALIDATE KEY RESULTS IN VITRO, AND A MOUSE MODEL WILL PROVIDE IN VIVO VALIDATION. TO ADD AN INNOVATIVE DIMENSION, LIVE CELL EVALUATIVE METHODS AND DISCOVERY TECHNIQUES WILL BE APPLIED, INCLUDING CA2+ IMAGING, MITOCHONDRIAL IMAGING, CELL-BASED REPORTER CONSTRUCTS, TRANSGENIC REPORTER MICE, RNA-SEQ AND SINGLE CELL RNA-SEQ (SCRNA-SEQ). RESULTS OF THE PLANNED STUDY WILL PROVIDE NEW KNOWLEDGE ABOUT HOW NM EXPOSURE LEADS TO OXS. MDIVI-1 HAS THE UNUSUAL CAPACITY TO ATTENUATE PATHOLOGICAL ROS PRODUCTION WHILE HAVING LIMITED IMPACT ON ROS IN HEALTHY CELLS, MAKING IT UNIQUELY ATTRACTIVE AS A POTENTIAL MCM.

CRITICAL ROLES FOR IRON AND COPPER DETOXIFICATION IN BORRELIA BURGDORFERI

PHASE 2 STUDY OF RHCC10 TO PREVENT NEONATAL BRONCHOPULMONARY DYSPLASIA

THE RELATION OF SOLUBLE KLOTHO WITH CARDIOVASCULAR DISEASE, CHRONIC KIDNEY DISEASE PROGRESSION, AND BLOOD PRESSURE IN THE SYSTOLIC BLOOD PRESSURE INTERVENTION TRIAL - ABSTRACT SOLUBLE A-KLOTHO (“KLOTHO”) HAS SYSTEMIC EFFECTS IN MAINTENANCE OF CELL HEALTH INCLUDING REDUCTION OF OXIDATIVE STRESS AND FIBROSIS IN THE HEART AND KIDNEY. KIDNEY TUBULES ARE THE PRIMARY SOURCE OF CIRCULATING (SOLUBLE) KLOTHO AND THEREFORE THE DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD) RESULTS IN KLOTHO DEFICIENCY. KLOTHO DEFICIENCY MAY ALSO PARADOXICALLY CONTRIBUTE TO CKD PROGRESSION. RODENT MODELS OF KLOTHO DEFICIENCY DISPLAY VULNERABILITY TO KIDNEY INJURY AND PROGRESSION OF KIDNEY DISEASE, WHILE ADMINISTRATION OF EXOGENOUS KLOTHO ATTENUATES KIDNEY DAMAGE AND DISEASE PROGRESSION. KLOTHO DEFICIENCY MAY ALSO CONTRIBUTE TO EXCESS CARDIOVASCULAR DISEASE (CVD) RISK IN CKD AS KLOTHO KNOCKOUT MICE DISPLAY VASCULAR CALCIFICATION AND PATHOLOGICAL CARDIAC REMODELING WITH CARDIAC HYPERTROPHY AND FIBROSIS. FURTHER, BLOOD PRESSURE (BP) MAY INFLUENCE KLOTHO LEVELS AS PRECLINICAL DATA SHOW THAT MULTIPLE MODELS OF HYPERTENSION ALL RESULT IN KLOTHO DEFICIENCY. THUS FAR, THE MAJORITY OF CLINICAL STUDIES EXAMINING SOLUBLE KLOTHO HAVE RELIED PRIMARILY ON A SINGLE COMMERCIAL SOURCE OF ELISA. THERE ARE CONCERNS ABOUT THE PERFORMANCE AND REPRODUCIBILITY OF THIS ASSAY AS THE CLINICAL DATA HAVE BEEN INCONSISTENT. SOME STUDIES HAVE REPORTED NO RELATIONSHIP OR HIGHER LEVELS OF SOLUBLE KLOTHO WITH REDUCED KIDNEY FUNCTION, WHILE OTHERS HAVE SHOWN A PARALLEL DECLINE IN KLOTHO AND KIDNEY FUNCTION. THIS DISCREPANCY HAS HINDERED WIDESPREAD MEASUREMENT OF KLOTHO IN LARGE-SCALE HUMAN STUDIES AND HAS LED TO A PAUCITY OF QUALITY DATA EXAMINING THE ROLE OF KLOTHO IN HUMAN CKD. SIMILARLY, THERE ARE NO LONGITUDINAL DATA ON CHANGES IN KLOTHO OVER TIME IN CKD. IN A PILOT PROJECT USING SAMPLES FROM THE SYSTOLIC BLOOD PRESSURE INTERVENTION TRIAL (SPRINT) WE COMPARED THE MOST WIDELY USED COMMERCIAL ELISA WITH AN IMMUNOPRECIPITATION-IMMUNOBLOT (IP-IB) ASSAY, AND FOUND THAT THE IP-IB ASSAY EXHIBITED SUPERIOR PERFORMANCE. SUBSEQUENTLY, WE HOPE TO ADDRESS THE CURRENT LACK OF HIGH QUALITY HUMAN STUDIES EXAMINING SOLUBLE KLOTHO AS A RISK FACTOR FOR CVD AND CKD PROGRESSION. SPRINT IS THE IDEAL COHORT TO ANSWER THESE QUESTIONS AS THE TRIAL ENROLLED 2646 PARTICIPANTS WITH CKD AND HAS DETAILED CVD AND KIDNEY OUTCOMES. THIS COHORT IS ALSO WELL-SUITED TO EXAMINE THE PATIENT-SPECIFIC AND DISEASE-SPECIFIC CLINICAL FACTORS THAT MAY IMPACT LONGITUDINAL CHANGES IN SOLUBLE KLOTHO INCLUDING: THE INTENSIVE VS. STANDARD BLOOD PRESSURE CONTROL INTERVENTION, MEASURES OF MINERAL METABOLISM INCLUDING FGF-23, AND MEASURES OF KIDNEY TUBULAR INJURY/HEALTH. WE PROPOSE TO MEASURE BASELINE SERUM AND URINE KLOTHO CONCENTRATIONS IN 2646 SPRINT PARTICIPANTS WITH CKD AT BASELINE AS WELL AS IN A PRE-SPECIFIED SUBSET OF 1000 PERSONS AT YEAR 1 AND YEAR 4 TO: 1) COMPARE THE IP-IB ASSAY WITH THE COMMERCIAL KLOTHO ELISA; 2) DETERMINE THE ASSOCIATION OF KLOTHO WITH CVD EVENTS, DEATH, AND CKD PROGRESSION; AND 3) IDENTIFY THE CLINICAL FACTORS THAT INFLUENCE LONGITUDINAL CHANGES IN KLOTHO INCLUDING INTENSIVE VS. STANDARD BP CONTROL, MARKERS OF MINERAL METABOLISM AND/OR KIDNEY TUBULAR HEALTH. SUCH DATA CAN COLLECTIVELY SET THE STAGE FOR FUTURE KLOTHO INTERVENTIONAL TRIALS, INFORM CLINICAL RISK- STRATIFICATION MODELS AND PROVIDE A FOUNDATION FOR TRANSLATIONAL RESEARCH IN KLOTHO BIOLOGY AND THERAPEUTICS.

ERBB SIGNALING IN FETAL TYPE II CELL GROWTH

BASIC MECHANISMS OF HUMAN CALCIFIC AORTIC VALVE DISEASE

GPCR VARIANTS AS GENETIC DETERMINANTS OF OBESITY

GENETIC MARKERS OF GIK EFFECT IN ACUTE CORONARY SYNDROME IN THE IMMEDIATE TRIAL

FOCUSED IMAGING AS A NOVEL DIAGNOSTIC STRATEGY FOR AORTIC STENOSIS - AORTIC STENOSIS (AS) IS A VALVE CONDITION THAT AFFECTS OVER 12.6 MILLION ADULTS AND CAUSES AN ESTIMATED 102,700 DEATHS EACH YEAR. MANY PATIENTS WITH AS DO NOT KNOW ABOUT THE DIAGNOSIS BECAUSE IT IS DIFFICULT TO DIAGNOSE WITH A STETHOSCOPE. IT IS ESTIMATED THAT THERE ARE OVER 560,000 UNDIAGNOSED CASES OF AS IN THE UNITED STATES ALONE. WHEN PATIENTS WITH SYMPTOMATIC AS ARE NOT TREATED, 50% WILL DIE IN 2 YEARS. WE HAVE DEVELOPED A METHOD TO AUTOMATE THE DIAGNOSIS OF AS FROM CARDIAC ULTRASOUND IMAGING USING MACHINE LEARNING. THIS REPRESENTS A NEW WAY TO DIAGNOSE AS. IN THIS PROPOSAL WE WILL IMPROVE THESE NETWORKS TO RELIABLY IDENTIFY SEVERE AS PATIENTS THAT SHOULD BE REFERRED FOR EVALUATION. ADDITIONALLY, WE WILL TRAIN THE NETWORKS TO WORK WITH PORTABLE HANDHELD ULTRASOUND DEVICES AND WE WILL STUDY HOW TO IMPLEMENT THIS TOOL IN PRIMARY CARE OFFICES TO SCREEN HIGH RISK PATIENTS. BY DEVELOPING AND VALIDATING INNOVATIVE MACHINE LEARNING (ML) METHODS FOR DIAGNOSING AS WE WILL ESTABLISH TOOLS TO IMPROVE THE IDENTIFICATION AND TREATMENT OF THIS LIFE-THREATING CONDITION.

INDUCTION OF TOLERANCE USING T CELLS TO DELIVER ANTIGEN

DISCOVERY OF THE BIOMARKER SIGNATURE FOR NEUROPATHIC CORNEAL PAIN - PROJECT ABSTRACT NEUROPATHIC CORNEAL PAIN (NCP) IS AN OCULAR TYPE OF NEUROPATHIC PAIN. IT CAUSES PATIENTS TO HAVE SEVERE DISCOMFORT AND A SEVERELY COMPROMISED QUALITY OF LIFE (QOL). THE LACK OF SIGNS OBSERVED BY STANDARD EXAMINATION HAS RESULTED IN MISDIAGNOSIS AS DRY EYE DISEASE (DED) RESULTING IN AN INEFFICIENT USE OF HEALTHCARE FUNDS. THE IDENTIFICATION OF A DIAGNOSTIC BIOMARKER FOR NCP AND DEVELOPMENT OF A DETECTION METHOD WOULD ALLOW ADEQUATE AND TIMELY TREATMENT, IMPROVE PATIENTS’ QOL, AND DECREASE THE HEALTH CARE SYSTEM’S FINANCIAL BURDEN. AN OPTICAL BIOPSY CAN BE PERFORMED USING LASER IN VIVO CONFOCAL MICROSCOPY (IVCM), WHICH ALLOWS FOR VISUALIZATION OF SUBBASAL CORNEAL NERVES AT A QUASI-HISTOLOGICAL LEVEL. PRELIMINARY DATA HAS SHOWN THAT IVCM IDENTIFIED MICRONEUROMAS (A BULB AT THE END OF A SEVERED NERVE CAUSED BY BUILD-UP OF MOLECULAR CONSTITUENTS) ARE PRESENT IN NCP, BUT NOT DED, PATIENTS. WE PROPOSE TO VALIDATE MICRONEUROMAS AS A NOVEL BIOMARKER FOR NCP. IN AIM 1 WE WILL USE OUR DATABASE OF OVER 2,000 DED/NCP SUBJECTS AND OVER 500,000 IVCM IMAGES TO CONFIRM THAT THE PRESENCE OF MICRONEUROMAS IS AN APPROPRIATE BIOMARKER FOR NCP BY COMPARING THE SENSITIVITY AND SPECIFICITY OF IDENTIFICATION OF NCP PATIENTS VIA MICRONEUROMAS TO OTHER IVCM PARAMETERS. THREE OBSERVERS WILL EACH GRADE IMAGES TWICE FOR THIS CONFIRMED BIOMARKER TO ASSESS INTER- AND INTRA-OBSERVER PRECISION, AND DESCRIPTIVE STATISTICS OF THE IVCM DATASETS WILL ALLOW FOR DETERMINATION OF THE MINIMUM NUMBER OF IMAGES NECESSARY FOR HIGH PRECISION OF MICRONEUROMA DETECTION. AIM 2 WILL PROVIDE BIOLOGICAL VALIDATION OF MICRONEUROMAS. BOTH THE INTENSITY OF OCULAR PAIN AND THE COMPROMISE TO QOL CAUSED BY OCULAR PAIN AS ASSESSED BY THE OCULAR PAIN ASSESSMENT SURVEY (OPAS) WILL BE COMPARED BETWEEN THOSE WITH MICRONEUROMAS AND THOSE WITHOUT. FURTHER, THE CHANGE IN OCULAR PAIN/DISCOMFORT IN RESPONSE TO INSTILLATION OF HYPEROSMOLAR SALINE INTO THE EYES WILL BE COMPARED BETWEEN THOSE WITH MICRONEUROMAS AND THOSE WITHOUT. IN AIM 3 WE WILL DEVELOP A VALIDATED ARTIFICIAL INTELLIGENCE (AI) PROGRAM FOR AUTOMATED IDENTIFICATION OF MICRONEUROMAS TO ALLOW RAPID AND WIDE-SCALE ADOPTION BY CLINICIANS. ACCURACY OF THE PROGRAM WILL BE DETERMINED BY EVALUATING THE AGREEMENT OF THE AI PROGRAM’S ASSESSMENT OF IVCM IMAGES WITH THE ASSESSMENT OF 2 OBSERVERS. A SIMILAR ASSESSMENT OF ACCURACY WILL BE ASSESSED USING IMAGES OBTAINED FROM AN INDEPENDENT SITE SO THAT INTER-SITE PRECISION CAN BE EVALUATED. THE AI PROGRAM WILL ALSO BE ASSESSED FOR ITS SPECIFICITY AND SENSITIVITY IN NCP IDENTIFICATION. AIM 4 WILL ESTABLISH THE CLINICAL UTILITY OF MICRONEUROMAS OBSERVED BY IVCM AS A BIOMARKER FOR NCP IN A PROSPECTIVE, MULTI-CENTER STUDY. THE BIOMARKER’S PRECISION, REFERENCE INTERVALS, AND HARMONIZATION OF PERFORMANCE BETWEEN SITES AS WELL AS THE SENSITIVITY AND SPECIFICITY OF NCP DIAGNOSIS WILL BE DETERMINED USING THIS PROSPECTIVE COHORT. NEXT, THE MICRONEUROMA FINDINGS WILL BE CORRELATED WITH THE OPAS AND HYPEROSMOLAR FUNCTIONAL TESTS FOR BIOLOGICAL VALIDATION. FINALLY, THE AI PROGRAM’S ABILITY TO PROVIDE A DIAGNOSIS OF NCP WILL BE TESTED USING THE IVCM IMAGES FROM THIS STUDY.

CHARACTERIZATION OF RAPIDLY PROGRESSIVE KNEE OSTEOARTHRITIS

FHOD3 REGULATION OF AUTOPHAGY PATHWAY IN CARDIOMYOPATHY - PROJECT SUMMARY CYTOSKELETAL REMODELING AND TURNOVER ARE CENTRAL CONTRIBUTORS TO LEFT VENTRICULAR (LV) REMODELING THAT UNDERLIES CARDIOMYOPATHY AND HEART FAILURE. FORMIN HOMOLOGY 2 DOMAIN CONTAINING-3 (FHOD3) IS A MEMBER OF THE FORMIN PROTEIN FAMILY THAT REGULATES CARDIAC ACTIN FILAMENT FORMATION. FHOD3 IS REQUIRED FOR SARCOMERE FORMATION DURING EMBRYONIC HEART DEVELOPMENT AND REMODELING OF THE ADULT HEART. WE IDENTIFIED A COMMON VARIANT, FHOD3V1151I (RS2303510), ASSOCIATED WITH HYPERTROPHIC CARDIOMYOPATHY (HCM). TO INVESTIGATE THE MECHANISTIC BASIS OF THE ASSOCIATION OF FHOD3V1151I WITH HCM, WE USED CRISPR TO CREATE AN FHOD3V1151I MOUSE MODEL AND DISCOVERED THAT FHOD3V1151I MICE HAVE NORMAL HEART SIZE AND CONTRACTILE FUNCTION IN THE ABSENCE OF HYPERTROPHIC STIMULUS. PROVOCATIVELY, THOUGH, FHOD3V1151I MICE DEVELOP EXCESSIVE CARDIAC HYPERTROPHY AND PHYSIOLOGIC FINDINGS OF HEART FAILURE, INCLUDING ACTIVATION OF THE FETAL GENE PROGRAM WITH PRESSURE OVERLOAD. USING OUR STATE-OF-THE-ART AUTOPHAGY DETECTING NANOPARTICLE IMAGING TECHNOLOGY WE DEMONSTRATE THAT FHOD3V1151I MICE HAVE IMPAIRED AUTOPHAGY. THE ROLE OF AUTOPHAGY DEFECTS ARE RECOGNIZED IN CARDIOMYOPATHY AND ARE THEREFORE EMERGING AS AN IMPORTANT MODIFIER TO THE CARDIAC RESPONSE TO STRESS THAT COULD IMPACT THE DEVELOPMENT OF HCM AND ASSOCIATED SYMPTOMS. IN THIS PROPOSAL, WE WILL COMPARE THE RESPONSE OF FHOD3V1151I MICE TO AUTOPHAGY STIMULATION (RAPAMYCIN) AND INHIBITION (BAFILOMYCIN). FURTHERMORE, WE WILL TEST THE ROLE OF THE FHOD3 VARIANT IN THE CONTEXT OF A MUTATION IN MYBPC3, WHICH SERVES AS A MOUSE MODEL OF HCM KNOWN TO HAVE DEFECTIVE AUTOPHAGY. BECAUSE FHOD3V1151I MICE HAVE REDUCED LEVELS OF THE EARLY AUTOPHAGY REGULATOR BECLIN, WE WILL ASSESS WHETHER THE RECOMBINANT PROTEIN TAT-BECLIN CAN RESCUE THE AUTOPHAGY DEFECT CAUSED BY FHOD3V1151I IN THE CONTEXT OF A MYBPC3 MUTATION THAT CAUSES HCM. FINALLY, SINCE EXTRACELLULAR VESICLE (EV) FORMATION IS A DIRECT CONSEQUENCE OF AUTOPHAGY AND WE DEMONSTRATE SIGNIFICANT DEFECTS IN EV PRODUCTION WITH FHOD3V1151I, WE WILL EVALUATE THE EFFECTS OF FHOD3 ON CELLULAR COMPONENT TRAFFICKING RELATED TO AUTOPHAGY AND EV PRODUCTION. CONSIDERING THAT THE FHOD3V1151I ALLELE IS CARRIED BY APPROXIMATELY ONE THIRD OF HUMANS OF ALL RACES AND ETHNICITIES, AND BECAUSE OF ITS ESTABLISHED ASSOCIATION WITH HCM AS A RISK ALLELE, THE POTENTIAL IMPACT OF THIS STUDY ON HUMAN HEART FAILURE IS SUBSTANTIAL. BY DEFINING THE MECHANISMS BY WHICH FHOD3 VARIANTS MODIFY CARDIAC AUTOPHAGY AND LV REMODELING, INCLUDING THE ROLE OF GENOTYPE-DEFINED PERSONALIZED MEDICINE STRATEGIES THAT MAY MODIFY THIS GENETIC RISK, THESE STUDIES HAVE THE POTENTIAL TO TRANSLATE INTO IMPROVED HEART FAILURE MANAGEMENT.

THE ROLE OF PLASMACYTOID DENDRITIC CELLS IN CORNEAL IMMUNITY - SUMMARY THE CORNEA IS AMONG THE FEW TISSUES THAT ENJOY IMMUNE PRIVILEGE, HOWEVER, CORNEAL IMMUNE PRIVILEGE IS NOT ABSOLUTE. IN MANY CORNEAL DISEASES, INCLUDING INFECTIOUS KERATITIS, DRY EYE DISEASE, AND CORNEAL INJURIES, INFILTRATING LEUKOCYTES CAN ADVANCE DISEASE PROGRESSION. OUR PRELIMINARY RESULTS SUGGEST THAT PLASMACYTOID DENDRITIC CELLS (PDCS), WHICH RESIDE IN THE CORNEA DURING STEADY STATE, ACTIVELY PARTICIPATE IN THE MAINTENANCE OF CORNEAL IMMUNE HOMEOSTASIS, AS THEIR DEPLETION LEADS TO ENHANCED CORNEAL LEUKOCYTE INFILTRATION AND AMPLIFIED ADAPTIVE IMMUNE RESPONSES IN DRAINING LYMPH NODES (DLNS). THUS, IN THIS APPLICATION, WE PROPOSE TO EVALUATE THE SIGNIFICANCE OF PDCS IN THE MAINTENANCE OF TOLERANCE AND THE MECHANISMS THROUGH WHICH PDCS CONTRIBUTE TO CORNEAL IMMUNE HOMEOSTASIS. WE WILL IDENTIFY POTENTIAL CANDIDATES THROUGH SINGLE CELL SEQUENCING OF PDCS. WE AIM TO STUDY THE ROLE OF PDCS IN MEDIATING MULTIPLE STEPS INVOLVED IN THE PROCESS OF INFLAMMATION, FROM LEUKOCYTE RECRUITMENT TO THE CORNEA, ANTIGEN UPTAKE AND PROCESSING BY ANTIGEN PRESENTING CELLS, THEIR EGRESS TO, AND ANTIGEN PRESENTATION IN DLNS, AND PRIMING OF T CELLS. ADDITIONALLY, WE HAVE OBSERVED THAT PDCS INTERACT DIRECTLY WITH T CELLS IN THE DLNS, AND SUPPORT DEVELOPMENT AND STABILIZATION OF REGULATORY T CELL (TREGS), IMPORTANT IMMUNOSUPPRESSIVE LYMPHOCYTES. WE AIM TO ANALYZE THE MOLECULAR MECHANISMS BY WHICH PDCS INDUCE AND MAINTAIN TREGS, AS WELL AS EXAMINE THE CLINICAL UTILITY OF ADOPTIVE TRANSFER OF PDC- INDUCED TREGS IN INFECTIOUS KERATITIS, DRY EYE DISEASE AND CORNEAL TRANSPLANTATION. WE ALSO PROPOSE TO STUDY THE FEASIBILITY, EFFICACY, AND POTENTIAL LOCAL AND SYSTEMIC SIDE EFFECTS OF LOCAL ADOPTIVE TRANSFER OF PDCS TO THE CORNEA FOR THE TREATMENT OF IMMUNE AND INFLAMMATORY DISEASES. NEXT, WE AIM TO EVALUATE THERAPEUTIC EFFICACY OF LOCAL ADOPTIVE TRANSFER OF PDCS OR APPLICATION OF PDC SECRETOME IN LIMITING CLINICAL SEVERITY OF THE DISEASE, INFILTRATION OF LEUKOCYTES, DISEASE PROGRESSION, AND COMPLICATIONS IN MODELS OF DRY EYE DISEASE AND HERPES SIMPLEX KERATITIS. THIS APPLICATION PROPOSES A PARADIGM SHIFT ON HOW PDCS MODULATE IMMUNITY, AND COULD RESULT IN THE INTRODUCTION OF NEW IMMUNOMODULATORY THERAPEUTIC AVENUES FOR OCULAR AS WELL AS SYSTEMIC INFLAMMATORY, AUTOIMMUNE, ALLOIMMUNE AND INFECTIOUS DISEASES.

ROLE OF BUB1 IN SV40 LARGE T ANTIGEN MEDIATED TRANSFORMATION AND REPLICATION

AKT IN T CELL DEVELOPMENT AND FUNCTION

ROLE OF PRB IN OSTEOGENESIS, CELL CYCLE EXIT AND CANCER

GENETIC MECHANISMS OF RETINAL DEGENERATIVE DISEASE

NOVEL CELLULAR THERAPIES FOR PH+ LEUKEMIA

MAP KINASE SIGNALING IN LYMPHOMA: A NOVEL THERAPEUTIC PARADIGM

CONVERSATIONAL AGENTS TO IMPROVE HPV VACCINE ACCEPTANCE IN PRIMARY CARE - UNIVERSAL HUMAN PAPILLOMAVIRUS (HPV) VACCINATION WOULD SIGNIFICANTLY DECREASE CERVICAL, VAGINAL, VULVAR, ANAL, AND ORAL CANCERS, AND REDUCE RACIAL DISPARITIES IN THESE CANCERS. HOWEVER, HPV VACCINATION RATES FOR U.S. ADOLESCENTS OF ALL RACES, ETHNICITIES, AND INCOME LEVELS REMAIN FAR BELOW NATIONAL TARGETS. INCREASING ANTI-VACCINE INFORMATION, LIMITED CLINICIAN TIME TO ENGAGE WITH HESITANT PARENTS, AND BACKLOGS OF PREVENTIVE CARE INCURRED DURING THE COVID PANDEMIC CONTRIBUTED TO DEFICITS OF HPV VACCINATION THAT MAY YEARS TO RESOLVE. EMBODIED CONVERSATIONAL AGENTS (ECAS) ARE ANIMATED COMPUTER AGENTS THAT SIMULATE FACE-TO-FACE CONVERSATION BETWEEN A PATIENT AND A CAREGIVER, USING BOTH VERBAL AND NONVERBAL CONVERSATIONAL BEHAVIOR, TO PROVIDE A NATURAL AND INTUITIVE COMPUTER INTERFACE THAT IS ACCESSIBLE TO PATIENTS OF ALL LEVELS OF HEALTH AND COMPUTER LITERACY. WE HAVE SUCCESSFULLY DEVELOPED AND EVALUATED THIS INTERFACE IN SEVERAL CLINICAL TRIALS TO MOTIVATE HEALTH BEHAVIOR CHANGE FOR A WIDE RANGE OF POPULATIONS, INCLUDING A PILOT EVALUATION OF AN ECA THAT PROMOTES HPV VACCINATION FOR THE FAMILIES OF PATIENTS WITH CERVICAL PRE-CANCER AND CANCER. IN THIS PROJECT WE WILL ADAPT THIS TECHNOLOGY TO PRODUCE ENGLISH AND SPANISH SMARTPHONE ECAS FOR HPV VACCINATION (ECA-HPV) TO PROVIDE VACCINE RECOMMENDATIONS AND MOTIVATIONAL INTERVIEWING TO PARENTS/GUARDIANS AND VACCINE-ELIGIBLE ADOLESCENTS AND FACILITATE COMMUNICATION WITH CLINIC STAFF. HPV VACCINE PROMOTION OVER TIME CAN LEAD TO ACCEPTANCE AMONG PARENTS WHO INITIALLY DECLINE, AND THE ECA CAN PROVIDE CONTINUAL INTERACTIONS BOTH PRIOR TO AND FOLLOWING CLINIC VISITS. WE WILL EVALUATE ECA-HPV IN A RANDOMIZED CONTROLLED TRIAL FOR HPV-VACCINE ELIGIBLE ADOLESCENTS AGED 9-12 TO EVALUATE ECA-HPV, COMPARING USUAL CARE (UC) (N=175) VERSUS USUAL CARE PLUS FOUR DESIGN VARIANTS OF THE ECA-HPV (UC+ECA) (N= 175 X 4 = 700). ALL INTERVENTION PARTICIPANTS WILL GET THE ECA-HPV FOR THE PARENT; THE DESIGN VARIANTS INCLUDE INCLUSION VS EXCLUSION OF ECA-HPV FOR THE ADOLESCENT AND INCLUSION VS EXCLUSION OF CLINIC NOTIFICATION OF INFORMATION FROM THE SYSTEM IN A 2X2 FACTORIAL DESIGN TO DIFFERENTIATE THE IMPACT OF THE ADOLESCENT- FACING AND CLINIC NOTIFICATION FEATURES OF THE INTERVENTION. THE RESEARCH TEAM IS NATIONALLY RECOGNIZED AS LEADERS IN HPV VACCINATION, HEALTH LITERACY, AND INNOVATIVE TECHNOLOGIES TO IMPROVE HEALTH. THIS STUDY WILL ADVANCE OUR RESEARCH ON THE DEVELOPMENT OF EASY-TO-USE TECHNOLOGIES TO EMPOWER PATIENTS. THIS SCALABLE APPROACH HAS A SIGNIFICANT POTENTIAL TO REDUCE VACCINE HESITANCY AND INCREASE ADOLESCENT VACCINATION. IF SUCCESSFUL, OUR TEAM WILL PROMOTE THE ECA-HPV THROUGH NATIONAL NETWORKS FOR BROAD IMPLEMENTATION AND WORK TO ADAPT ECA-HPV TO INCLUDE OTHER CHILDHOOD, ADOLESCENT, MATERNAL, AND ADULT IMMUNIZATIONS.

INDUCTION OF REGULATORY T CELLS TO CONTROL IBD

INTRACELLULAR MITOCHONDRIAL ENZYME REPLACEMENT THERAPY FOR HEART AND SKELETAL MYOPATHY IN BARTH SYNDROME

THE ROLE OF PLATELETS IN TUMOR GROWTH, WOUND HEALING AND OTHER ANGIOGENESIS DISEA

NEMCH CLINICAL RESEARCH ON AIDS TRAINING GRANT

TPL2 IN INTESTINAL TUMORIGENESIS

EFFECTS OF AGE AND RACE ON GFR ESTIMATION IN A POPULATION-BASED COHORT

MODERNIZING META-ANALYSIS TO FACILITATE COMPARATIVE EFFECTIVENESS REVIEWS

SEROTONIN AND THE RHO SIGNALING PATHWAY IN SMOOTH MUSCLE CELLS

HOW DOES ANDROGEN INHIBIT FETAL MATURATION

LONGITUDINAL FOLLOW-UP TO THE NATIONAL FACULTY SURVEY

PROTEASE-ACTIVATED RECEPTORS IN VASCULAR INTEGRITY AND DYSFUNCTION

AUTOCRINE ROLE OF CYTOKINES IN VASCULAR SMOOTH MUSCLE

REGULATION OF AKT SIGNALING BY DETERGENT RESISTANT MEMBRANE ASSOCIATED PROTEIN CLIPR-59

COGNITION AND DIALYSIS

NOVEL PRECLINICAL TESTING STRATEGIES FOR TREATMENT OF METASTATIC PHEOCHROMOCYTOMA

NICHD COOPERATIVE MULTICENTER NEONATAL RESEARCH NETWORK

ANGIOGENIN AND PLEXIN-B2 IN THERAPEUTIC RESISTANCE AND DISEASE RELAPSE OF GBM - PROJECT SUMMARY GLIOBLASTOMA (GBM) IS A FATAL DISEASE. THE STANDARD OF CARE OF GBM HAS NOT CHANGED OVER DECADES. TUMOR RECURRENCE OCCURS UNIVERSALLY AND THE RECURRED GBM LACKS EFFECTIVE THERAPEUTICS. GLIOMA STEM CELLS (GSCS), WHICH ARE RESISTANT TO RADIO- AND CHEMO-THERAPY, ARE A MAJOR CAUSE OF GBM RECURRENCE. IDENTIFICATION AND CHARACTERIZATION OF REGULATORS AND PATHWAYS THAT MAINTAIN THE STEMNESS PROPERTIES OF GSCS WILL HELP REVEAL NEW TARGETS TO ELIMINATE, DIMINISH, OR EXHAUST GSCS TO OVERCOME THERAPEUTIC RESISTANCE AND TO PREVENT DISEASE RECURRENCE. WE HAVE DISCOVERED THAT ANGIOGENIN (ANG), A SECRETED RIBONUCLEASE, AND ITS FUNCTIONAL RECEPTOR PLEXIN-B2 (PLXNB2), A SINGLE PASS TRANSMEMBRANE PROTEIN, CONSTITUTE A LIGAND-RECEPTOR PAIR THAT ENHANCES THE STEMNESS OF PATIENT-DERIVED GSCS BY PROMOTING SMALL RNA BIOGENESIS, IN PARTICULAR, THE PRODUCTION OF TRNA- DERIVED STRESS-INDUCED SMALL RNAS (TIRNAS), AND PRIMARILY THE 5’TIRNAGLY-GCC. PLXNB2 INHIBITION, BY EITHER GENE KNOCKOUT OR SPECIFIC MONOCLONAL ANTIBODIES (MABS), REDUCES THE SELF-RENEWAL ABILITY AND DIMINISHES THE TUMORIGENIC CAPACITY OF PATIENT-DERIVED GSCS. A COMBINATORIAL TREATMENT WITH PLXNB2 MABS AND TEMOZOLOMIDE (TMZ) DELAYED THE RECURRENCE OF GSC-DRIVED ORTHOTOPIC GBM AND PROLONGED ANIMAL SURVIVAL AS COMPARED TO TMZ MONOTHERAPY. PLXNB2 MAB THERAPY WAS FOUND TO REDUCE THE INTRA-TUMOR LEVEL OF TIRNAS INCLUDING 5’TIRNAGLY-GCC. THERE WAS AN INVERSE CORRELATION BETWEEN THE 5’TIRNAGLY-GCC LEVEL IN THE TUMOR AND ANIMAL SURVIVAL. WE THEREFORE PROPOSE TO CHARACTERIZE THE ANG-PLXNB2-TIRNA AXIS AS A NOVEL REGULATORY PATHWAY THAT MAINTAINS THE STEMNESS PROPERTIES OF GSCS AND THAT CAN BE TARGETED TO PREVENT OR DELAY GBM RECURRENCE UPON CHEMO- AND RADIO-THERAPY. SPECIFIC AIM 1 IS TO CHARACTERIZE THE FUNCTION OF THE ANG/PLXNB2 AXIS IN REGULATION OF GSC PROPERTIES AND GBM RECURRENCE. WE WILL 1) EXAMINE THE ROLE OF ANG/PLXNB2 IN PRONEURAL TYPE AND MESENCHYMAL TYPE GSCS TO UNDERSTAND IF THE REGULATORY FUNCTION IS LIMITED TO A SPECIFIC GSC TYPE OR IF IT IS MORE BROADLY APPLICABLE; 2) DIFFERENTIATE THE FUNCTION OF ANG AND SEMAPHORIN 4C, THE OTHER HIGH AFFINITY LIGAND OF PLXNB2, IN GSCS. SPECIFIC AIM 2 IS TO ELUCIDATE THE MECHANISM BY WHICH ANG/PLXNB2 REGULATES GSC STEMNESS AND GBM RECURRENCE. WE WILL 1) EXAMINE THE FUNCTION AND MECHANISM OF 5’TIRNAGLY-GCC IN REGULATING GSC STEMNESS AND GBM CHEMORESISTANCE; 2) EXAMINE THE FUNCTIONS OF OTHER TIRNA SPECIES THAT ARE SIGNIFICANTLY REGULATED BY ANG/PLXNB2; 3) CONDUCT PROTEOMICS STUDIES TO IDENTIFY TIRNA-REGULATED PROTEINS, AND CHARACTERIZE HOW THEY MEDIATE GSC STEMNESS AND CHEMORESISTANCE. WE EXPECT THAT WE WILL BE ABLE TO DEMONSTRATE ANG AND PLXNB2 AS NOVEL GSC REGULATORS, CHARACTERIZE THE MOLECULAR MECHANISM BY WHICH THEY MAINTAIN GBM STEMNESS, AND ESTABLISH ANG-PLXNB2-TIRNA AXIS AS A TARGETABLE PATHWAY FOR THE PURPOSE OF PREVENTING GBM RECURRENCE UPON RADIO- AND CHEMO-THERAPY.

REGULATION OF THE IMMUNE CELL GLYCOME IN CORNEAL INJURY

TRH REGULATION/BIOSYNTHESIS AND PARAVENTRICULAR NUCLEUS

REGULATION AND FUNCTION OF CDK5 AND EZRIN IN SENESCENCE

HIV PATHOGENESIS TRAINING PROGRAM

PROGRESSION OF SUB-CLINICAL ATHEROSCLEROSIS

THE STRESS-ACTIVATED PROTEIN KINASE PATHWAY

ACUTE PANCREATITIS

COMPARATIVE EFFECTIVENESS OF ECG SCREENING IN CHILDREN WITH ATTENTION DEFICIT HYP

FUNCTIONAL ASSAY DEVELOPMENT FOR TAFAZZIN ENZYME REPLACEMENT CANDIDATE SELECTION - ABSTRACT: FUNCTIONAL ASSAY DEVELOPMENT FOR TAFAZZIN ENZYME REPLACEMENT CANDIDATE SELECTION IN THE PROPOSED RESEARCH PROJECT, WE WILL PERFORM KEY BIOCHEMICAL, CELLULAR AND PHYSIOLOGICAL STUDIES TO EVALUATE THE POTENTIAL OF VARIOUS MODIFIED RECOMBINANT TAFAZZIN ENZYME THERAPEUTICS TO BECOME THE FIRST EFFECTIVE TREATMENT FOR BARTH SYNDROME, A RARE, LIFE-THREATENING DISORDER WITH NO EFFICACIOUS THERAPY. BARTH SYNDROME IS A RARE X-LINKED DISORDER AFFECTING 1:300,000 LIVE BIRTHS, RESULTING FROM DEFECTS IN THE GENE ENCODING TAFAZZIN, AN ACYLTRANSFERASE THAT MODIFIES CARDIOLIPIN TO THE TETRALINOLEOYL FORM AND IS ESSENTIAL FOR MITOCHONDRIAL RESPIRATION. PATIENTS WITH BARTH SYNDROME DEVELOP CARDIOMYOPATHY, MUSCULAR HYPOTONIA AND CYCLIC NEUTROPENIA DURING CHILDHOOD, RARELY SURVIVING TO MIDDLE AGE. AT PRESENT, NO EFFECTIVE THERAPY EXISTS FOR THESE PATIENTS. WE ARE DEVELOPING POTENTIAL ENZYME REPLACEMENT THERAPEUTICS IN WHICH RECOMBINANT TAFAZZIN IS MODIFIED TO CONTAIN A CELLULAR PENETRATING PEPTIDE THAT PROMOTES UPTAKE INTO TAFAZZIN-DEFICIENT CELLS, SOMETIMES IN CONJUNCTION WITH AN ENDOSOMAL ESCAPE PEPTIDE TO FACILITATE ESCAPE FROM LYSOSOMAL DEGRADATION. WE HAVE FOUND THAT THESE RECOMBINANT TAFAZZIN ENZYME REPLACEMENT THERAPEUTICS (RTERTS) CAN ENTER TAFAZZIN-DEFICIENT CELLS, LOCALIZE TO MITOCHONDRIA AND CORRECT BOTH CARDIOLIPIN REMODELING AND MITOCHONDRIAL RESPIRATION DEFECTS, IN VITRO AND IN VIVO TO VARYING DEGREES. TO FACILITATE THE COMMERCIALIZATION OF THESE REAGENTS, WE WILL DEVELOP STANDARDIZED BIOCHEMICAL, CELLULAR AND PHYSIOLOGICAL ASSAYS TO DIRECTLY COMPARE ENZYMATIC FUNCTION, CELLULAR UPTAKE, RESCUE OF CARDIOLIPIN REMODELING DEFECTS, AND RESCUE OF DEFECTIVE MITOCHONDRIAL RESPIRATION IN CULTURED CELLS. BASED ON THESE STUDIES, WE HAVE DEVELOPED A SELECTION ALGORITHM TO IDENTIFY A COHORT OF POTENTIAL LEAD CANDIDATES THAT DEMONSTRATE THE GREATEST BIOCHEMICAL AND BIOLOGICAL ACTIVITY IN VITRO. THE TOP CANDIDATES IDENTIFIED BY THIS ALGORITHM WILL UNDERGO PRODUCTION PROCESS OPTIMIZATION AND EVALUATION FOR ACTIVITY IN VIVO. THE IN VIVO EVALUATION WILL CONSIST OF PHARMACOKINETICS, TISSUE DISTRIBUTION, TOXICOLOGY AND EFFICACY STUDIES IN TAFAZZIN KNOCKOUT MICE USING AN IN HOUSE TAFAZZIN LC-MS PEPTIDE DETECTION ASSAY, AN IN HOUSE ELISA ASSAY TO MEASURE ANTIBODY FORMATION, IN CONJUNCTION WITH MEASUREMENTS OF TAFAZZIN FUNCTION AND LEFT VENTRICULAR FUNCTION. WE BELIEVE THAT OUR STUDIES WILL ESTABLISH STANDARDIZED ASSAYS TO CHARACTERIZE POTENTIAL ENZYME REPLACEMENT THERAPIES FOR BARTH SYNDROME IN THE R61 PHASE, THEREBY FACILITATING EVALUATION OF POTENTIAL LEAD CANDIDATES IN A MOUSE MODEL OF BARTH SYNDROME IN THE R33 PHASE, ULTIMATELY LEADING TO THE IDENTIFICATION OF A LEAD CANDIDATE FOR FURTHER CLINICAL DEVELOPMENT.

THE NOVEL ONCOGENE JCF1 IN DEVELOPMENT AND ONCOGENESIS

VITAMIN D STATUS IN RELATION TO INCIDENT TYPE 2 DIABETES AND CARDIOMETABOLIC RISK

THE ASSOCIATION OF FGF-23 AND KLOTHO WITH COGNITIVE IMPAIRMENT AND CEREBROVASCULAR DISEASE IN CHRONIC KIDNEY DISEASE

CLINICAL RESEARCH TRAINING IN INFECTIOUS DISEASES

INTER-CELLULAR SIGNALING OF INVASTION RECEPTORS IN THE TUMOR MICROENVIRONMENT

PALLIATIVE CARE FOR HIGH-RISK TAVR PATIENTS: THE IMPACT OF MULTIMORBIDITY

HYPOXIA-INDUCED ENDOTHELIAL BARRIER DYSFUNCTION

REMOTE TAI CHI FOR KNEE OSTEOARTHRITIS: AN EMBEDDED PRAGMATIC TRIAL - PROJECT SUMMARY/ABSTRACT SYMPTOMATIC OSTEOARTHRITIS (OA) AFFECTS OVER 32.5 MILLION INDIVIDUALS IN THE U.S. AND IS A LEADING CAUSE OF DISABILITY AND INCREASING MEDICAL COSTS. TOXICITIES ASSOCIATED WITH DRUG THERAPIES FOR KNEE OA PAIN HAVE CAUSED THE NUMBER OF RECOMMENDED TREATMENTS TO DECREASE OVER TIME. THERE IS NOW A CRITICAL SHORTAGE OF TREATMENT OPTIONS FOR PEOPLE WITH KNEE OA, ESPECIALLY BECAUSE COMORBIDITIES THAT COMPLICATE TREATMENT SELECTION ARE HIGHLY PREVALENT IN THIS OLDER ADULT POPULATION. TAI CHI, A MULTI-DIMENSIONAL PRACTICE THAT INTEGRATES PHYSICAL, PSYCHOSOCIAL, AND BEHAVIORAL COMPONENTS, HAS EXHIBITED CLINICALLY SIGNIFICANT IMPROVEMENTS IN CHRONIC KNEE OA PAIN CONDITIONS. THE AMERICAN COLLEGE OF RHEUMATOLOGY CLINICAL PRACTICE GUIDELINES STRONGLY RECOMMEND TAI CHI AS AN INTERVENTION FOR KNEE OA. RECENT STUDIES CONDUCTED DURING THE PANDEMIC SUGGEST THAT REMOTELY DELIVERED TAI CHI IS A PROMISING AND SCALABLE STRATEGY FOR KNEE OA PAIN. HOWEVER, CRITICAL GAPS REMAIN AS TO THE REAL-WORLD EFFECTIVENESS OF REMOTE TAI CHI FOR KNEE OA AND ITS IMPLEMENTATION ACROSS MULTIPLE HEALTH CARE SYSTEMS. WE PROPOSE AN EMBEDDED, PRAGMATIC, RANDOMIZED TRIAL THAT WILL COMPARE THE EFFECTS OF A 3-MONTH TWICE WEEKLY REMOTELY DELIVERED WEB-BASED TAI CHI INTERVENTION VERSUS ROUTINE CARE IN 20-25 CLINICS ACROSS FOUR HEALTH CARE SYSTEMS (TUFTS MEDICAL CENTER, BOSTON MEDICAL CENTER, UNIVERSITY OF CALIFORNIA LOS ANGELES HEALTH, AND CLEVELAND CLINIC OHIO AND CLEVELAND CLINIC FLORIDA) IN FOUR GEOGRAPHIC REGIONS (EASTERN MASSACHUSETTS, SOUTHERN CALIFORNIA, NORTHEAST OHIO, SOUTHERN FLORIDA). WE WILL ENROLL 600 DIVERSE PATIENTS WITH A CLINICAL DIAGNOSIS OF KNEE OA. PARTICIPANTS WILL BE EVALUATED AT BASELINE AND 3 MONTHS, WITH ADDITIONAL FOLLOW-UP AT 6 AND 12 MONTHS. WE HYPOTHESIZE THAT IMPLEMENTATION OF REMOTELY DELIVERED TAI CHI IS FEASIBLE ACROSS FOUR HEALTH CARE SYSTEMS AND THAT TAI CHI, COMPARED TO ROUTINE CARE, WILL IMPROVE PHYSICAL HEALTH (INCLUDING KNEE- RELATED PAIN AND FUNCTION) AND MENTAL HEALTH AS WELL AS HEALTHCARE UTILIZATION. OUR INNOVATIVE STUDY IS THE FIRST RIGOROUS MULTI-SITE, EMBEDDED, PRAGMATIC TRIAL OF A REMOTE TAI CHI MIND-BODY PROGRAM, IN THE MULTIPLE HEALTH CARE SYSTEMS OUTPATIENT PRACTICE AND UTILIZING WEB-BASED TECHNOLOGY, DESIGNED TO IMPROVE PATIENT CENTERED OUTCOMES OF KNEE OA. THE RESULTS WILL ENABLE WIDESPREAD ADOPTION OF MIND-BODY APPROACHES FOR KNEE OA ACROSS HEALTH CARE SYSTEMS AND LAY THE GROUNDWORK FOR FUTURE TRIALS COMPARING THE EFFECTIVENESS OF DIFFERENT IMPLEMENTATION STRATEGIES.

METABOLIC BASIS OF RETINOPATHY OF PREMATURITY AND POTENTIAL TREATMENT WITH ANAPLEROTIC SUBSTRATES - PROJECT SUMMARY/ABSTRACT SUPPLEMENTAL OXYGEN IS PROVIDED TO PREMATURE INFANTS TO PREVENT MORTALITY. HYPEROXIA PREVENTS MORTALITY, HOWEVER, HYPEROXIC EXPOSURE OF PREMATURE INFANTS INHIBITS RETINAL NEUROVASCULAR DEVELOPMENT AND CAUSES RETINOPATHY OF PREMATURITY (ROP). FINDINGS FROM OUR WORK AND OTHER GROUPS INDICATE THAT ROP DEVELOPMENT INVOLVES DEFICITS IN LIVER METABOLISM. FOR EXAMPLE, DHA, AA ARE PRODUCED IN THE LIVER, AND THESE HAVE BEEN ASSOCIATED WITH THE ROP. IN ADDITION, WE HAVE DEMONSTRATED THAT THE LIVER-BASED HIF1-Α IS REQUIRED TO PRODUCE THE RETINAL SERINE/ONE-CARBON METABOLITES TO PREVENT OXYGEN-INDUCED RETINOPATHY (OIR). INFANTS WITH LOW WEIGHT AT BIRTH ARE MORE PRONE TO ROP, IMPLYING THAT NUTRITION PLAYS A ROLE IN ROP DEVELOPMENT. IN ADDITION, PREMATURE INFANT MOTHERS HAVE DIFFERENT FAT COMPOSITIONS IN THEIR MILK. THERE ARE HIGHER AMOUNTS OF MEDIUM- CHAIN FATTY ACIDS (MCFAS) AND LONG-CHAIN POLYUNSATURATED FATTY ACIDS (LCPUFAS) IN THE MILK OF MOTHERS OF PREMATURE INFANTS. ALTHOUGH LCPUFAS HAVE BEEN STUDIED, BOTH IN THE OIR MODEL AND IN ROP CLINICAL TRIALS, THE ROLE OF ENERGY-GENERATING MCFAS REMAINS UNKNOWN. OUR RECENT PUBLICATION HIGHLIGHTS THAT HYPEROXIA DOWNREGULATES THE ENTRY OF GLYCOLYTIC CARBON INTO THE TRICARBOXYLIC ACID CYCLE (TCA CYCLE) AND UPREGULATES GLUTAMINE-FUELED ANAPLEROSIS IN THE MÜLLER CELLS IN RESPONSE TO HYPEROXIA. THIS LOWERS THE AMOUNT OF GLUTAMINE AVAILABLE FOR ENDOTHELIAL CELL PROLIFERATION. WE HYPOTHESIZE, PROVIDING A SUBSTRATE THAT CAN FEED INTO TCA, CAN PREVENT GLUTAMINE DIVERSION INTO TCA CYCLE. ONE OF THE TOP ALTERNATIVE SUBSTRATES IN THE EARLY STAGES OF DEVELOPMENT IS MCFA FROM MATERNAL NUTRITION. WE COMPARED THE FATTY ACID Β-OXIDATION GENES IN THE RETINA. WE FOUND STATISTICALLY SIGNIFICANTLY HIGHER EXPRESSION OF ONLY MCFA UTILIZATION AND KETONE BODY UTILIZATION ENZYMES IN OIR-RESISTANT MOUSE STRAIN. OUR PRELIMINARY DATA SHOWS A HIGHER AVAILABILITY OF MCFA OCTANOATE IN THE BLOOD OF OIR-RESISTANT STRAIN. IN ADDITION, OUR LIVER RNASEQ DATA INDICATES HIGHER CONVERSION OF MCFA-COAS INTO FREE FATTY ACID MCFAS AND KETONE BODIES. WE TESTED THE UTILIZATION OF MEDIUM-CHAIN FATTY ACID-OCTANOATE IN THE RETINAL EXPLANT EXPERIMENTS AND FOUND INCREASED UTILIZATION IN RESPONSE TO HYPEROXIA. ALTOGETHER, OUR DATA INDICATE THAT A BALANCE BETWEEN FATTY ACID UTILIZATION AND NITROGEN COMPOUND-BASED ANAPLEROSIS MAY BE THE UNDERLYING CAUSE OF OXYGEN-INDUCED RETINOPATHY DEVELOPMENT. THE AIM OF THIS GRANT IS TO STUDY FATTY ACID METABOLIC EXCHANGES BETWEEN LIVER AND RETINA AT SYSTEMS LEVELS, AND TO USE ANAPLEROTIC SUBSTRATES IN CONJUNCTION WITH ADENO-ASSOCIATED VIRUSES (AAVS) BASED GENETIC MANIPULATIONS OF THE FATTY ACID METABOLIC GENES, TO PREVENT OXYGEN-INDUCED RETINOPATHY.

KIDNEY FUNCTION AND AGING

PREVENTION OF ANTHRACYCLINE CHEMOTHERAPY CARDIOTOXICITY

IRON EXCESS AND RISK OF INFECTION IN LIVER TRANSPLANT RECIPIENTS

DEVELOPMENT OF A SUBUNIT VACCINE AGAINST BABESIOSIS CAUSED BY BABESIA MICROTI

FUNCTIONAL ASSAY DEVELOPMENT FOR TAFAZZIN ENZYME REPLACEMENT CANDIDATE SELECTION - ABSTRACT: FUNCTIONAL ASSAY DEVELOPMENT FOR TAFAZZIN ENZYME REPLACEMENT CANDIDATE SELECTION IN THE PROPOSED RESEARCH PROJECT, WE WILL PERFORM KEY BIOCHEMICAL, CELLULAR AND PHYSIOLOGICAL STUDIES TO EVALUATE THE POTENTIAL OF VARIOUS MODIFIED RECOMBINANT TAFAZZIN ENZYME THERAPEUTICS TO BECOME THE FIRST EFFECTIVE TREATMENT FOR BARTH SYNDROME, A RARE, LIFE-THREATENING DISORDER WITH NO EFFICACIOUS THERAPY. BARTH SYNDROME IS A RARE X-LINKED DISORDER AFFECTING 1:300,000 LIVE BIRTHS, RESULTING FROM DEFECTS IN THE GENE ENCODING TAFAZZIN, AN ACYLTRANSFERASE THAT MODIFIES CARDIOLIPIN TO THE TETRALINOLEOYL FORM AND IS ESSENTIAL FOR MITOCHONDRIAL RESPIRATION. PATIENTS WITH BARTH SYNDROME DEVELOP CARDIOMYOPATHY, MUSCULAR HYPOTONIA AND CYCLIC NEUTROPENIA DURING CHILDHOOD, RARELY SURVIVING TO MIDDLE AGE. AT PRESENT, NO EFFECTIVE THERAPY EXISTS FOR THESE PATIENTS. WE ARE DEVELOPING POTENTIAL ENZYME REPLACEMENT THERAPEUTICS IN WHICH RECOMBINANT TAFAZZIN IS MODIFIED TO CONTAIN A CELLULAR PENETRATING PEPTIDE THAT PROMOTES UPTAKE INTO TAFAZZIN-DEFICIENT CELLS, SOMETIMES IN CONJUNCTION WITH AN ENDOSOMAL ESCAPE PEPTIDE TO FACILITATE ESCAPE FROM LYSOSOMAL DEGRADATION. WE HAVE FOUND THAT THESE RECOMBINANT TAFAZZIN ENZYME REPLACEMENT THERAPEUTICS (RTERTS) CAN ENTER TAFAZZIN-DEFICIENT CELLS, LOCALIZE TO MITOCHONDRIA AND CORRECT BOTH CARDIOLIPIN REMODELING AND MITOCHONDRIAL RESPIRATION DEFECTS, IN VITRO AND IN VIVO TO VARYING DEGREES. TO FACILITATE THE COMMERCIALIZATION OF THESE REAGENTS, WE WILL DEVELOP STANDARDIZED BIOCHEMICAL, CELLULAR AND PHYSIOLOGICAL ASSAYS TO DIRECTLY COMPARE ENZYMATIC FUNCTION, CELLULAR UPTAKE, RESCUE OF CARDIOLIPIN REMODELING DEFECTS, AND RESCUE OF DEFECTIVE MITOCHONDRIAL RESPIRATION IN CULTURED CELLS. BASED ON THESE STUDIES, WE HAVE DEVELOPED A SELECTION ALGORITHM TO IDENTIFY A COHORT OF POTENTIAL LEAD CANDIDATES THAT DEMONSTRATE THE GREATEST BIOCHEMICAL AND BIOLOGICAL ACTIVITY IN VITRO. THE TOP CANDIDATES IDENTIFIED BY THIS ALGORITHM WILL UNDERGO PRODUCTION PROCESS OPTIMIZATION AND EVALUATION FOR ACTIVITY IN VIVO. THE IN VIVO EVALUATION WILL CONSIST OF PHARMACOKINETICS, TISSUE DISTRIBUTION, TOXICOLOGY AND EFFICACY STUDIES IN TAFAZZIN KNOCKOUT MICE USING AN IN HOUSE TAFAZZIN LC-MS PEPTIDE DETECTION ASSAY, AN IN HOUSE ELISA ASSAY TO MEASURE ANTIBODY FORMATION, IN CONJUNCTION WITH MEASUREMENTS OF TAFAZZIN FUNCTION AND LEFT VENTRICULAR FUNCTION. WE BELIEVE THAT OUR STUDIES WILL ESTABLISH STANDARDIZED ASSAYS TO CHARACTERIZE POTENTIAL ENZYME REPLACEMENT THERAPIES FOR BARTH SYNDROME IN THE R61 PHASE, THEREBY FACILITATING EVALUATION OF POTENTIAL LEAD CANDIDATES IN A MOUSE MODEL OF BARTH SYNDROME IN THE R33 PHASE, ULTIMATELY LEADING TO THE IDENTIFICATION OF A LEAD CANDIDATE FOR FURTHER CLINICAL DEVELOPMENT.

REGULATION OF SMOOTH MUSCLE HYPERPLASTIC GROWTH IN PULMONARY

INNATE IMMUNOMODULATION OF RETINAL NEOVASCULARIZATION - PROJECT SUMMARY PROLIFERATIVE RETINOPATHIES, CHARACTERIZED BY THE GROWTH OF PATHOLOGICAL BLOOD VESSELS (NEOVESSELS), ARE THE LEADING CAUSES OF BLINDNESS IN ALL AGE GROUPS. RETINOPATHY OF PREMATURITY (ROP) IS OF PARTICULAR SIGNIFICANCE IN THE PEDIATRIC POPULATION. IN THIS CONDITION, WIDESPREAD ISCHEMIA DRIVES RETINAL NEOVASCULARIZATION THAT CAN LEAD TO RETINAL DETACHMENT AND PERMANENT VISION LOSS. THE UNDERLYING SIGNALING MECHANISMS THAT ORCHESTRATE THE GROWTH OF NEOVESSELS REMAIN INCOMPLETELY UNDERSTOOD. DEFINING THE MOLECULAR BASIS THAT GOVERNS NEOVASCULARIZATION (NV) IS NECESSARY FOR THE DEVELOPMENT OF NEW OR IMPROVED THERAPEUTIC STRATEGIES. OUR GOAL IS TO DELINEATE THE REGULATORY MECHANISMS THAT FACILITATE NEOVASCULAR GROWTH AND REGRESSION. NORMAL RETINAL VASCULAR DEVELOPMENT IS TIGHTLY REGULATED BY MULTICELLULAR-DERIVED CUES. AT EARLY PHASES OF PHYSIOLOGICAL VASCULAR GROWTH, SPROUTING ENDOTHELIAL TIP CELLS CLOSELY INTERACT AND MIGRATE OVER THE ASTROCYTES TEMPLATE TO FORM THE PRIMARY RETINAL VASCULAR LAYER. DURING THIS PROCESS, MICROGLIA FACILITATE THE SPATIAL ESTABLISHMENT OF THE ASTROCYTE AND VASCULAR NETWORKS. ON THE OTHER HAND, THE CELLULAR GUIDANCE MECHANISM(S) INVOLVED IN PATHOLOGICAL VASCULAR GROWTH ARE NOT CLEARLY KNOWN. OUR PRELIMINARY DATA SHOWS THAT THE ISCHEMIA- INDUCED PATHOLOGICAL VASCULAR GROWTH IN THE RETINA IS GUIDED BY PERIPHERAL IMMUNE CELLS, AND NOT BY ASTROCYTES OR MICROGLIA. FURTHER PRELIMINARY STUDIES DEMONSTRATE THAT LOCALIZED CHEMOKINE SIGNALING AIDS THE RECRUITMENT OF PERIPHERAL IMMUNE CELLS THAT SUBSEQUENTLY PROMOTES NEOVASCULAR GROWTH. ALTHOUGH THE MICROGLIAL-NEOVESSEL INTERACTIONS ARE ABSENT AT EARLY PHASES OF NV, MICROGLIAL RECRUITMENT AND WRAPPING OF NEOVASCULAR TUFTS ARE INCREASED AT PEAK PHASES OF NV. MICROGLIA ARE KNOWN TO PHAGOCYTOSE AND ELIMINATE DYING OR IMMATURE CELLS THROUGH COMPLEMENT ACTIVATION. OUR PRELIMINARY DATA SHOWS THAT THE LOSS OF COMPLEMENT RECEPTORS REDUCED NEOVASCULAR REGRESSION. BASED ON THESE FINDINGS, WE HYPOTHESIZE THAT NEOVASCULAR PROGRESSION IS RELATED TO DISTINCT ENDOTHELIAL/MYELOID CELL-DERIVED CHEMOKINE SIGNALING, WHILE NEOVASCULAR REGRESSION IS RELATED TO MICROGLIAL ACTIVATION OF THE COMPLEMENT PATHWAY. WE WILL SUBSTANTIATE OR REFUTE OUR HYPOTHESIS IN THE FOLLOWING TWO SPECIFIC AIMS. AIM 1: TO DETERMINE THE ROLE OF CHEMOKINE SIGNALING IN FACILITATING NON-RESIDENT IMMUNE CELL RECRUITMENT AND NEOVASCULAR GROWTH. AIM 2: TO DEFINE THE ROLE OF MICROGLIAL COMPLEMENT RECEPTORS IN REGULATING NEOVASCULAR REGRESSION. WE WILL UTILIZE INNOVATIVE MULTIPLEX IN-SITU HYBRIDIZATION, CELL TYPE-SPECIFIC MRNA SEQUENCING, MULTIMODAL SINGLE CELL SEQUENCING, UNIQUE REPORTER MICE, AND CRE-LOX ANIMALS FOR CELL-SPECIFIC DELETION. WE ANTICIPATE THAT THE SUCCESSFUL COMPLETION OF THE PROPOSED STUDIES WILL SIGNIFICANTLY ADVANCE OUR UNDERSTANDING OF SPATIOTEMPORAL INNATE IMMUNE REGULATION OF NEOVASCULARIZATION AND HELP IDENTIFY NOVEL OR ENHANCED TREATMENT STRATEGIES FOR RELATED VASO-PROLIFERATIVE RETINOPATHIES.

NITRIC OXIDE SIGNALING MECHANISMS IN VASCULAR CELLS

PHYSICIAN & SCIENTIST TRAINING IN DEVELOPMENTAL GENETICS

VITAMIN D FOR TYPE 2 DIABETES (D2D TRIAL)

COMPARATIVE EFFECTIVENESS OF MIND-BODY INTERVENTIONS FOR OSTEOARTHRITIS - INDIVIDUAL PATIENT DATA NETWORK META-ANALYSIS

RELATION BETWEEN ACUTE CHANGES IN KIDNEY FUNCTION WITH CLINICAL OUTCOMES AMONG PATIENTS WITH HEART FAILURE - ABSTRACT BASELINE REDUCED KIDNEY FUNCTION IS HIGHLY PREVALENT AMONG PATIENTS WITH ACUTE HEART FAILURE (AHF) AND IS ONE OF THE MOST POWERFUL RISK FACTORS FOR ADVERSE CLINICAL OUTCOMES. THE ASSOCIATION BETWEEN ACUTE KIDNEY FUNCTION DECLINES AND OUTCOMES, HOWEVER, REMAIN CONTROVERSIAL, WITH SOME STUDIES SHOWING ACUTE DECLINES IN ESTIMATED GLOMERULAR FILTRATION (EGFR) TO BE ASSOCIATED WITH WORSE OUTCOMES BUT OTHER STUDIES NOT. THE GOAL OF DR. MCCALLUM’S PROPOSAL IS TO BETTER UNDERSTAND THE MECHANISMS OF ACUTE EGFR DECLINES THAT OCCUR IN THE SETTING OF AHF AND EXAMINE HOW ACUTE EGFR DECLINES ARE RELATED TO OUTCOMES INCLUDING LONG TERM KIDNEY FUNCTION, MORTALITY AND AHF HOSPITALIZATIONS. THE OVERALL HYPOTHESIS IS THAT THREE KEY COMPONENTS—CONGESTION, CARDIAC HEMODYNAMICS, AND NEUROHORMONAL (NH) ACTIVITY—ARE THE PRIMARY RISK FACTORS FOR ACUTE EGFR DECLINES, AND THAT THE RELATION BETWEEN ACUTE EGFR DECLINES AND CLINICAL OUTCOMES NEEDS TO BE INTERPRETED WITHIN THE CONTEXT OF CHANGES IN THESE THREE FACTORS. IN ORDER TO EXAMINE THESE RELATIONS, HER AIMS WOULD INCLUDE 1) RETROSPECTIVE ANALYSIS OF PATIENTS ADMITTED TO TUFTS MEDICAL CENTER FOR AHF AND REQUIRING A PULMONARY ARTERY (PA) CATHETER (N=890) FOR REPEATED MEASURES OF CONGESTION AND CARDIAC HEMODYNAMICS; 2) PROSPECTIVE ENROLLMENT OF 140 PATIENTS ADMITTED TO TUFTS MEDICAL CENTER FOR AHF WITH AN INDWELLING PA CATHETER TO ASSAY FOR REPEATED MEASURES OF PLASMA NH ACTIVITY; AND 3) ADOPTION OF MULTI-TRAJECTORY MODELING TO DEVELOP CLINICAL PHENOTYPES OF ACUTE CARDIORENAL SYNDROME (CRS) BY INCORPORATING TRAJECTORIES OF EGFR CHANGE, CONGESTION, CARDIAC HEMODYNAMICS, AND NH ACTIVITY. THE CAREER DEVELOPMENT PLAN INCORPORATES DIDACTIC TRAINING IN LONGITUDINAL DATA ANALYSIS INCLUDING JOINT MODELING AND MULTI-TRAJECTORY MODELING, BIOMARKER METHODOLOGY, INTRODUCTORY INFORMATICS FOR ELECTRONIC HEALTH RECORD RESEARCH, AS WELL AS IMMERSION AND PRACTICAL TRAINING IN CARDIAC HEMODYNAMICS AND PROSPECTIVE PATIENT RECRUITMENT, ALL UNDER THE MENTORSHIP OF AN EXPERIENCED GROUP OF NEPHROLOGISTS, CARDIOLOGISTS AND STATISTICIANS WITH EXPERTISE IN VARIOUS ASPECTS OF THE CRS. SUCCESSFUL COMPLETION OF THESE AIMS IS FEASIBLE, AS SHOWN BY DR. MCCALLUM’S PRELIMINARY DATA UNDER HER INSTITUTIONAL KL2 FUNDING, AS WELL HER TRACK RECORD OF PRODUCTIVITY UNDER HER PRIMARY MENTOR DR. MARK SARNAK. HER CO-MENTOR WILL BE DR. JEFFREY TESTANI, A CARDIOLOGIST AND DIRECTOR OF HEART FAILURE RESEARCH AT YALE UNIVERSITY WHO HAS EXPERTISE IN THE CRS, HAS COLLABORATED WITH DR. MCCALLUM ON SEVERAL MANUSCRIPTS, AND HAS INCORPORATED HER INTO HIS RESEARCH GROUP AND SPONSORED SEVERAL TRIPS FOR HER TO HIS RESEARCH LAB AT YALE. WITH THIS K23 AWARD, DR. MCCALLUM WILL RECEIVE EXTENSIVE TRAINING IN BIOSTATISTICAL METHODS, DATASET CREATION, CRS PATHOPHYSIOLOGY, BIOMARKER METHODOLOGY, PRIMARY DATA COLLECTION AND PROSPECTIVE STUDY DESIGN. IN AGGREGATE, COMPLETION OF THESE AIMS WILL PROVIDE DR. MCCALLUM WITH EXPERTISE IN THE CRS AND ARM HER WITH THE TOOLS NECESSARY TO SUCCESSFULLY COMPETE FOR INDEPENDENT FUNDING.

PRENATAL DIAGNOSIS OF BRAIN MALFORMATIONS: IMPROVING ASSESSMENT OF PROGNOSIS

PRO-INFLAMMATORY MEDIATOR CROSSTALK INDUCES COX-2 IN MYOFIBROBLASTS VIA PKC/PKD

VASCULAR PANNEXIN 1 IN ISCHEMIC STROKE

DEVELOPMENTAL-BEHAVIORAL PEDIATRICS TRAINING PROGRAM

MULTIPLEXED MOLECULAR IMAGING OF CELL DEATH PATHWAYS

DETERMINATION OF MATERNAL-FETAL PHOSPHATE TRANSPORT MECHANISMS AND THE ROLE OF SODIUM-DEPENDENT PHOSPHATE TRANSPORTERS IN EXTRAEMBRYONIC TISSUES

HIV: METABOLIC ABNORMALITIES

ENDOTHELIAL REGULATION OF IL17 PRODUCING T EFFECTOR CELL MIGRATION

STRUCTURAL AND MOLECULAR BASIS OF DRUG-INDUCED IKACH REDUCTION

ROLE OF BORRELIA INTEGRIN BINDING PROTEINS IN LYME ARTHRITIS

TRIAL OF VITAMIN D TO REDUCE PROGRESSION OF KNEE OA

GENETIC ANALYSIS OF FEEDING BEHAVIOR AND FAT DEPOSITION

MECHANISMS OF VARICOSE VEIN FORMATION

ESTROGEN AND MECHANISMS OF CARDIOMYOCYTE PROTECTION

SUBSTANCE P & THE REGULATION OF INTESTINAL INFLAMMATION

CARDIAC FIBROSIS PROGRESSIVE HEART FAILURE: THE ROLE OF ENDOGLIN

NAMIBIA ART PATIENT TRACING INTENSIFICATION AND PREDICTORS OF LOSS TO FOLLOW-UP

RAPID QUANTITATIVE COMPOSITE MRI MEASUREMENT OF KNEE OA STRUCTURAL PROGRESSION

GLUCOCORTICOID REGIMENS AND CARDIOVASCULAR RISK

RECOGNITION OF HOST CATECHOLAMINES IN BORRELIA BURGDORFERI GENE REGULATION

HEME OXYGENASE POLYMORPHISMS AND HEPATOPULMONARY SYNDROME

DEVELOPMENT OF A MULTIVALENT VACCINE FOR MOUSE RESERVOIRS OF DEER TICK PATHOGENS

SHIGA TOXIN & RICIN: MECHANISMS OF RIBOTOXIC STRESS

XENODIAGNOSIS OF LYME DISEASE

ROLE OF 12-LIPOXYGENASE IN HYPOXIA-INDUCED PULMONARY HYPERTENSION

NEONATAL SALIVARY GENOMIC PROFILES TO ACCESS FEEDING TOLERANCE AND DISEASE

ARTERIAL ENDOTHELIAL PANNEXIN 1 IN ISCHEMIC STROKE-INDUCED VASCULAR DEMENTIA WITH AGE AND SEX - PROJECT SUMMARY/ABSTRACT ISCHEMIC STROKE IS A LEADING CAUSE OF MORBIDITY AND MORTALITY. RISK FOR ISCHEMIC STROKE INCREASES WITH AGE IN BOTH MEN AND WOMEN, ALTHOUGH WOMEN HAVE A HIGHER LIFETIME RISK OF STROKE, HIGHER RATE OF DEATH DUE TO STROKE AND POORER OUTCOMES, SUCH AS WORSE MOBILITY AND ANXIETY/DEPRESSION, FOLLOWING AN ISCHEMIC STROKE. THERAPEUTIC INTERVENTION DURING AND AFTER ISCHEMIC STROKE IS CURRENTLY LIMITED TO REMOVAL OF THE PHYSICAL OCCLUSION WITHIN THE BLOOD VESSEL, AN INTERVENTION FOR WHICH MANY PATIENTS DO NOT QUALIFY. TO IDENTIFY ALTERNATIVE NOVEL THERAPEUTIC TARGETS TO IMPROVE ISCHEMIC STROKE OUTCOMES, WE EXAMINED THE ROLE OF CEREBRAL ENDOTHELIAL PANNEXIN1 (PANX1) CHANNELS. PANX1 CHANNELS ARE THE PRIMARY NUCLEOTIDE RELEASE CHANNELS, WHICH CAN REGULATE ACTIVATION OF DOWNSTREAM PURINERGIC RECEPTORS AND CAUSE DETRIMENTAL STROKE OUTCOMES. WE PREVIOUSLY DEMONSTRATED THAT DELETION OF ENDOTHELIAL PANX1 REDUCES CEREBRAL ARTERY MYOGENIC REACTIVITY, VASOCONSTRICTION IN RESPONSE TO INCREASED LUMINAL PRESSURE, WHICH REGULATES CEREBRAL BLOOD FLOW. DELETION OF ENDOTHELIAL PANX1 ALSO REDUCED POST-ISCHEMIC STROKE INFARCT VOLUME. PRELIMINARY MECHANISTIC DATA SUGGESTS AN INTERACTION BETWEEN ARTERIAL ENDOTHELIAL PANX1 AND ΑVΒ3 INTEGRINS, MECHANOSENSORY PROTEINS THAT MAY ACTIVATE PANX1 CHANNELS DURING MYOGENIC REACTIVITY. ADDITIONALLY, OUR PRELIMINARY DATA DEMONSTRATE AN INCREASE IN PANX1 EXPRESSION IN CEREBRAL ENDOTHELIAL CELLS IN AGED 18-MONTH-OLD MICE. WE SHOW THAT INDUCED OVEREXPRESSION OF ENDOTHELIAL PANX1 IN YOUNG MICE IMPAIRS CEREBRAL BLOOD FLOW RECOVERY 24 HR POST-ISCHEMIC STROKE, RESULTING IN INCREASED INFARCT VOLUME SPECIFICALLY IN FEMALE MICE. TAKEN TOGETHER, THESE DATA SUGGEST A DETRIMENTAL ROLE FOR ENDOTHELIAL PANX1 THAT CONTRIBUTES TO POOR ISCHEMIC STROKE OUTCOME, PARTICULARLY IN FEMALES, AND MAY FACILITATE POST-ISCHEMIC STROKE VASCULAR DEMENTIA. THIS PROPOSAL TESTS THE HYPOTHESIS THAT CEREBRAL ARTERIAL ENDOTHELIAL PANX1 REGULATES CEREBRAL MYOGENIC TONE VIA INTERACTION WITH INTEGRIN ΑVΒ3, WHICH CONTRIBUTES TO IMPAIRED CBF RECOVERY DURING ISCHEMIC STROKE LEADING TO POOR STROKE OUTCOMES AND COGNITIVE IMPAIRMENT IN AGED FEMALES WITH THE FOLLOWING SPECIFIC AIMS. AIM 1 WILL EXPLORE THE INTEGRIN ΑVΒ3-PANX1-PURINERGIC RECEPTOR INTERACTION IN REGULATION OF CEREBRAL VASCULAR TONE WITH AGE AND POST-ISCHEMIC STROKE. IN AIM 2, WE WILL DETERMINE IF OVARIAN ESTROGEN IS NECESSARY FOR EC PANX1-DEPENDENT CEREBRAL ARTERIAL FUNCTION AND CHRONIC ISCHEMIC STROKE OUTCOME. AIM 3 WILL EXAMINE IF ARTERIAL EC PANX1 REGULATES CEREBRAL ARTERIAL FUNCTION AND CHRONIC ISCHEMIC STROKE OUTCOME IN A SEX- OR AGE-DEPENDENT MANNER. FURTHERMORE, WE WILL DETERMINE IF POST-REPERFUSION PHARMACOLOGICAL INHIBITION OF PANX1 IS PROTECTIVE AGAINST CHRONIC ISCHEMIC STROKE OUTCOMES IN AGED MICE. SUCCESSFUL COMPLETION OF OUR STUDY WILL PROVIDE INSIGHT INTO THE SEX- AND AGE-SPECIFIC MECHANISTIC ROLE OF PANX1 WITHIN ARTERIAL CEREBRAL ENDOTHELIAL CELLS IN THE REGULATION OF CEREBRAL BLOOD FLOW AND ITS CONTRIBUTION TO ISCHEMIC STROKE OUTCOME. THESE DATA MAY IDENTIFY MULTIPLE SEX- SPECIFIC THERAPEUTIC TARGETS FOR PHARMACOLOGICAL INTERVENTION FOLLOWING AN ISCHEMIC STROKE LEADING TO PRECISION MEDICINE STRATEGIES TO IMPROVE ISCHEMIC STROKE OUTCOMES AND REDUCE STROKE-INDUCED VASCULAR DEMENTIA.

HEALTH CARE AND OTHER FACILITIES

PROTEASE ACTIVATED RECEPTORS IN CANCER INVASION

THE ROLE OF FETAL CELL MICROCHIMERISM IN MATERNAL REPAIR

HEALTH CARE QUALITY AND OUTCOMES IN MEDICARE