Northshore University Healthsystem

SYSTEMATIC FUNCTIONAL INTERPRETATION OF REGULATORY VARIANTS IN SCHIZOPHRENIA

DECIPHERING THE HORMONAL AND NOCICEPTIVE MECHANISMS UNDERLYING BLADDER PAIN

PSYCHOSOCIAL INTERVENTION, MATERNAL INFLAMMATION, AND BIRTH OUTCOMES: CENTERING VS. ROUTINE PRENATAL CARE (PIINC) STUDY

MODELING ALZHEIMER'S DISEASE GENETIC VARIANTS IN HIPSC

EARLY MENSTRUAL PAIN IMPACT ON MULTISENSORY HYPERSENSITIVITY

MOLECULAR EPIDEMIOLOGY OF PARKINSON'S DISEASE

A NOVEL DATA SCIENCE AND NETWORK ANALYSIS APPROACH TO QUANTIFYING FACILITATORS AND BARRIERS OF LOW TIDAL VOLUME VENTILATION IN AN INTERNATIONAL CONSORTIUM OF MEDICAL CENTERS

IDENTIFYING THE CONTRIBUTIONS OF GESTATIONAL AND CAREGIVING ENVIRONMENTS TO SOCIOECONOMIC DISPARITIES IN CHILD LANGUAGE AND COGNITIVE DEVELOPMENT. - PROJECT SUMMARY/ABSTRACT IN THE UNITED STATES, CHILDREN’S DEVELOPMENT DIFFERS MARKEDLY AS A FUNCTION OF THEIR FAMILY’S SOCIOECONOMIC STATUS (SES). SOME OF THE MOST PRONOUNCED AND CONSEQUENTIAL SES DISPARITIES ARE IN LANGUAGE AND COGNITIVE DEVELOPMENT, WHICH ARE EVIDENT AS EARLY AS TWO YEARS OF AGE AND, BY KINDERGARTEN ENTRY, PREDICT WITH DEPRESSING ACCURACY CHILDREN’S LONG-TERM ACADEMIC TRAJECTORIES. YET WHILE SOCIAL SCIENCE HAS IDENTIFIED A VARIETY OF STRUCTURAL, CONTEXTUAL, AND PSYCHOLOGICAL FACTORS THAT CONTRIBUTE TO DISPARITIES IN CHILD DEVELOPMENT, WE HAVE LIMITED UNDERSTANDING OF HOW THESE FACTORS “GET UNDER THE SKIN” TO INFLUENCE BIOLOGICAL PROCESSES THAT ARE PROXIMALLY INVOLVED IN BRAIN MATURATION AND SHAPE KEY DEVELOPMENTAL OUTCOMES. THIS PROPOSAL INTEGRATES APPROACHES TO UNDERSTANDING DEVELOPMENTAL DISPARITIES FROM THE BIOLOGICAL AND PSYCHOLOGICAL SCIENCES. THEORISTS IN THE BIOLOGICAL SCIENCES HAVE PROPOSED THAT DISADVANTAGE GETS BIOLOGICALLY EMBEDDED DURING GESTATION, IN PART VIA IMMUNE RESPONSES TO STRESS THAT RESULT IN “ADVERSE GESTATIONAL ENVIRONMENTS” (AGES). ANIMAL STUDIES HAVE CONFIRMED THAT STRESSFUL EXPOSURES CAN CONTRIBUTE TO ADVERSE GESTATIONAL ENVIRONMENTS AND TO SUBSEQUENT OXIDATIVE NEURONAL INJURY AND IMPAIRED DEVELOPMENT, YET HUMAN STUDIES HAVE YET TO EXAMINE WHETHER AGES ARE ASSOCIATED WITH SOCIOECONOMIC DISPARITIES IN LANGUAGE AND COGNITION. WE LEVERAGE AN EXISTING NIH-FUNDED STUDY OF DISPARITIES IN PERINATAL OUTCOMES, WHERE IN-DEPTH ASSESSMENTS OF SES AND THE GESTATIONAL ENVIRONMENT ARE BEING PERFORMED IN 600 PREGNANT INDIVIDUALS FROM DIVERSE BACKGROUNDS. WE WILL FOLLOW CHILDREN BORN TO THESE INDIVIDUALS, COLLECTING MEASURES OF COGNITIVE AND LANGUAGE DEVELOPMENT DURING THE INFANT-TODDLER PERIOD AS WELL AS PRESCHOOL OUTCOMES AT AGE 5 YEARS. AIM 1 WILL DETERMINE IF ADVERSE GESTATIONAL ENVIRONMENTS RESULTING FROM MATERNAL STRESS MEDIATE SOCIOECONOMIC DISPARITIES IN CHILD LANGUAGE AND COGNITIVE DEVELOPMENT. AIM 2 WILL DEEPEN UNDERSTANDING INTO THE PLACENTAL CHARACTERISTICS OF ADVERSE GESTATIONAL ENVIRONMENTS THAT ARE ASSOCIATED WITH LOWER LANGUAGE AND COGNITIVE DEVELOPMENT. AIM 3 WILL EXAMINE THE COMBINED CONTRIBUTIONS OF AGES AND POSTNATAL CAREGIVING ENVIRONMENTS IN PREDICTING LANGUAGE AND COGNITIVE DEVELOPMENT. ACROSS THESE AIMS, WE UTILIZE STATE-OF-THE-ART METHODS FROM THE SOCIAL, BEHAVIORAL, AND BIOLOGICAL SCIENCES, AND ADOPT A CULTURALLY AND LINGUISTICALLY RESPONSIVE APPROACH TO ASSESSMENT OF CHILD LANGUAGE AND COGNITIVE DEVELOPMENT. THIS STUDY WILL ANSWER KEY QUESTIONS ABOUT THE ORIGINS OF SES DISPARITIES IN LANGUAGE AND COGNITIVE DEVELOPMENT THAT HAVE IMPORTANT IMPLICATIONS FOR THEORY, POLICY, AND PRACTICE.

TARGETING INTERINDIVIDUAL VARIABILITY IN NSAID RESPONSES TO MITIGATE CHRONIC PELVIC PAIN RISK IN DYSMENORRHEA - MENSTRUAL PAIN (DYSMENORRHEA) IS A MAJOR CAUSE OF DISTRESS, DISABILITY, AND DEVELOPMENT OF CHRONIC PELVIC PAIN (CPP). VERY LITTLE IS KNOWN ABOUT HOW LOCAL UTERINE INFLAMMATION AND CENTRAL NEURAL DYSREGULATION INTERACT TO CAUSE PAINFUL PERIODS. UNDERSTANDING THEIR INTERACTION AND HOW IT MIGHT WORSEN CENTRAL NEURAL HYPERSENSITIVITY IS ESSENTIAL TO PREVENT DYSMENORRHEA FROM PROGRESSING INTO CPP CONDITIONS LIKE BLADDER PAIN SYNDROME, IRRITABLE BOWEL SYNDROME, OR ENDOMETRIOSIS. THERE ARE TWO FACTORS IN DYSMENORRHEA WE HAVE STUDIED THAT HOLD PROMISE AS TARGETS TO REDUCE FUTURE RISK OF CPP – THE PRESENCE OF CO-OCCURRING BLADDER HYPERSENSITIVITY AND THE INDIVIDUAL RESPONSE TO COMMON ANTI-INFLAMMATORY TREATMENTS. THE EXPANSION OF PAIN FROM ONE PELVIC ORGAN TO NEARBY ONES SUGGESTS SENSORY PROCESSING DYSREGULATION IN THE SPINAL CORD OR BRAIN. OUR PRELIMINARY DATA SHOWS THAT EFFECTIVE NSAID THERAPY FOR DYSMENORRHEA MAY REDUCE FUTURE CPP RISK BY NORMALIZING LOCAL NERVE ACTIVATION, INFLAMMATORY MOLECULES IN THE UTERINE LINING, AND PAINFUL HYPERSENSITIVITY IN ADJACENT PELVIC ORGANS. TO DISTINGUISH THE ROLE OF DIFFERENT SENSORY MECHANISMS IN CPP PROGRESSION, OUR INTERDISCIPLINARY TEAM WILL USE A COLLECTION OF VALIDATED SENSORY TASKS INVOLVING MECHANICAL, THERMAL, ELECTRICAL STIMULATION AND BLADDER FILLING. OUR PROPOSAL ALSO PAIRS HIGH-DENSITY ELECTROENCEPHALOGRAPHY WITH SENSORY TESTING TO IDENTIFY BRAIN DIFFERENCES RELATED TO ABNORMAL PAIN INTERPRETATION. WE PLAN TO ADMINISTER THESE TASKS ALONG WITH SYMPTOM QUESTIONNAIRES TO UNDERSTAND WHY SOME WOMEN WITH MENSTRUAL PAIN RESPOND BETTER TO NSAIDS, AND WHICH FACTORS PREDICT DIMINISHED CPP RISK FOLLOWING AN OPTIMIZED PROGRAM TO REDUCE MENSTRUAL PAIN. IN AIM 1 WE WILL CONDUCT A ONE- YEAR, RANDOMIZED CONTROLLED TRIAL (N=300) OF OPTIMIZED NSAID VS. PLACEBO TREATMENT FOR PERIOD PAIN IN MODERATE-PLUS DYSMENORRHEA SUFFERERS. WE WILL DETERMINE WHETHER ACTIVE TREATMENT, MENSTRUAL PAIN RELIEF, AND LOWER LEVELS OF UTERINE INFLAMMATORY MOLECULES PREDICT LOWER NONMENSTRUAL PELVIC PAIN (NMPP, A MARKER FOR FUTURE CPP RISK) AT ONE YEAR POST-TREATMENT. AIM 2, CONDUCTED WITHIN THE AIM 1 STUDY STRUCTURE, WILL ESTABLISH WHICH SPECIFIC SENSORY TESTS PREDICT REDUCTIONS IN NMPP FOLLOWING TREATMENT. EEG WILL BE USED TO PINPOINT PRECISE MECHANISMS FOR DIFFERENCES IN THESE SENSORY RESPONSES. COLLECTIVELY, THIS STUDY OF HIGHER-RISK WOMEN IS DESIGNED TO CHARACTERIZE HOW MENSTRUAL PAIN AND BLADDER HYPERSENSITIVITY INTERACT TO PROMOTE CPP, AND IF THESE FACTORS PREDICT WHO BENEFITS FROM EARLY PREVENTATIVE TREATMENT. THE APPROACH IS NOVEL FOR USING A SAMPLE OF WOMEN ENRICHED FOR FUTURE PAIN RISK (WOMEN WITH DYSMENORRHEA AND BLADDER PAIN) AND FOR CONDUCTING FUTURE PAIN-RISK PREDICTION WITH RECOGNIZED FACTORS: SENSORY TESTING PROFILES, ADJACENT ORGAN PAIN INVOLVEMENT, AND OBSERVED RESPONSE TO A TARGETED TREATMENT. STRUCTURAL EQUATION MODELING WILL BE USED TO FORMALLY DEFINE HOW THESE INTERACT TO CAUSE CPP WHILE CONTROLLING FOR OTHER KEY PAIN RISK FACTORS, SUCH AS RELATIVE LOCAL INFLAMMATION AND PSYCHOSOCIAL PROFILES. THESE STUDY RESULTS OBTAINED BY A DIVERSE TEAM OF INTERDISCIPLINARY COLLABORATORS ARE EXPECTED TO MARKEDLY IMPROVE OUR UNDERSTANDING OF PAIN RISK HETEROGENEITY FOR CHRONIC PAIN PREVENTION

INTEGRATING EPIGENOMICS WITH DNA BREATHING DYNAMICS FOR HUMAN NON-CODING DISEASE VARIANTS

ANESTHESIA-INDUCED LEARNING DEFICIENCY AND BRAIN HYPEROXIA

FEMALE SEXUAL ORIENTATION GWAS

COMMUNITY CHILD HEALTH NETWORK-LAKE COUNTY, IL

MECHANISTIC CHARACTERIZATION OF UTERINE PAIN (M-CUP) TO IMPROVE DIAGNOSIS AND TREATMENT FOR DYSMENORRHEA

NEURONAL VULNERABILITY TO LIPID DROPLETS AND CHOLESTEROL IN ALZHEIMER'S DISEASE - ABSTRACT ALZHEIMER'S DISEASE (AD) IS A DEVASTATING NEURODEGENERATIVE DISORDER THAT AFFLICTS OVER 6.5 MILLION AMERICANS. DESPITE DECADES OF RESEARCH ON AMYLOID-SS (ASS) AND TAU LESIONS, EFFECTIVE TREATMENT REMAINS OUT OF REACH. MOUNTING AD GENOME-WIDE ASSOCIATION STUDIES (GWAS) RISK LOCI PROVIDE OPPORTUNITIES FOR UNDERSTANDING DISEASE BIOLOGY AND DEVELOPING EFFECTIVE TREATMENT. MULTIPLE AD GWAS RISK GENES, SUCH AS APOE, ARE PIVOTAL FOR LIPID METABOLISM THAT IS ESSENTIAL TO BRAIN HEALTH AND DISEASE. UNDER STRESS OR IN THE AGING BRAIN, BOTH ASTROCYTES AND MICROGLIA SHOW ABNORMAL LIPID METABOLISM AND ACCUMULATION OF LIPID DROPLETS (LD). ALTHOUGH GLIAL LD ARE KNOWN TO BE LARGELY NEUROPROTECTIVE, LD FORMATION IN HUMAN NEURONS AND ITS CELLULAR AND MOLECULAR RAMIFICATIONS ARE LESS CLEAR. WITH EXCITATORY NEURONS (EX) DERIVED FROM HUMAN INDUCED PLURIPOTENT STEM CELLS (IPSC), WE HAVE SHOWN THAT APOE4 EX NEURONS CO-CULTURED WITH ASTROCYTES ACCUMULATED MORE LD THAN APOE2/3 NEURONS. OUR SINGLE-CELL TRANSCRIPTOMIC ANALYSIS OF AD BRAIN ALSO IDENTIFIED AN IMPAIRED NEURON- OLIGODENDROCYTE PRECURSOR CELL (OPC) COMMUNICATION MEDIATED BY APOE AND ITS RECEPTOR LDLR. INTERESTINGLY, NEURAL CHOLESTEROL WAS RECENTLY FOUND TO BE ESSENTIAL TO OPC PROLIFERATION AND REMYELINATION. WE THUS HYPOTHESIZE THAT ABNORMAL NEURONAL LD AND CHOLESTEROL IN AD CONTRIBUTE TO NEURONAL DAMAGE AND IMPAIRED NEURON REMYELINATION. LEVERAGING OUR EXPERTISE ON USING IPSC-DERIVED NEURONS AND CORTICAL ORGANOIDS AS CELLULAR MODELS FOR BRAIN DISORDERS, WE WILL CHARACTERIZE THE CELL TYPE VULNERABILITY TO LD/CHOLESTEROL AND THE CORRESPONDING EPIGENOMIC/TRANSCRIPTOMIC CHANGES IN THE CONTEXT OF AD RISK ALLELES. IN AIM 1, TO DETERMINE THE NEURAL VULNERABILITY TO LD AND ITS CLINICAL RELEVANCE IN AD, WE WILL CO-CULTURE EX AND INHIBITORY (INH) NEURONS OF A COHORT OF 60 PATIENT-SPECIFIC IPSC LINES, AND ASSAY NEURAL LD, FREE FATTY ACIDS, CHOLESTEROL, AND NEURAL MORPHOMETRICS, WHICH WILL THEN BE ASSOCIATED WITH APOE ALLELES AND NON-APOE AD POLYGENIC RISK SCORES. THESE CELLULAR PHENOTYPES WILL ALSO BE CORRELATED WITH PATIENTS’ LONGITUDINAL PLASMA LIPID LEVELS AND OTHER CLINICAL OUTCOMES. IN AIM 2, TO UNDERSTAND MOLECULAR MECHANISMS UNDERLYING NEURAL VULNERABILITY TO LD, WE WILL PERFORM SINGLE-CELL RNA/ATAC-SEQUENCING ON THE SAME NEURAL CO-CULTURES USED IN AIM 1 TO IDENTIFY GENES WITH CHROMATIN ACCESSIBILITY AND TRANSCRIPTION CORRELATED WITH CELLULAR LD IN EACH CELL TYPE. IN AIM 3, TO EXAMINE THE EFFECT OF AD RISK ALLELES ON CHOLESTEROL-MEDIATED NEURON-OPC COMMUNICATION AND MYELINATION, WE WILL FIRST USE CRISPR EDITING TO GENERATE ISOGENIC IPSC LINES CARRYING AD RISK ALLELES AND THEN DIFFERENTIATE THEM INTO MYELINATING CEREBRAL ORGANOIDS. WE WILL EXAMINE THE EFFECTS OF AD RISK ALLELES ON NEURONAL CHOLESTEROL LEVELS AS WELL AS THE OPC PROLIFERATION AND NEURON MYELINATION. THIS STUDY WILL SIGNIFICANTLY ADVANCE OUR UNDERSTANDING OF THE CELLULAR AND MOLECULAR MECHANISMS OF NEURONAL VULNERABILITY TO ABNORMAL LD AND CHOLESTEROL IN AD.

1/2 AN INTEGRATIVE GENETIC INVESTIGATION OF SCHIZOPHRENIA

A GENOME-WIDE ASSOCIATION STUDY OF SCHIZOPHRENIA

COMMUNITY CLINICAL ONCOLOGY PROGRAM

ROLE OF INTERNEURONS IN BRAIN TISSUE OXYGEN REGULATION

LONGITUDINAL CHANGES IN THE INTRA-RENAL OXYGENATION BY BOLD MRI IN PATIENTS WITH

IMPROVED DETECTION OF CEREBRAL METASTASES USING A USING A NOVEL T1 RELAXATION-ENHANCED STEADY-STATE (T1RESS) MRI TECHNIQUE - CONTRAST-ENHANCED MAGNETIC RESONANCE IMAGING (MRI) IS THE CORNERSTONE FOR BRAIN TUMOR DIAGNOSIS AND TREATMENT PLANNING. WHILE ITS SENSITIVITY FOR METASTASES IS SUPERIOR TO THAT OF CT OR PET-CT, SMALL LESIONS (<5- MM) AND LEPTOMENINGEAL SPREAD MAY STILL BE MISSED, WHICH CAN HAVE A MAJOR IMPACT ON PROGNOSIS AND PLANNING FOR STEREOTACTIC RADIOSURGERY, AS WELL AS ON THE USE OF TARGETED BIOLOGICS THAT CROSS THE BLOOD-BRAIN BARRIER. A METHOD THAT COULD FURTHER IMPROVE THE SENSITIVITY AND SPECIFICITY OF MRI FOR BRAIN TUMORS WOULD BE OF GREAT CLINICAL BENEFIT. TOWARDS THIS END, WE HAVE DEVELOPED A NEW CLASS OF PULSE SEQUENCES, CALLED T1 RELAXATION-ENHANCED STEADY-STATE (T1RESS), THAT GREATLY IMPROVES THE VISIBILITY OF TUMORS IN CONTRAST- ENHANCED MRI. COMPARED WITH EXISTING NEUROIMAGING TECHNIQUES, T1RESS AT LEAST DOUBLES THE TUMOR-TO- BACKGROUND CONTRAST WHILE SIGNIFICANTLY IMPROVING THE TUMOR-TO-BACKGROUND CONTRAST-TO-NOISE RATIO. AN “UNBALANCED” VERSION (UT1RESS) RENDERS BLOOD VESSEL DARK AND IS THE FOCUS OF OUR PROPOSAL. IN A PRELIMINARY STUDY OF 54 ADULT PATIENTS THAT WAS PUBLISHED IN SCIENCE ADVANCES, UT1RESS PROVIDED A REMARKABLE TWOFOLD OR GREATER IMPROVEMENT IN TUMOR-TO-BRAIN CONTRAST ALONG WITH A MARKED IMPROVEMENT IN LESION-TO-BRAIN CONTRAST-TO-NOISE IN COMPARISON TO STANDARD-OF-CARE MPRAGE AND OTHER PULSE SEQUENCES THAT ARE COMMONLY USED TO IMAGE BRAIN TUMORS. WE FOUND THAT EVEN SMALL METASTATIC TUMOR DEPOSITS AND LEPTOMENINGEAL LESIONS THAT WERE DIFFICULT TO DISTINGUISH FROM SMALL BLOOD VESSELS WITH STANDARD IMAGING TECHNIQUES COULD BE UNAMBIGUOUSLY IDENTIFIED. THE PRIMARY HYPOTHESIS OF THIS FIVE-YEAR GRANT PROPOSAL IS THAT T1RESS WILL SIGNIFICANTLY IMPROVE THE SENSITIVITY FOR SMALL BRAIN METASTASES COMPARED WITH EXISTING MRI PULSE SEQUENCES, WHILE ALSO REDUCING SCAN TIMES. A SECONDARY HYPOTHESIS IS THAT THE TWOFOLD IMPROVEMENT IN TUMOR-TO-BRAIN CONTRAST OBTAINED WITH UT1RESS CAN BE USED TO ENABLE A SUBSTANTIAL TWOFOLD REDUCTION IN GADOLINIUM-BASED CONTRAST AGENT (GBCA) DOSAGE. STUDIES OF PHANTOMS, HEALTHY VOLUNTEERS, AND PATIENTS WITH BRAIN TUMORS ALONG WITH BLOCH EQUATION MODELING WILL BE USED TO GUIDE SEQUENCE OPTIMIZATION. THESE OPTIMIZATION EFFORTS WILL BE FOLLOWED BY A TWO- INSTITUTION STUDY TO DETERMINE THE ACCURACY OF THE TECHNIQUE. OUR SPECIFIC AIMS ARE AS FOLLOWS: 1. TO APPLY UT1RESS IN HEALTHY SUBJECTS AND PATIENTS WITH BRAIN TUMORS TO SYSTEMATICALLY EVALUATE THE IMPACT OF VARIOUS SEQUENCE PARAMETERS ON IMAGE APPEARANCE, CONTRAST, SNR, AND LESION SHARPNESS, AND TO OPTIMIZE THE TECHNIQUE TO MAXIMIZE TUMOR VISIBILITY WHILE MINIMIZING SCAN TIME AND IMAGE ARTIFACTS. 2. TO PERFORM A PILOT STUDY TO DETERMINE WHETHER METRICS OF TUMOR VISIBILITY USING UT1RESS AND A TWOFOLD REDUCED GBCA CONTRAST AGENT DOSAGE ARE NONINFERIOR TO MPRAGE WITH A STANDARD CONTRAST AGENT DOSAGE. 3. TO PERFORM A TWO-SITE RESEARCH TRIAL AT 3T TO CHARACTERIZE THE APPEARANCE OF BRAIN METASTASES WITH UT1RESS, AND TO DETERMINE ITS ACCURACY FOR SMALL BRAIN METASTASES COMPARED TO STANDARD-OF-CARE MPRAGE.

INFLAMMATORY PATHWAYS IN BPH/LUTS

VITAMIN D AND PROGESTINS FOR THE CHEMOPREVENTION OF FALLOPIAN TUBE/OVARIAN CANCER

GENE EXPRESSION IN AN AFRICAN AMERICAN SCHIZOPHRENIA DATASET

PROJECT DESCRIPTION: ENDEAVOR HEALTH AIMS TO DEVELOP AND IMPLEMENT A HOSPITAL-BASED COMMUNITY VIOLENCE INTERVENTION PROGRAM, ENDEAVOR TO HEAL, AT THREE OF THEIR EIGHT HOSPITALS ON CHICAGO, ILS NORTH SIDE AND NORTH SUBURBS (SWEDISH HOSPITAL, EVANSTON HOSPITAL AND HIGHLAND PARK HOSPITAL). THE ENDEAVOR TO HEAL PROGRAMS GOAL IS TO DECREASE INSTANCES OF VIOLENT INJURY WITHIN HIGH-CRIME NEIGHBORHOODS IN THE ENDEAVOR HEALTH SERVICE AREA, THEREBY CONTRIBUTING TO AN OVERALL REDUCTION IN VIOLENT CRIME IN CHICAGO, AND ITS SURROUNDING SUBURBS BY USING A SYSTEMATIC APPROACH THAT INCORPORATES COLLABORATIVE PARTNERSHIPS, COMMUNITY ENGAGEMENT, AND EVIDENCE-BASED VIOLENCE PREVENTION AND INTERVENTION METHODS. THE CORE STRATEGIES TO MEET THESE OBJECTIVES INCLUDE: RAPID RESPONSE AND CRISIS INTERVENTION, INTENSIVE CASE MANAGEMENT, MENTAL HEALTH SERVICES, HOSPITAL-COMMUNITY COLLABORATION, AND WORKFORCE DEVELOPMENT. ENDEAVOR TO HEAL DEFINES THE TARGET POPULATION AND HIGH-RISK INDIVIDUALS (ADULTS AND YOUTH OVER THE AGE OF 16) AS THOSE WHO HAVE EXPERIENCED VIOLENT INJURY, SUCH AS GUNSHOT WOUNDS, STABBINGS, OR PHYSICAL ASSAULT, AND ARE ADMITTED TO ONE OF THE THREE PARTICIPATING HOSPITALS. THE PROGRAM WILL ALSO CONSIDER INDIVIDUALS WITH A HISTORY OF VIOLENT VICTIMIZATION OR INVOLVEMENT IN COMMUNITY VIOLENCE TO BE AT HIGH RISK. ENDEAVOR HEALTH HAS SUBSTANTIAL EXPERIENCE WORKING DIRECTLY WITH SURVIVORS OF VIOLENCE THROUGH BOTH MEDICAL INTERVENTION AND PROGRAMMATIC INITIATIVES AIMED AT PREVENTION AND INTERVENTION AND WILL BUILD SUPPORTIVE SERVICES FOR VICTIMS OF VIOLENT INJURY THROUGH INDIVIDUALIZED TREATMENT PLANS, ACCESS TO INDIVIDUAL AND GROUP THERAPY, ENGAGEMENT IN COMMUNITY-BASED AGENCIES DEDICATED TO ADDRESSING SOCIAL DETERMINANTS AND EQUITY IN CARE, AND OTHER SERVICES AIMED AT REDUCING RISK OF REINJURY. THE ENDEAVOR TO HEAL PROGRAM WILL ADDRESS HEALTHCARE DISPARITIES ACROSS THE CARE CONTINUUM THROUGH PARTNERSHIP WITH COMMUNITY ORGANIZATIONS THAT SHARE OUR VISION TO IMPROVE EQUITABLE HEALTH OUTCOMES AND WILL CONDUCT A PROCESS AND OUTCOMES EVALUATION TO ASSESS PROGRAMMATIC SUCCESS.

MOLECULAR CONTROL OF EGF RECEPTOR DOWN-REGULATION

ANTI-INFECTIVE STEWARDSHIP USING THE WISCA TOOL IN THE ELECTRONIC MEDICAL RECORD

JOINT MAPPING OF GENOME-WIDE GENE EXPRESSION AND ASSOCIATION IN A SCHIZOPHRENIA D

SYSTEMIC DELIVERY OF AN ONCOLYTIC ADENOVIRUS TARGETING TGF? TO ENHANCE ANTI-PD-1 AND ANTI-CTLA-4 THERAPY FOR TRIPLE NEGATIVE BREAST CANCER - PROJECT SUMMARY THE DEVELOPMENT OF NOVEL THERAPIES FOR THE TREATMENT OF BREAST CANCER IS A MAJOR UNMET NEED. IN RECENT YEARS, IMMUNE CHECKPOINT INHIBITORS INCLUDING ANTI-PD-1, ANTI-PD-L1 AND ANTI-CTLA-4 HAVE SHOWN PROMISE AS ANTITUMOR AGENTS, AND ARE APPROVED FOR THE TREATMENT OF SEVERAL MALIGNANCIES. CLINICAL TRIALS IN BREAST CANCER PATIENTS HAVE SHOWN THAT ABOUT 20% OF TRIPLE NEGATIVE BREAST CANCERS (TNBC) RESPOND FAVORABLY TO ANTI-PD-1 ANTIBODIES AND ATEZOLIZUMAB, AN ANTI-PD-L1 ANTIBODY IN COMBINATION WITH NAB-PACLITAXEL (ABRAXANE) IS NOW FDA APPROVED FOR ADVANCED STAGE TNBC PATIENTS WITH POSITIVE PDL-1 EXPRESSION. HOWEVER, MANY TNBC PATIENTS ARE RESISTANT TO ANTI-PD-1/PDL-1 AND ANTI-CTLA-4 TREATMENTS WHICH COULD BE DUE TO WEAK IMMUNOGENICITY OF THE TUMORS AND POOR INFLAMMATORY BUT HIGHLY IMMUNE SUPPRESSIVE TUMOR MICROENVIRONMENT. IN RECENT YEARS TGFSS HAS BEEN SHOWN TO BE A STRONG IMMUNE SUPPRESSOR AND CAN POTENTIALLY PRODUCE A TUMOR MICROENVIRONMENT THAT IS RESISTANT TO ANTI-PD-1 AND ANTI-CTLA-4 THERAPY. TO OVERCOME RESISTANCE TO ANTI-PD-1 AND ANTI-CTLA-4 WE HAVE DEVELOPED ADENOVIRUSES (AD) EXPRESSING STGFSSRIIFC (SOLUBLE TGFSS RECEPTOR II FUSED WITH HUMAN IGG FC). STGFSSRIIFC ACTS AS A TGFSS DECOY, AND CAN INHIBIT TGFSS PATHWAYS. INITIALLY, WE CREATED AD5 BASED AD.ST EXPRESSING STGFSSRIIFC. TO REDUCE HEPATIC/SYSTEMIC TOXICITY ASSOCIATED WITH SYSTEMIC DELIVERY OF AD.ST, WE CREATED MHAD.ST, A LIVER-DETARGETED VIRUS, BY REPLACING HYPERVARIABLE REGIONS (HVRS) (1-7) OF AD.ST WITH AD48 HVRS. TO ENHANCE TUMOR SPECIFICITY, WE HAVE NOW CREATED MHADLYP.ST BY INTRODUCING LYP-1 PEPTIDE, A 9-AMINO ACID LONG TUMOR HOMING-CELL PEPTIDE, INTO THE HI LOOP OF THE MHAD.ST FIBER. IN THIS PROPOSAL, WE WILL TEST THE HYPOTHESES THAT SYSTEMIC ADMINISTRATION OF MHADLYP.ST IN MICE BEARING 4T1 TRIPLE NEGATIVE MAMMARY TUMORS WILL RESULT IN REDUCED HEPATIC/SYSTEMIC TOXICITY BUT PRODUCE HIGH LEVELS OF STGFSSRIIFC AND INHIBIT TGFSS PATHWAYS. THIS WILL ALTER THE TUMOR MICROENVIRONMENT, INDUCE TUMOR IMMUNITY, AND OVERCOME RESISTANCE TO ANTI-PD-1 AND ANTI-CTLA-4., AND EXAMINE THE EXPRESSION PROFILES OF TGFSS-1, TGFSS-1 REGULATED GENES, AND PD-1 AND CTLA-4 SIGNALING PATHWAYS. WE WILL EXAMINE IMMUNO-PHENOTYPES IN TUMORS, PERIPHERAL BLOOD AND SPLEEN (AIM 1). NEXT, WE WILL EXAMINE MHADLYP.ST, ANTI-PD-1 AND ANTI-CTLA-4 COMBINATION THERAPIES IN MOUSE TUMOR MODELS. WE WILL CONDUCT RNA-SEQ ANALYSIS OF THE WHOLE TRANSCRIPTOMES, AND EXAMINE THE ROLE OF IMMUNE ACTIVATION IN MEDIATING THE ANTI-TUMOR RESPONSES (AIM 2). WE WILL TEST THE HYPOTHESIS THAT SYSTEMIC ADMINISTRATION OF MHLYPAD.ST, IN COMBINATION WITH ANTI-PD-1 AND ANTI- CTLA-4 IN MICE WITH PRE-ESTABLISHED METASTASES WILL BE EFFECTIVE (AIM 3). TO GUIDE US FOR THE COMBINATION THERAPY TRIALS WITH MHADLYP.ST, ANTI-PD-1 AND ANTI-CTLA-4, WE WILL EXAMINE HUMAN TNBC TUMORS BY NANOSTRING TECHNOLOGY FOR RNA PROFILING, AND WILL FURTHER EXAMINE THE TGFSS-1 AND OTHER RELEVANT BIOMARKERS AND TILS IN HUMAN TNBC TUMORS. WE WILL ALSO SCREEN THE HUMAN POPULATION FOR THE AD NEUTRALIZING ANTIBODIES TITERS (AIM 4). WE BELIEVE THAT OUR RESEARCH DESCRIBED HERE IS CRITICAL TO BRING FORWARD OUR ONCOLYTIC VIRUS MHADLYP.ST TARGETING TGFSS IN COMBINATION WITH ANTI-PD-1 AND ANTI-CTLA-4 FOR CLINICAL EVALUATION IN TNBC PATIENTS.

NONENHANCED 3T QISS MR ANGIOGRAPHY OF THE PERIPHERAL ARTERIES

EFFECTS OF TNF BLOCKADE ON HUMAN BPH/LUTS - SUMMARY BENIGN PROSTATIC HYPERPLASIA (BPH) AND ASSOCIATED LOWER URINARY TRACT SYMPTOMS (LUTS) ARE A MAJOR CAUSE OF MORBIDITY IN AGING MEN, RESULTING IN MAJOR ECONOMIC COSTS IN BOTH DIRECT HEALTHCARE EXPENDITURE AS WELL AS LOST PRODUCTIVITY. THE PATHOGENESIS OF BPH/LUTS IS MULTIFACTORIAL. HOWEVER, CURRENT MEDICAL BPH TREATMENT GENERALLY FOLLOWS A SCRIPTED FORMAT USING TWO APPROACHES: -ADRENERGIC BLOCKERS (-BLOCKERS) TO RELAX MUSCLE TONE AND 5- REDUCTASE INHIBITORS (5ARI) TO SHRINK THE PROSTATE. MANY MEN FAIL THESE MEDICAL TREATMENTS, RESULTING IN AROUND 120,000 SURGICAL INTERVENTIONS ANNUALLY IN THE UNITED STATES. COMMON PRO-INFLAMMATORY CO-MORBIDITIES INCLUDE OBESITY AND DIABETES. INFLAMMATION IS STRONGLY ASSOCIATED WITH INCREASED LUTS SEVERITY AND ALSO WITH THE FAILURE OF EXISTING MEDICAL TREATMENTS FOR BPH RESULTING IN PROGRESSION TO SURGERY. LINKS BETWEEN AUTOIMMUNE INFLAMMATORY (AI) DISEASES AND BPH ARE NOW WELL ESTABLISHED WITH COMMON COMORBIDITIES INCLUDING PSORIASIS AND RHEUMATOID ARTHRITIS. AI DISEASE PATIENTS HAVE AROUND A 50% INCREASE IN BPH PREVALENCE. WE RECENTLY SHOWED THAT AI DISEASE TREATMENT, SPECIFICALLY WITH TNF-ANTAGONISTS, REDUCED SUBSEQUENT BPH DIAGNOSES DOWN TO OR EVEN BELOW THE BASELINE POPULATION INCIDENCE. THIS EFFECT WAS NOT OBSERVED WITH THE BROAD SPECTRUM IMMUNE-SUPPRESSANT METHOTREXATE. WE ALSO SHOWED BOTH SUPPRESSION OF THE DEVELOPMENT OF PROSTATE HYPERPLASIA AND THE SHRINKAGE OF EXISTING ENLARGED GLANDS IN MOUSE MODELS TREATED WITH TNF-ANTAGONISTS. THE PROSTATES OF PATIENTS TREATED WITH THESE AGENTS DEMONSTRATE REDUCED PROLIFERATION AND INFLAMMATION. THIS STRONGLY SUGGESTS THAT APPROACHES THAT TARGET IMMUNOMODULATORY PATHWAYS, SPECIFICALLY TNF BLOCKADE, MAY BE BENEFICIAL IN THE PREVENTION AND/OR TREATMENT OF BPH/LUTS. PATHWAY ANALYSIS IN TNF-ANTAGONIST-TREATED MOUSE MODELS DEMONSTRATED THAT BLOCKADE OF THIS PATHWAY REDUCES ANTIGEN PRESENTATION AND INFLAMMATORY SIGNALING DOWNSTREAM OF TNF RECEPTOR 2. OVERALL THESE CHANGES WERE CONSISTENT WITH TNF BLOCKADE REDUCING BOTH OVERALL CELLULAR PROLIFERATION AND THE SUPPRESSION OF APOPTOSIS. THERE ARE LIMITED MEDICAL OPTIONS TO TREAT PATIENTS WITH BPH/LUTS AND NO NEW MEDICAL TREATMENTS HAVE BEEN DEVELOPED IN NEARLY 30 YEARS. THIS PROPOSAL WILL TEST THAT IDEA IN A PILOT TRIAL WITH SUBSEQUENT TISSUE AND GENOMIC ANALYSIS TO IDENTIFY PATHWAYS THAT MAY BE CONCURRENTLY TARGETED AS WELL AS PROVIDE DATA TO ASSIST IN FUTURE PATIENT STRATIFICATION. THE MAJOR IMPACT OF THIS WORK WILL BE TO TEST AN EXISTING AND WIDELY USED DRUG AS A POSSIBLE NOVEL APPROACH TO TREAT BPH. IF SUCCESSFUL, THIS WORK WOULD SET THE STAGE FOR INTEGRATING A NEW APPROACH WITH EXISTING THERAPIES FOR THE BPH/LUTS PATIENT POPULATION WITH LARGE PROSTATES. WE WILL PURSUE THREE AIMS, THAT WILL: 1) EVALUATE THE EFFICACY OF TNF ANTAGONIST ACTION IN BPH/LUTS, 2) DEFINE THE CONSEQUENCES OF TNF ANTAGONIST THERAPY ON HUMAN PROSTATE TISSUE, AND, 3) IDENTIFY GENETIC PREDICTORS TO STRATIFY PATIENTS WITH DIFFERENTIAL RESPONSE TO TNF ANTAGONISTS.

RAPID REAL-TIME MR ANGIOGRAPHY OF SUSPECTED STROKE

ROLE OF INTERNEURONS IN RESTING STATE FMRI CONNECTIVITY DURING NORMAL DEVELOPMENT AND AFTER PERINATAL BRAIN INJURY - DESPITE IMPROVEMENTS OF NEONATAL INTENSIVE CARE OVER RECENT DECADES, HYPOXIC-ISCHEMIC PERINATAL BRAIN INJURY REMAINS A MAJOR CAUSE OF NEURODEVELOPMENTAL IMPAIRMENT AMONG TERM AND PRETERM INFANT, INCLUDING MOTOR, BEHAVIORAL AND COGNITIVE DEFICITS. DIAGNOSIS OF COGNITIVE AND BEHAVIORAL ABNORMALITIES CANNOT BE ACCURATELY MADE UNTIL 2-3 YEARS OLD. CURRENT STATE OF THE ART PROVIDES NO OBJECTIVE FUNCTIONAL MEASURES OF BRAIN INJURY IN NEWBORNS THAT PREDICT LONG TERM COGNITIVE AND BEHAVIORAL DEFICITS. CLEARLY THERE IS A NEED FOR AN EARLY NON-INVASIVE MEASURE THAT CAN PROGNOSTICATE FOR COGNITIVE PROBLEMS IN LATER DEVELOPMENT AND PROVIDE AN OPPORTUNITY FOR EARLY INTERVENTION. AMONG FEW AVAILABLE MODALITIES TO ASSESS FUNCTIONAL BRAIN DEVELOPMENT IS RESTING STATE FUNCTIONAL MRI (RSFMRI). THIS MODALITY IS PARTICULARLY SUITED FOR NEONATAL AND INFANT STUDIES SINCE IT REQUIRES MINIMAL SUBJECT COOPERATION, EASY TO IMPLEMENT, SHORT IN DURATION, AND CAN BE DONE IN NATURAL SLEEP. HOWEVER, MECHANISM AND ORIGINS OF RSFMRI SIGNAL ARE POORLY UNDERSTOOD. EMERGING CELLULAR MECHANISMS OF MICROVASCULAR TONE REGULATION AND OUR PRELIMINARY OBSERVATIONS SUGGEST THAT ACTIVITY OF GABAERGIC INTERNEURONS, AND NOT PRIMARY NEURONS, MAY PLAY A SIGNIFICANT ROLE IN EARLY LOCAL RSFMRI CONNECTIVITY. DEVELOPMENTAL SHIFT TO HIGHER FREQUENCIES AND INCREASED AMPLITUDES OF RSFMRI BOLD OSCILLATIONS IN THIS RANGE COINCIDES WITH THE MATURATION OF INTERNEURONS IN SOMATOSENSORY CORTEXES IN EARLY PERINATAL PERIOD. WE HYPOTHESIZED THAT PROPERTIES OF RSFMRI SIGNAL IN THE HIGHER RANGE OF RSFMRI AND LOCAL RSFMRI CONNECTIVITY IS LARGELY DETERMINED BY ACTIVITY OF INTERNEURONS AND THUS REFLECT MATURATION PROGRESSION OF CORTICAL INTERNEURONS DURING NORMAL PERINATAL DEVELOPMENT AND AFTER INJURY. THE OVERALL GOALS OF THE PROPOSAL ARE TO EXPLORE CELLULAR MECHANISMS OF RSFMRI REGULATION, DISCOVER AND VALIDATE CELL SPECIFIC INFORMATION IN RSFMRI CONNECTIVITY THAT INFORMS US ABOUT THE STATE OF FUNCTIONAL MATURATION OF CORTICAL INTERNEURONS IN EARLY POSTNATAL PERIOD IN RABBIT. USING SIMULTANEOUS RECORDING OF NEURONAL ACTIVITY, LOCAL TISSUE OXYGEN FLUCTUATIONS DURING MRI ACQUISITION IN AIM 1 WE WILL CHARACTERIZE PHYSIOLOGICAL MECHANISMS MODULATING RESTING STATE FMRI SIGNAL IN RABBIT CORTEX DURING POSTNATAL DEVELOPMENT. ROLE OF INTERNEURONS WILL BE EXPLORED USING PHARMACOLOGICAL INTERVENTIONS TO SELECTIVELY BLOCK ACTIVITY OF INTERNEURONS AND AND/OR PYRAMIDAL NEURONS. SPECIFIC SIGNATURE OF INTERNEURON CONTRIBUTION TO RSFMRI SIGNAL AND LOCAL CONNECTIVITY BETWEEN NEIGHBORING VOXELS WILL BE DETERMINED DURING NORMAL POSTNATAL DEVELOPMENT AND APPLIED TO PREDICT INJURY TO INTERNEURONS AND COGNITIVE ABNORMALITIES IN AIM 2 IN A RABBIT MODEL OF ANTENATAL HYPOXIC ISCHEMIC INJURY.

BOLD MRI: APPLICATION TO INTRARENAL OXYGENATION

NON-CONTRAST MAGNETIC RESONANCE ANGIOGRAPHY OF PERIPHERAL VASCULAR DISEASE

TOLL-LIKE RECEPTOR SIGNALING IN THE PATHOGENESIS AND PREVENTION OF PREMATURITY

SPINAL SEROTONIN IN CEREBRAL PALSY

PRE-PROCEDURAL EVALUATION OF HIGH-RISK PATIENTS USING NEXT-GENERATION RADIAL QISS

DETECTION, EDUCATION, RESEARCH AND DECOLONIZATION WITHOUT ISOLATION IN LONG-TERM

PREVENTION OF PRETERM BIRTH USING THE COLLECTIN SURFACTANT PROTEIN A (SP-A)

AP-1 FACTORS IN THE PATHOGENESIS AND PROGRESSION OF BENIGN PROSTATIC HYPERPLASIA

2/2 TARGETED SEQUENCING AND FUNCTIONAL EVALUATION OF MUTATIONS IN SCHIZOPHRENIA

PERINATAL WHITE MATTER DEVELOPMENT AND FETAL HYPOXIA

VALIDATING MOUSE MODELS OF PROSTATIC HYPERPLASIA - OVERALL: SUMMARY THIS P20 FORWARD CENTER WILL SUPPORT A PROJECT CONCEIVED AND EXECUTED BY THREE EARLY STAGE INVESTIGATORS (ESIS) TO ADDRESS A PROBLEM THAT IS IMPORTANT TO THE FIELD OF BENIGN PROSTATE RESEARCH AND TO OTHER FIELDS MORE BROADLY: THE RELEVANCE OF SPECIFIC GENETICALLY ENGINEERED MOUSE MODELS TO HUMAN DISEASE. THE NEED FOR ANIMAL MODELS IN BIOMEDICAL RESEARCH AND THE UTILITY OF MICE, SPECIFICALLY, IS WELL RECOGNIZED AND ACCEPTED. A NUMBER OF MOUSE MODELS THAT PURPORT TO REPRESENT THIS DISEASE HAVE BEEN GENERATED. IT IS WELL RECOGNIZED IN THE FIELD THAT NONE OF THESE IS A GOOD OVERALL REPRESENTATION OF THE HUMAN CONDITION. AS SUCH, CRITICISM OF MODELS IS A COMMON ISSUE IN GRANT AND PAPER REVIEW. THIS IS A PROBLEM FOR ALL INVESTIGATORS IN THE FIELD AND CAN BE PARTICULARLY DAMAGING TO ESIS WHO DO NOT HAVE RESOURCES TO GENERATE DATA FROM MULTIPLE LINES. THE CENTER WILL BRING TOGETHER TWO BIOLOGISTS (DRS. POPOVICS AND VICKMAN) WITH COMPLEMENTART SKILL SETS AND AN INTEREST IN BPH, , CONTRIBUTING EXPERTISE IN MOUSE MODELS AND INFLAMMATION, WITH A BIOINFORMATICIAN (DR. LANMAN) TO DEVELOP NEW APPROACHES TO CORRELATE TRANSCRIPTOMIC DATA FROM MICE WITH EXISTING HUMAN BPH DATASETS TO ESTABLISH A REFERENCE DTABASE ENCOMPASSING SIMILARITIES AND DIFFERENCES BETWEEN INDIVIDUAL MOUSE MODELS AND SALIENT ASPECTS OF HUMAN DISEASES. SUCCESSFUL DEVELOPMENT OF THESE METHODS WILL ALLOW BROAD APPLICATION OF THE APPROACH ACROSS A RANGE OF DISEASES WHERE SUCH PROBLEMS EXIST. THE PROJECT WILL ESTABLISH STANDARDS AND BENCHMARKS FOR COMPARING MOUSE MODELS TO HUMAN BPH AND IDENTIFYING COMMONALITIES AND DISPARITIES BETWEEN THE TWO. THIS WILL FACILITATE THE SELECTION OF THE BEST MODELS AND WILL ENCOURAGE SIMILAR CHARACTERIZATION AND COMPARISON OF OTHER MODELS IN THE FIELD. THE DATA WILL BE MADE AVAILABLE TO THE SCIENTIFIC COMMUNITY, AS A COLLECTION IN THE CELLXGENE PORTAL AND AS AN RSHINY APPLICATION. CONSISTENT WITH THE STATED GOALS OF THE RFA THE ADMINISTRATIVE CORE AND ITS DIRECTOR (THE PI, DR. HAYWARD) WILL SUPPORT THE PROJECT AND SPECIFICALLY WILL PROVIDE ACCESS TO RESOURCES AND EXPERTISE TO ASSIST THE THREE ESIS IN THE DEVELOPMENT OF NEW FUNDING PROPOSALS DERIVATIVE FROM THE DATA GENERATED HERE. THE ADMINISTRATIVE CORE WILL ALSO OVERSEE THE FISCAL AND REGULATORY ASPECTS OF THE CENTER AND WILL PROVIDE MECHANISMS FOR REGULAR CONTACTS BETWEEN THE PROJECT INVESTIGATORS AND THE BROADER RESEARCH COMMUNITY, IN PARTICULAR WITH PAST AND PRESENT CAIRIBU MEMBERS, FOSTERING OPPORTUNITIES TO PRESENT DATA AND FURTHERING CAREER OPPORTUNITIES. THE ADMINSTRATIVE CORE WILL ALSO COORDINATE WITH EXPERTS IN THE FIELD TO SUPPORT THE DEVELOPMENT AND SUBMISSION OF NEW GRANT PROPOSALS FROM THE ESIS. THE IMMEDIATE GOAL OF THIS CENTER IS TO SUPPORT THE DEVELOPMENT OF DATA THAT WILL CONTRIBUTE TO THE CAREER DEVELOPMENT AND FUNDING SUCCESS OF THREE EARLY STAGE INVESTIGATORS IN THE FIELD OF BENIGN UROLOGIC RESEARCH, BRING NEW IDEAS AND RETAIN EXPERTISE IN THE FIELD. THE LONG-TERM GOAL IS FOR THE ESIS TO ACHIEVE SIGNIFICANT INDEPENDENT CAREERS.

TARGETING RACIAL DISPARITIES IN STROMAL DGAT TO SUPPRESS AGGRESSIVE PROSTATE CANCER

HIPPOCAMPAL MICROSTRUCTURE AND FUNCTION IN APP TG MICE

ONCOLYTIC ADENOVIRUS-STGFBETARIIFC TARGETING BREAST CANCER BONE METASTASIS

DIAGNOSTICS FOR RAPID TREATMENT AND CONTROL OF MULTIDRUG-RESISTANCE IN HEALTHCARE

DNA DAMAGE CHECKPOINT AND CANCER

THE ROLE OF MUTATIONS IN BRCA2 AND OTHER KNOWN AND NOVEL CANCER SUSCEPTIBILITY GENES IN INHERITED RISK FOR LETHAL PROSTATE CANCER

MOLECULAR MECHANISM OF GRANULE-MEDIATED APOPTOSIS

MCH RESEARCH

5/5-THE PSYCHIATRIC GWAS CONSORTIUM: INTEGRATED & COORDINATED GWAS META-ANALYSES

ANTI-ANGIOGENIC BARRIERS TO TUMOR DEVELOPMENT

PAF RECEPTOR TRAFFICKING AND FUNCTION IN EPITHELIAL CELLS

INTRARENAL OXYGENATION: AN EARLY MARKER FOR RISK OF DEVELOPING AKI

INTEGRATIVE ANALYSES OF CLINICAL PHARMACOGENETIC DATA TO PREVENT HOSPITAL READMISSION IN REAL-WORLD HEALTH SYSTEMS - PROJECT SUMMARY/ABSTRACT ADVERSE DRUG REACTIONS RELATED TO INADEQUATELY DOSED OR PRESCRIBED MEDICATIONS ARE A MAJOR CAUSE OF MORBIDITY, MORTALITY, AND HOSPITAL READMISSIONS IN THE UNITED STATES. PHARMACOGENETICS RESEARCH HAS IDENTIFIED GENETIC VARIANTS ASSOCIATED WITH RESPONSE OR TOXICITY FOR HUNDREDS OF DRUGS, AND VARIANT GENOTYPES CARRIED BY SOME INDIVIDUALS MAY CONTRIBUTE DISPROPORTIONATELY TO MEDICATION-RELATED HOSPITAL ADMISSIONS. YET THE CLINICAL UTILITY OF PHARMACOGENETICS (PGX) WHEN IMPLEMENTED IN HEALTHCARE SYSTEMS HAS NOT BEEN WIDELY ESTABLISHED. IN A RESOURCE-LIMITED HEALTH SYSTEM, IT IS NOT PRACTICAL TO GENOTYPE EVERY PATIENT, BUT IF WE CAN IDENTIFY PATIENTS AT HIGHER RISK OF HOSPITAL ADMISSION BASED ON MEDICATION PRESCRIBING EVENTS, WE COULD BE BETTER ABLE TO DISCERN WHICH PATIENTS TO APPROACH WITH PREEMPTIVE GENOTYPING. WE PROPOSE A COHORT STUDY WITHIN TWO LEARNING HEALTHCARE SYSTEMS WITH ESTABLISHED PGX IMPLEMENTATION PROGRAMS – NORTHSHORE UNIVERSITY HEALTHSYSTEM AND THE UNIVERSITY OF CHICAGO CENTER – IN A POOLED, ETHNICALLY DIVERSE PATIENT POPULATION OF 5,726 PATIENTS – TO EVALUATE THE AGGREGATE IMPACT OF PHARMACOGENETIC DRUG INTERACTIONS ON READMISSIONS AND EMERGENCY DEPARTMENT (ED) VISITS ATTRIBUTABLE TO ADVERSE DRUG REACTIONS INCLUDING INADEQUATE DRUG RESPONSE, OVER A TWO-YEAR FOLLOW-UP PERIOD. THE OVERALL GOAL OF THIS PROJECT IS TO DEVELOP NOVEL ANALYTIC METHODS TO QUANTIFY THE CONTRIBUTION OF GENE-X-DRUG INTERACTIONS AFTER HOSPITAL DISCHARGE TO ED VISITS AND READMISSIONS, AND TO IDENTIFY THOSE INDIVIDUALS AT GREATEST RISK OF THESE OUTCOMES. AIM 1 IS TO ESTIMATE THE RATE OF COMBINED 90-DAY ED VISITS AND READMISSIONS ATTRIBUTABLE TO INADEQUATE DRUG RESPONSE OR TOXICITY AND IDENTIFY THE CLINICAL AND DEMOGRAPHIC PREDICTORS OF THOSE ADMISSIONS. AIM 2 IS TO IDENTIFY 90-DAY ED VISITS AND READMISSIONS ASSOCIATED WITH ADVERSE DRUG REACTIONS AMONG PATIENTS DISCHARGED ON MEDICATIONS FOR WHICH THERE IS EVIDENCE OF GENETIC VARIABILITY FOR OUTCOMES – FOCUSING ON MEDICATIONS WITH HIGH-LEVEL EVIDENCE GUIDELINES FROM THE CLINICAL PHARMACOGENOMICS IMPLEMENTATION CONSORTIUM AND FOOD AND DRUG ADMINISTRATION LABELS PRESCRIBED AND CONTINUED AT HOSPITAL DISCHARGE ON 90-DAY READMISSIONS. AIM 3 WILL BE TO DETERMINE THE CONTRIBUTION OF SPECIFIC GENOTYPES TO MEDICATION-RELATED 90-DAY ED VISITS AND READMISSIONS VISITS AMONG GENOTYPED PATIENTS. THIS PROJECT IS RESPONSIVE TO RFA HG-20-037 ADVANCING GENOMIC MEDICINE RESEARCH BY FACILITATING ANALYSIS OF CLINICAL GENOMIC DATA AND WILL LEVERAGE THE EXTENSIVE EXPERIENCE OF OUR TEAM AND DATASET FROM TWO DIVERSE, REAL-WORLD HEALTHCARE SYSTEMS ACROSS CHICAGOLAND. OUR MULTIDISCIPLINARY, COLLABORATIVE TEAM, AIDED BY USE OF NATURAL LANGUAGE PROCESSING, WILL SCREEN ELECTRONIC HEALTH RECORDS TO EXTRACT DE-IDENTIFIED PATIENT DATA, CURATE, AND APPLY INNOVATIVE, INTEGRATED ANALYTIC METHODS TO BETTER IDENTIFY PATIENTS WHO COULD BENEFIT THE MOST FROM PREEMPTIVE PGX GENOTYPING AND PHARMACOVIGILANCE TO PREVENT ED VISITS AND READMISSIONS. IF, AS WE HYPOTHESIZE, OUR ANALYSES DEMONSTRATE THAT GENE-X-DRUG INTERACTIONS CONTRIBUTE SUBSTANTIALLY TO 90-DAY ED VISITS AND READMISSIONS, THESE METHODS CAN BE AUTOMATED AND WILL BE TRANSPORTABLE TO OTHER HEALTH SYSTEMS TO GUIDE PREEMPTIVE GENOTYPING PROTOCOLS FOR THE HIGHEST RISK PATIENTS TO PREVENT HOSPITAL READMISSIONS. THESE RESULTS WILL INFORM THE DESIGN OF A FUTURE CLINICAL EFFECTIVENESS TRIAL OF TAILORED, PGX INTERVENTIONS TO PREVENT ADVERSE DRUG REACTIONS AND ASSOCIATED READMISSIONS.

PROSPECTIVE RCT OF OBSTRUCTED DEFECATION SURGERY: COMPARING TRANSVAGINAL RECTOPEXY, VENTRAL MESH RECTOPEXY AND POP REPAIR (PROD TRIAL) - OBSTRUCTED DEFECATION (OD), DEFINED AS INCOMPLETE EMPTYING OF STOOL, IS A WIDELY PREVALENT DISORDER IN WOMEN’S HEALTH AND RESULTING IN MAJOR QUALITY OF LIFE (QOL) AND HEALTHCARE BURDEN. SUCCESSFUL MANAGEMENT HAS BEEN IMPAIRED, HISTORICALLY, BY DEFICIENCIES RELATING TO BOTH DIAGNOSIS AND TREATMENT. FIRST, THERE HAS BEEN A PERSISTENT MISCONCEPTION THAT OD IN THE ABSENCE OF DYSSYNERGIA (I.E., UNCOORDINATED CONTRACTION OF PELVIC FLOOR) RESULTS FROM PROLAPSE OF THE POSTERIOR VAGINAL WALL (‘RECTOCELE’) AND IMPROVES AFTER ITS REPAIR. IN FACT, PRIOR STUDIES HAVE CONFIRMED THAT THIS FORM OF OD RESULTS FROM SUPPORT DEFECTS INVOLVING THE RECTUM RATHER THAN VAGINA (8-10), AND MOREOVER THAT RECTOCELE REPAIRS ARE UNRELIABLE IN RELIEVING OD SYMPTOMS. RECENT WORK FROM OUR CENTER CONFIRMED RECTAL DETACHMENT AND HYPERMOBILITY TO BE THE MAJOR DETERMINANTS OF OD IN THE IRRESPECTIVE OF THE PRESENCE OF A RECTOCELE. SECONDLY, TRADITIONAL DIAGNOSTIC MODALITIES TO ASSES RECTAL SUPPORT AS THE SOURCE OF OD ARE EXPENSIVE (E.G. MRI DEFECOGRAPHY) AND/OR INVASIVE (E.G. ANAL MANOMETRY), AND OFTEN GENERATE FINDINGS WITH UNCLEAR CLINICAL CORRELATION AND IMPACT ON CARE. FINALLY, AVAILABLE SURGERIES TO REPAIR RECTAL SUPPORT DEFECTS HAVE BEEN LIMITED TO INVASIVE TRANSABDOMINAL OR PERINEAL METHODS, TYPICALLY INVOLVING MESH IMPLANTATION AND RESERVED FOR SEVERE CASES, E.G. THOSE WITH OVERT RECTAL PROLAPSE. LAPAROSCOPIC OR OPEN VENTRAL MESH RECTOPEXY IS THE MOST WIDELY ACCEPTED OPERATION TO STABILIZE RECTAL SUPPORT. WE ARE TESTING THE HYPOTHESIS THAT OD SYMPTOMS IN THE ABSENCE OF DYSSYNERGIA PRIMARILY RESULT FROM DEFICIENCIES IN RECTAL SUPPORT AND THAT PATIENTS PRESENTING OD SYMPTOMS WITH OR WITHOUT VAGINAL PROLAPSE UNDERGOING OUR NEW DIAGNOSTIC EVALUATION AND SURGICAL TREATMENT WILL HAVE IMPROVED OUTCOMES RELATIVE TO THE CURRENT STANDARD OF CARE AT 2 YEARS AFTER SURGERY. OUR STUDY IS DESIGNED TO EVALUATE PRIMARY AND SECONDARY OUTCOMES RELATING TO THE TWO RECTOPEXY PROCEDURES ON OD AT 2 YEARS FOLLOW UP ACROSS TWO INSTITUTIONS. THIS CLINICAL DATA WILL BE COMPLEMENTED BY A COMPUTATIONAL MODELING APPROACH THAT AIMS TO PROVIDE INSIGHT INTO THE MOST LIKELY CONTRIBUTORS TO OD SYMPTOMS, I.E. VAGINAL VERSUS RECTAL SUPPORT DEFECTS. AIM 1: COMPARE OCCULT RECTAL HYPERMOBILITY AS MEASURED USING POSTERIOR COMPARTMENT DYNAMIC ULTRASOUND IMAGING VERSUS MR DEFECOGRAPHY. POSTERIOR COMPARTMENT DYNAMIC ULTRASOUND IS A NOVEL APPROACH FOR IDENTIFYING THE UNDERLYING ANATOMIC CAUSE OF OD IN WOMEN SUFFERING FROM OD SYMPTOMS WITHOUT COEXISTING FUNCTIONAL BOWEL DISORDERS (E.G. NORMAL BM FREQUENCY AND STOOL TYPE, AND ABSENCE OF DYSSYNERGIA). AIM 2: COMPARE ANATOMIC, FUNCTIONAL, AND HEALTH-RELATED QUALITY OF LIFE OUTCOMES IN FEMALE SUBJECTS WITH MODERATE TO SEVERE OD SYMPTOMS, AND RECTAL HYPERMOBILITY DIAGNOSED BY ULTRASOUND, WHO ARE RANDOMIZED TO MINIMALLY INVASIVE TRANSVAGINAL RECTOPEXY VERSUS ABDOMINAL VENTRAL RECTOPEXY AT 2 YEARS AFTER SURGERY. AIM 3: DEVELOP AND VALIDATE A COMPUTATIONAL FINITE ELEMENT MODEL AND STATISTICAL SHAPE MODELING APPROACH TO DESCRIBE THE MECHANICS OF NORMAL DEFECATION AND THE ROLE OF RECTAL AND VAGINAL SUPPORT DEFICIENCIES IN CAUSING OD SYMPTOMS.

THE ROLE OF PAF AND TLR IN NEC

LEUKOCYTIC PHENOTYPES ASSOCIATED WITH BPH PROGRESSION

SWEDISH HOSPITAL SANE PROGRAM EXPANSION

OPTIMIZING UTILIZATION OF LAY HEALTH WORKERS TO ADDRESS MATERNAL AND CHILD HEALTH DISPARITIES: A COMPREHENSIVE EVALUATION OF A CLINICALLY INTEGRATED BREASTFEEDING PEER COUNSELING PROGRAM - BREASTFEEDING PROVIDES UNIQUE AND PROFOUND MATERNAL AND INFANT HEALTH BENEFITS. IF 90% OF US PARENT- INFANT DYADS BREASTFED EXCLUSIVELY FOR THE FIRST SIX MONTHS AND SUPPLEMENTED THROUGH 12 MONTHS, 2600 EXCESS MATERNAL DEATHS AND 721 INFANT DEATHS COULD BE AVERTED EACH YEAR. DESPITE THESE SUBSTANTIAL HEALTH BENEFITS CONFERRED BY BREASTFEEDING, ONLY 45% OF US BIRTH PARENTS MEET THIS 6-MONTH GOAL, AND PARENTS OF COLOR AND THOSE IN LOW INCOME FAMILIES FACE ADDITIONAL BARRIERS TO BREASTFEEDING SUCCESS, RESULTING IN DOUBLE THE RISK OF INFANT MORBIDITY AND MORTALITY. CLINICALLY-INTEGRATED BREASTFEEDING PEER COUNSELING (CI-BPC) HAS BEEN SHOWN TO EFFECTIVELY PROMOTE RACIAL AND ECONOMIC EQUITY IN BREASTFEEDING OUTCOMES. DESPITE THE DEMONSTRATED EFFECTIVENESS OF CI-BPC, THERE REMAIN CRITICAL KNOWLEDGE GAPS REGARDING PROGRAM DESIGN AND COSTS. THUS, THE SCIENTIFIC OBJECTIVE OF THIS K01 APPLICATION IS TO EVALUATE THE IMPLEMENTATION OF AN EFFECTIVE CI-BPC PROGRAM AND DETERMINE THE ESSENTIAL PROGRAM ACTIVITIES, IDENTIFY SIGNIFICANT PATIENT-LEVEL AND CONTEXTUAL FACTORS RELEVANT TO IMPLEMENTATION, AND DETERMINE THE ECONOMIC IMPACT OF CI-BPC FOR PATIENTS, HEALTH SYSTEMS, AND SOCIETY. CLOSING THESE GAPS IN KNOWLEDGE WILL SUPPORT WIDER ADOPTION OF CI-BPC BY PROVIDING A FRAMEWORK FOR IMPLEMENTATION AND EVALUATION. MY CENTRAL HYPOTHESIS IS THAT CI-BPC COUNSELLING INCREASES PATIENT BREASTFEEDING KNOWLEDGE AND SOCIAL SUPPORT, LEADING TO INCREASED EMPOWERMENT AND REDUCED STRESS, AND THAT THE IMPROVEMENTS IN BREASTFEEDING RATES CONFERRED BY CI-BPC WILL BE ASSOCIATED WITH LOWER COST OF HEALTHCARE UTILIZATION FOR INFANTS IN THE FIRST 6 MONTHS POST-DELIVERY. SPECIFICALLY, I AIM: (1) TO DETERMINE THE ESSENTIAL PROGRAM ACTIVITIES OF AN EFFECTIVE HOSPITAL CI-BPC PROGRAM, IDENTIFY RELEVANT CONTEXTUAL FACTORS, AND ADAPT THE PROGRAM TO OPTIMIZE BREASTFEEDING OUTCOMES FOR BLACK AND LATINX PATIENTS; (2) TO DETERMINE WHETHER THE ADAPTED CI-BPC PROGRAM IS MORE EFFECTIVE AT IMPROVING BREASTFEEDING OUTCOMES, ATTITUDE, KNOWLEDGE, AND SUPPORT COMPARED TO STANDARD PRENATAL CARE, AND (3) TO DETERMINE PATIENT, PROGRAM, HEALTHCARE, AND SOCIETAL COSTS FOR CI-BPC. THIS PROJECT WILL EVALUATE AN INNOVATIVE HOSPITAL-BASED CI-BPC PROGRAM AT NORTHSHORE UNIVERSITY HEALTHSYSTEM THAT HAS DEMONSTRATED SIGNIFICANT REDUCTION IN BREASTFEEDING DISPARITIES. MY INTIMATE ROLE WITH THIS CI-BPC PROGRAM AND MY EXPERTISE IN MIXED-METHODS FIELD-BASED AND CLINICAL RESEARCH HAS EQUIPPED ME WITH THE SKILLS TO UNDERTAKE SUCH A PROJECT, BUT I NEED ADDITIONAL MENTORSHIP AND TRAINING IN IMPLEMENTATION SCIENCE, CLINICAL INTERVENTION RESEARCH, AND HEALTHCARE ECONOMICS. THE TRAINING AND RESEARCH ARE SIGNIFICANT BECAUSE DISPARITIES IN MATERNAL AND CHILD HEALTH IN THE US ARE GROWING, AND AN EVIDENCE-BASIS IS ESSENTIAL TO REPLICATE AND SCALE UP INTERVENTIONS THAT PROMOTE HEALTH EQUITY. THIS INNOVATIVE RESEARCH WILL GENERATE NOVEL DATA REGARDING CI-BPC PROGRAM DESIGN AND ECONOMIC IMPACT OF CI-BPC THAT WILL INFORM BROADER IMPLEMENTATION OF THIS INTERVENTION. THIS APPLICATION IS RESPONSIVE TO SEN NOT-HS-21-014: AHRQ ANNOUNCES INTEREST IN HEALTH SERVICES RESEARCH TO ADVANCE HEALTH EQUITY.

NOVEL PELVIC FLOOR PAIN MEASURES TO ENHANCE FEMALE PELVIC PAIN EVALUATION

MITOCHONDRIA, SUPEROXIDE & MNSOD IN A FETAL HYPOXIC CEREBRAL PALSY MODEL

LIPID-RICH TREM2+ MACROPHAGES: A TARGETABLE PROMOTER OF BENIGN PROSTATIC HYPERPLASIA - SUMMARY BENIGN PROSTATIC HYPERPLASIA (BPH) IS A COMMON DISEASE IN AGING MEN RESULTING IN LOWER URINARY TRACT SYMPTOMS (LUTS). CHRONIC INFLAMMATION IS CLEARLY ASSOCIATED WITH BPH AND SOME HAVE HYPOTHESIZED THAT INFLAMMATORY SIGNALS CAN DIRECTLY STIMULATE PROSTATIC HYPERPLASIA, BUT DEFINED MECHANISMS ARE LIMITED. OUR GROUP DEMONSTRATED THAT TREATMENT WITH SYSTEMIC TNF-ANTAGONISTS DECREASES PROSTATIC HYPERPLASIA AND MACROPHAGE (Mɸ) INFILTRATION IN HUMANS AND MOUSE MODELS. WE RECENTLY DISCOVERED THAT LIPID-RICH TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS 2 (TREM2)-EXPRESSING MɸS ACCUMULATE IN BPH AS PROSTATE SIZE INCREASES AND LUTS WORSEN, SUGGESTING THAT THIS SUBPOPULATION COULD BE A NEW, SPECIFIC THERAPEUTIC TARGET. THE MECHANISMS RESPONSIBLE FOR LIPID ACCUMULATION IN TREM2+ MɸS AND THEIR ROLE IN PROSTATIC GROWTH ARE UNCLEAR. OUR PRELIMINARY DATA INDICATE THAT PRIMARY TREM2+ MɸS INCREASE THE LIPID LEVEL AND SIZE OF PROSTATIC EPITHELIAL SPHEROIDS COMPARED TO TREM2- MΦS. ADDITIONALLY, VOIDING DYSFUNCTION INDUCED BY STEROID HORMONE IMBALANCE IN C57BL/6J MICE DOES NOT OCCUR IN TREM2-/- MICE, IMPLICATING AN IMPORTANT ROLE FOR TREM2+ MɸS IN DEVELOPING LUTS. TREM2+ MɸS MAY HAVE ALTERED FUNCTIONS DUE TO LIPID-ACCUMULATION, WHICH WE POSTULATE IS DUE TO UPREGULATION OF OXIDIZED LDL RECEPTOR CD36 AND ALTERATIONS IN LIPOGENESIS (LIPID FORMATION) AND LIPOLYSIS (LIPID BREAKDOWN) RESULTING IN A NET-GAIN OF NEUTRAL LIPID, OFTEN STORED AS LIPID DROPLETS. WE DETERMINED THAT LIPID-RICH MɸS HAVE DECREASED PRODUCTION OF THE ANTI-INFLAMMATORY PROTEIN THROMBOSPONDIN-1 (TSP1), WHICH MAY CONTRIBUTE TO THE GLOBAL LOSS OF TSP1 PROTEIN KNOWN TO OCCUR IN HUMAN BPH. TNF-ANTAGONIST TREATMENT IN NOD MICE RESTORES TSP1 EXPRESSION IN THE PROSTATE, SUGGESTING PREVIOUSLY UNRECOGNIZED SIGNALING CROSSTALK BETWEEN TSP1 AND TNF. LOSS OF TSP1 AND INCREASES IN TNF OCCUR IN THE MICROENVIRONMENT AS BPH PROGRESSES. WE HYPOTHESIZE THAT TREM2+ MɸS INCREASE INTRACELLULAR NEUTRAL LIPID VIA CD36-MEDIATED LIPID-UPTAKE, CONTRIBUTING TO THE LOSS OF TSP1 AND THE INCREASE IN Mɸ-DERIVED LIPID ENERGY FUELS EPITHELIAL AND STROMAL PROLIFERATION IN A TNF-HIGH BPH ENVIRONMENT. MOREOVER, WE PREDICT THAT TREATMENT WITH A NOVEL LIGAND-INDEPENDENT TREM2 INHIBITOR OR A TSP1 MIMETIC WILL REDUCE INFLAMMATION AND EPITHELIAL PROLIFERATION TO SUPPRESS BPH IN ANIMAL MODELS. THE AIMS OF THIS PROPOSAL ARE TO 1) DEFINE THE MECHANISMS CONTRIBUTING TO THE ACCUMULATION OF NEUTRAL LIPID IN TREM2+ MACROPHAGES AND THE FUNCTIONAL CONSEQUENCES OF MACROPHAGES ENRICHED WITH LIPID, 2) DETERMINE HOW TREM2+ MACROPHAGES DIRECTLY OR INDIRECTLY PROMOTE PROSTATE EPITHELIAL AND STROMAL CELL PROLIFERATION, AND 3) EVALUATE IF INHIBITING TREM2 SIGNALING OR RESTORING TSP1 VIA SYSTEMIC PEPTIDES CAN DECREASE LIPID-RICH TREM2+ MACROPHAGE ABUNDANCE AND DECREASE PROLIFERATION/SYMPTOMS IN BPH MODELS. OUR RESEARCH TEAM BRINGS EXPERTISE IN PROSTATE BIOLOGY, BPH INFLAMMATION, LIPID METABOLISM, PATHOLOGY, AND EX VIVO TISSUE EXPLANT CULTURE. THESE STUDIES WILL PROVIDE A MECHANISTIC UNDERSTANDING OF HOW MΦS CONTRIBUTE TO BPH AND IDENTIFY NOVEL THERAPEUTIC OPTIONS FOR INFLAMMATION-MEDIATED PROSTATIC HYPERPLASIA.

ROLE OF INTERNEURONS IN RESTING STATE FMRI CONNECTIVITY DURING NORMAL DEVELOPMENT AND AFTER PERINATAL BRAIN INJURY

NEURONAL NITRIC OXIDE SYNTHASE IN EARLY CRITICAL FETAL BRAIN INJURY FROM HYPOXIA

THE PSYCHOSOCIAL & GENETIC BASIS OF ESTROGEN METABOLISM & BLOOD PRESSURE IN AGING

TRANSLATOME PROFILING OF NICOTINE ADDICTION

INTRA-RENAL BOLD MRI: APPLICATION TO DIABETIC NEPHROPATHY

PROJECTION IMAGING OF PERIPHERAL VASCULAR CALCIFICATIONS

META-ANALYSIS OF MALE SEXUAL ORIENTATION

DETECTION OF HOST RESPONSE IN CLOSTRIDIUM DIFFICILE INFECTION

ROLE OF GUT MICROBIOTA IN SUSCEPTIBILITY OF PRETERM INFANTS TO HYPOXIC BRAIN INJURY

NONINVASIVE IMAGING OF UTERINE PHYSIOLOGY TO IMPROVE TREATMENT FOR DYSMENORRHEA

LIPID-RICH MACROPHAGES AT THE TUMOR-ADIPOSE INTERFACE: A NEW TARGET FOR LOCALLY-INVASIVE PROSTATE CANCER THERAPY - SUMMARY MACROPHAGES ARE IMPORTANT CONTRIBUTORS TO THE BIOLOGY OF THE TUMOR MICROENVIRONMENT. AS TUMORS PENETRATE THE PROSTATIC CAPSULE THEY INVADE A LIPID-RICH DEPOT KNOWN AS THE PERI-PROSTATIC FAT (PPF). AN ABILITY TO UTILIZE THIS ENERGY SOURCE IS IMPORTANT FOR TUMOR PROGRESSION. PPF IS A WHITE ADIPOSE TISSUE (WAT) THAT ENCASES THE PROSTATE AND IS A DEPOT OF ADIPOCYTES AND RESIDENT MACROPHAGES TERMED ADIPOSE TISSUE MACROPHAGES (ATMS). PPF AND ACTIVATED ATMS ARE RELATIVELY UNDERSTUDIED COMPONENTS OF THE TUMOR MICROENVIRONMENT (TME). ADIPOSE TISSUES REPRESENT A NUTRIENT RESERVOIR FROM WHICH TUMOR CELLS CAN GAIN ACCESS TO ADIPOKINES. “BROWNING” OF WAT RESULTS IN A MORE VASCULAR AND MULTILOCULAR FAT PHENOTYPE AND IT IS NOT CLEAR WHETHER THIS REPRESENTS AN ADAPTIVE METABOLIC RESPONSE IN PPF TO SUPPRESS OR ACCELERATE TUMOR GROWTH. THERE IS HETEROGENEITY IN LIPID AVAILABILITY IN THE PROSTATE TME: ATMS RESIDE IN A LIPID-RICH STORAGE ENVIRONMENT COMPOSED PRIMARILY OF ADIPOCYTES WHEREAS TUMOR ASSOCIATED MACROPHAGES (TAMS) INHABIT STROMA WHERE THERE IS A PAUCITY OF ADIPOCYTES. METABOLIC REPROGRAMMING IN TUMOR CELLS IS WELL DOCUMENTED; HOWEVER, LIMITED RECENT STUDIES HAVE REPORTED THAT ATMS IN VISCERAL FAT OR BREAST TME CAN ACQUIRE A METABOLICALLY ACTIVATED PHENOTYPE (MME) DISTINCT FROM THE M1/M2 PHENOTYPES. OUR PRELIMINARY STUDIES IDENTIFIED A POTENTIALLY CRITICAL IMMUNO-METABOLIC SIGNALING AXIS IN MACROPHAGES INVOLVING PRO-INFLAMMATORY RECEPTOR INTERACTING PROTEIN 140 (RIP140), LIPID-REGULATING FATTY ACID BINDING PROTEINS 4/5 (FABP4/5) AND DIACYLGLYCEROL O-ACYLTRANSFERASE 1 (DGAT1) THAT SYNTHESIZES NEUTRAL LIPIDS AND IS REQUIRED FOR FAT ABSORPTION AND STORAGE. RIP140, A CO-ACTIVATOR OF NF-KB, IS IMPORTANT FOR PROMOTING PRO- INFLAMMATORY CYTOKINES CHARACTERISTIC OF M1 ACTIVATION, IN MACROPHAGE M1/M2 POLARIZATION, AND IN BROWNING OF WAT. BOTH FABPS AND DGAT1 CAN BE REGULATED IN VIVO AND IN VITRO USING SMALL MOLECULE INHIBITORS SOME OF WHICH ARE IN DEVELOPMENT AND BEING TESTED AS POTENTIAL THERAPIES. THE PROPOSED STUDY WILL INVESTIGATE A CENTRAL HYPOTHESIS: PPF IS A HIGHLY DYNAMIC DEPOT, AND INCREASED LIPID STORES IN THE TME CAN PROMOTE TUMOR PROGRESSION BY TRIGGERING LIPID-RICH ATMS TO SECRETE PRO-TUMORIGENIC CYTOKINES/CHEMOKINES AND LIPID MEDIATORS, THUS, SWITCHING ATMS TO A HARMFUL PRO-INFLAMMATORY MME PHENOTYPE. WE WILL USE IN VIVO AND IN VITRO MODELS TO TEST WHETHER ALTERING DGAT1 OR FABP4/5 ACTIVITY IS TUMOR SUPPRESSIVE. OUR AIMS WILL DEFINE MECHANISMS REGULATING THE IMMUNO-METABOLIC AXIS IN ATMS AND TAMS IN PROSTATE CANCER (PCA), AND DETERMINE WHETHER THE MME PHENOTYPE SUBPOPULATION IS INCREASED IN LOCALLY INVASIVE PCA. TO OUR KNOWLEDGE, THIS IS THE FIRST STUDY TO INVESTIGATE THE ROLE AND FUNCTIONAL SIGNIFICANCE OF AN UNDERSTUDIED PHENOTYPE, MME, THAT MERGES BOTH INFLAMMATORY AND LIPID SIGNALING PATHWAYS IN THE PROSTATE TME. TARGETED THERAPIES WILL BE TESTED IN MULTICELLULAR ORGANOID CULTURES AND RELEVANT MURINE XENOGRAFT MODELS. SUCCESSFUL COMPLETION OF THESE STUDIES WILL SET THE STAGE FOR MORE COMPREHENSIVE PRE-CLINICAL INVESTIGATIONS AND POTENTIAL TRANSLATION TO THE CLINIC IN THE MEDIUM TERM.

IN VIVO FRACTIONAL BLOOD VOLUME: CONTRIBUTIONS TO RENAL BOLD MRI. - OUR LABORATORY HAS PIONEERED THE USE OF BLOOD OXYGENATION LEVEL DEPENDENT (BOLD) MRI THE KIDNEYS AS A WAY OF EVALUATING ITS OXYGENATION STATUS. SEVERAL INVESTIGATORS AROUND THE WORLD HAVE VALIDATED THE TECHNIQUE. HOWEVER, IT REMAINS AS A QUALITATIVE MEASURE AND ITS SPECIFICITY TO OXYGENATION IS NOT VALIDATED. EVEN THOUGH IT IS KNOWN THEORETICALLY THAT A ROLE EXISTS FOR THE FRACTIONAL BLOOD VOLUME (FRACTION OF THE TISSUE OCCUPIED BY BLOOD VESSELS) IN BOLD MRI, WITH THE LACK OF DATA IT HAS BEEN TACITLY ASSUMED TO BE EITHER SMALL OR NON-EXISTENT. HOWEVER, RECENT DEVELOPMENTS ALLOW US TO MEASURE REGIONAL FBV USING BLOOD POOL CONTRAST AGENTS. HERE, WE WANT TO FOR THE FIRST TIME MEASURE REGIONAL FBV IN HUMAN KIDNEYS AND SEE (I) WHETHER IT IS DIFFERENT IN CORTEX AND MEDULLA; (II) WHETHER MEDULLARY FBV REDUCES WHEN ADMINISTERING FUROSEMIDE AS SUGGESTED BY RECENT DATA IN RAT KIDNEYS; AND (III) WHETHER REGIONAL FBV IS REDUCED IN INDIVIDUALS WITH CHRONIC KIDNEY DISEASE (CKD). IF THE PROPOSED STUDY IS SUCCESSFUL, IT MAY SUPPORT THE USE OF FBV AS AN INDEPENDENT IMAGING MARKER. IN ADDITION, THE DATA WILL HAVE A SIGNIFICANT IMPACT ON THE INTERPRETATION OF RENAL BOLD MRI DATA.

THE INTRA-RENAL OXYGENATION IN CKD AS EVALUATED BY BOLD MRI

A HIGH THROUGHPUT, HUMAN, IN VITRO MODEL OF NEURONAL STRETCH INJURY

GENETIC PERTURBATION OF A SCHIZOPHRENIA SUSCEPTIBILITY LOCUS IN ISOGENIC HUMAN NE

MR-GUIDED ENDOVASCULAR INTERVENTION USING OFF-RESONANCE CONTRAST ANGIOGRAPHY

FAMILIAL FEMALE SEXUAL ORIENTATION PHENOTYPES

MULTI-CHANNEL RECEIVER INTEGRATED WITH RECONFIGURABLE PROCESSORS FOR MRI

TWOFOLD REDUCTION IN GADOLINIUM DOSE FOR BRAIN MRI EXAMS USING A NOVEL UNBALANCED T1 RELAXATION-ENHANCED STEADY-STATE (UT1RESS) TECHNIQUE - CONTRAST-ENHANCED MAGNETIC RESONANCE IMAGING (MRI) IS THE CORNERSTONE FOR BRAIN TUMOR DIAGNOSIS AND TREATMENT PLANNING. WHILE ITS SENSITIVITY FOR METASTASES IS SUPERIOR TO THAT OF CT OR PET-CT, SMALL LESIONS (<5- MM) AND LEPTOMENINGEAL SPREAD MAY STILL BE MISSED, WHICH CAN HAVE A MAJOR IMPACT ON PROGNOSIS AND PLANNING FOR STEREOTACTIC RADIOSURGERY, AS WELL AS ON THE USE OF TARGETED BIOLOGICS THAT CROSS THE BLOOD-BRAIN BARRIER. A METHOD THAT COULD FURTHER IMPROVE THE SENSITIVITY AND SPECIFICITY OF MRI FOR BRAIN TUMORS WOULD BE OF GREAT CLINICAL BENEFIT. TOWARDS THIS END, WE HAVE DEVELOPED A NEW CLASS OF PULSE SEQUENCES, CALLED T1 RELAXATION-ENHANCED STEADY-STATE (T1RESS), THAT GREATLY IMPROVES THE VISIBILITY OF TUMORS IN CONTRAST- ENHANCED MRI. COMPARED WITH EXISTING NEUROIMAGING TECHNIQUES, T1RESS AT LEAST DOUBLES THE TUMOR-TO- BACKGROUND CONTRAST WHILE SIGNIFICANTLY IMPROVING THE TUMOR-TO-BACKGROUND CONTRAST-TO-NOISE RATIO. AN “UNBALANCED” VERSION (UT1RESS) RENDERS BLOOD VESSEL DARK AND IS THE FOCUS OF OUR PROPOSAL. IN A PRELIMINARY STUDY OF 54 ADULT PATIENTS THAT WAS PUBLISHED IN SCIENCE ADVANCES, UT1RESS PROVIDED A REMARKABLE TWOFOLD OR GREATER IMPROVEMENT IN TUMOR-TO-BRAIN CONTRAST ALONG WITH A MARKED IMPROVEMENT IN LESION-TO-BRAIN CONTRAST-TO-NOISE IN COMPARISON TO STANDARD-OF-CARE MPRAGE AND OTHER PULSE SEQUENCES THAT ARE COMMONLY USED TO IMAGE BRAIN TUMORS. WE FOUND THAT EVEN SMALL METASTATIC TUMOR DEPOSITS AND LEPTOMENINGEAL LESIONS THAT WERE DIFFICULT TO DISTINGUISH FROM SMALL BLOOD VESSELS WITH STANDARD IMAGING TECHNIQUES COULD BE UNAMBIGUOUSLY IDENTIFIED. THE PRIMARY HYPOTHESIS OF THIS TWO-YEAR GRANT PROPOSAL IS THAT R21 GRANT PROPOSAL IS THAT THE TWOFOLD OR GREATER IMPROVEMENT IN SENSITIVITY TO GADOLINIUM ENHANCEMENT PROVIDED BY UT1RESS WILL ENABLE A CORRESPONDING TWOFOLD REDUCTION IN GBCA DOSE, WITH NON-INFERIOR DIAGNOSTIC ACCURACY COMPARED TO FULL DOSE MRI USING STANDARD NEUROIMAGING TECHNIQUES. STUDIES OF PHANTOMS, HEALTHY VOLUNTEERS, AND PATIENTS WITH BRAIN TUMORS ALONG WITH BLOCH EQUATION MODELING WILL BE USED TO GUIDE SEQUENCE OPTIMIZATION. OUR SPECIFIC AIMS ARE AS FOLLOWS: 1. TO MAXIMIZE THE SENSITIVITY OF UT1RESS TO GADOLINIUM ENHANCEMENT WHILE OPTIMIZING IMAGE QUALITY AND MINIMIZING SCAN TIME. 2. TO PERFORM A SINGLE SITE RESEARCH TRIAL AT 3 TESLA TO DETERMINE WHETHER HALF DOSE CONTRAST-ENHANCED MRI USING UT1RESS IS NON-INFERIOR TO FULL DOSE CONTRAST-ENHANCED MRI USING A STANDARD NEUROIMAGING TECHNIQUE IN PATIENTS WITH BRAIN TUMORS.

NEUROPHYSIOLOGICAL DIAGNOSTICS FOR MENSTRUAL PAIN

IMPROVING FLEXIBLE SIGMOIDOSCOPY IN WOMEN BY OPTICAL ANALYSIS OF MICROVASCULATURE

GENDER SELECTIVITY TO COLON CANCER CHEMOPREVENTION BY NSAIDS

UNDERSTANDING MECHANISMS OF FETAL HYPOXIC BRAIN INJURY RESULTING IN CEREBRAL PALS

DEVELOPING A PREVENTIVE CURE FOR CEREBRAL PALSY

TROPONIN STRUCTURE & FUNCTION IN CARDIOMYOPATHY

MECHANISMS OF VASOACTIVE MEDIATOR ACTION IN FGR

IMPROVING DIAGNOSIS OF HYPERTENSION IN CHILDREN (IDHC)

GYNECOLOGIC CANCER TRANSLATIONAL RESEARCH CENTER OF EXCELLENCE

MECHANISMS OF BPH PROGRESSION

FUNCTIONAL STUDY OF DSS1, A BRCA2 BINDING PROTEIN

9.4T MRI GRADIENTS - THE REQUESTED INSTRUMENT, THE GRADIENT SYSTEM FOR A 9.4T IMAGER, REPRESENTS A SUBSTANTIAL ADVANCEMENT IN THE METHODOLOGY OF TRANSLATIONAL RESEARCH. THIS DEVICE WILL REPLACE THE CURRENT, DEGRADING SYSTEM CURRENTLY IN USE IN THE IMAGER. THE CURRENT GRADIENT IS SUFFERING FROM OVER 15 YEARS OF WEAR, WHICH HAS LED TO THE DETERIORATION OF THE INSULATION MATERIALS THAT SEPARATE THE GRADIENT AND SHIM COILS. CONSEQUENTLY, WE HAVE OBSERVED THAT THE ELECTRICAL COUPLINGS BETWEEN THE GRADIENT AND SHIM COILS CAUSED A SIGNIFICANT DISTORTION IN THE IMAGES PRODUCED. THIS INDICATION, AMONG OTHERS OUTLINED IN THE PROPOSAL BELOW SUGGEST THAT THE CURRENT GRADIENT SYSTEM IS AT INCREASING RISK OF SUDDEN FAILURE WITHOUT ANY WARNING. THE GRADIENT SYSTEM’S INTEGRATED DESIGN WILL BE A COMPLETE AND LASTING FIX FOR THESE ISSUES. FURTHERMORE, IT WILL PERMIT RESEARCHERS TO CONTINUE AND ACCOMPLISH IMPORTANT NIH-FUNDED RESEARCH, THROUGH THE USE OF VARIOUS MAGNETIC RESONANCE (MR) MODALITIES WHICH PROMOTE ROBUST EMPIRICAL FINDINGS. THE PROPOSED PROJECTS THAT WILL UTILIZE THE SYSTEM WILL AIM TO IDENTIFY THE DEVELOPMENTAL AND CELLULAR MECHANISMS OF RESTING STATE FUNCTIONAL MR IMAGING (FMRI) IN HEALTHY STATE AND AFTER PERINATAL BRAIN INJURY, THE MR SIGNATURE OF DEVELOPMENTAL EFFECTS AFTER NEONATAL ANESTHESIA, UNDERSTAND THE PHYSIOLOGY OF VISCERAL PAIN, ETC. AT PRESENT, NORTHSHORE UNIVERSITY HEALTHSYSTEM DOES NOT CURRENTLY POSSESS AN ALTERNATIVE INSTRUMENT CAPABLE OF CONDUCTING THIS TYPE OF RESEARCH EVEN THOUGH THE PI AND THEIR TEAM ALREADY HAS OBTAINED THE NECESSARY EXPERIENCE AND EXPERTISE TO SAFELY AND EFFECTIVELY IMPLEMENT AND OPERATE THE GRADIENT SYSTEM WITH IMMEDIATE EFFECT. THE GRADIENT SYSTEM ALONG WITH THE ENTHUSIASTIC INSTITUTIONAL SUPPORT WILL UNQUESTIONABLY FACILITATE THE PROGRESSION OF RESEARCH IN LINE WITH THE MISSION OF NIGMS AS WELL AS NORTHSHORE UNIVERSITY HEALTHSYSTEM BY ENABLING IMMEDIATE AND IMPACT-DRIVEN RESEARCH TO PRESERVE AND IMPROVE HUMAN LIFE.

NOVEL MOLECULAR TARGET OF COLON CANCER CHEMOPREVENTION BY POLYETHYLENE GLYCOL

RAPID NOVEL MOLECULAR DETECTION OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS

NURSE ANESTHETIST TRAINEESHIPS

MRI-COMPATIBLE HIGH RESOLUTION MICROENDOSCOPIC SYSTEM - THE REQUESTED INSTRUMENT, THE OASIS IMPLANT MICROENDOSCOPE, REPRESENTS A REVOLUTIONARY ADVANCEMENT IN THE METHODOLOGY OF TRANSLATIONAL RESEARCH. THE UNIQUE DEVICE IS ENGINEERED IN SUCH A WAY THAT MITIGATES MUCH OF THE LIMITATIONS OF OTHER AVAILABLE IMAGING IMPLANTS. ITS LIGHTWEIGHT AND ELECTRONIC-FREE HEADMOUNT ALLOWS MORE NATURAL BEHAVIOR TO BE EXHIBITED, AS IT IS DESIGNED TO ENABLE THE SUBJECT ANIMAL TO RESPOND AS FREELY AS POSSIBLE TO ITS ENVIRONMENT. FURTHERMORE, IT PERMITS RESEARCHERS TO SIMULTANEOUSLY REPORT DIRECT OBSERVATIONS OF NEURONAL ACTIVATION OBTAINED THROUGH THE IMPLANT MICROENDOSCOPE AND INDIRECT OBSERVATIONS VIA FUNCTIONAL MAGNETIC RESONANCE IMAGING (FMRI). THIS METHOD OF INTERROGATION IS LIKELY TO YIELD INCREDIBLY ROBUST EMPIRICAL FINDINGS. SPECIFICALLY, THE PROPOSED PROJECTS THAT WILL UTILIZE THE DEVICE WILL AIM TO IDENTIFY THE DEVELOPMENTAL AND CELLULAR MECHANISMS OF RESTING STATE FMRI, THE EFFECTS OF NEONATAL ANESTHESIA ON BRAIN TISSUE OXYGEN DYNAMICS, AND UNDERSTAND THE PHYSIOLOGY OF THE RAPHE MAGNUS AND ITS ROLE IN VISCERAL PAIN. AT PRESENT, NORTHSHORE UNIVERSITY HEALTHSYSTEM DOES NOT CURRENTLY POSSESS AN INSTRUMENT CAPABLE OF CONDUCTING THIS TYPE OF RESEARCH EVEN THOUGH THE PI ALREADY HAS OBTAINED THE NECESSARY EXPERIENCE AND EXPERTISE TO SAFELY AND EFFECTIVELY OPERATE THE DEVICE WITH IMMEDIATE EFFECT. THE OASIS IMPLANT MICROENDOSCOPE ALONG WITH THE ENTHUSIASTIC INSTITUTIONAL SUPPORT WILL UNQUESTIONABLY FACILITATE THE PROGRESSION OF RESEARCH IN LINE WITH THE MISSION OF NIGMS AS WELL AS NORTHSHORE UNIVERSITY HEALTHSYSTEM BY ENABLING IMMEDIATE AND IMPACT-DRIVEN RESEARCH TO PRESERVE AND IMPROVE HUMAN LIFE.

IDENTIFYING DIAGNOSTIC PATHWAYS FOR UNDIFFERENTIATED ABDOMINAL PAIN USING ELECTRO

NURSE ANESTHETIST TRAINEESHIPS

NURSE ANESTHETIST TRAINEESHIPS

HERSHEY CONFERENCE ON DEVELOPMENTAL BRAIN INJURY

NURSE ANESTHETIST TRAINEESHIPS

PHASE I TRIAL OF NALTREXONE FOR MESENTERIC PANNICULITIS IND 112251, MAY 4, 2011

NURSE ANESTHETIST TRAINEESHIPS

NURSE ANESTHETIST TRAINEESHIPS

ADVANCED EDUCATION NURSING TRAINEESHIP

NURSE ANESTHETIST TRAINEESHIPS

ADVANCED EDUCATION NURSING TRAINEESHIP

MCH RESEARCH