Thomas Jefferson University

TRANSLATIONAL RESEARCH IN CANCER

CARES ACT - HIGHER EDUCATION EMERGENCY RELIEF FUND-IHE/INSTITUTION - THOMAS JEFFERSON UNIVERSITY

CARES ACT FUNDS - THOMAS JEFFERSON UNIVERSITY

ETHANOL EFFECTS ON THE TRANSCRIPTIONAL REGULATORY NETWORK IN LIVER REGENERATION

CLINICAL PHARMACOLOGY TRAINING PROGRAM

G PROTEIN-COUPLED RECEPTOR REGULATION IN AIRWAY MYOCYTES

PARADIGMS OF WOUND HEALING AND FIBROSIS IN THE EYE

CONTINUATION AND EXPANSION OF THE DRUG INDUCED LIVER INJURY NETWORK(PHILLY-DILIN)

JEFFERSON ALUMNI HALL 3 WEST LAB MODERNIZATION

ROLE OF HIF-1 IN INTERVERTEBRAL DISC FUNCTION

RESPIRATORY MOTOR NEURON PROTECTION FOLLOWING CERVICAL SPINAL CORD INJURY

REPURPOSING CLASSICAL DEATH PATHWAYS FOR SIGNALING ROLES IN LENS DIFFERENTIATION

TJU-JNMC GLOBAL NETWORK FOR WOMEN'S & CHILDREN'S HEALTH RESEARCH UNIT

TRNA IN CODON USAGE

2D AND 3D CONTRAST-ENHANCED ULTRASOUND EVALUATION OF HCC CHEMOEMBOLIZATION

POST DPP FOLLOW-UP STUDY

NEUROHUMORAL CONTROL OF INTERNAL ANAL SPHINCTER

NONINVASIVE SUBHARMONIC AIDED PRESSURE ESTIMATION OF PORTAL HYPERTENSION

ENVIRONMENT AND GENE EFFECTS ON BRAIN AND BEHAVIOR

CA2+ AND ROS CROSSTALK SIGNALING IN CARDIAC MITOCHONDRIA

PRECLINICAL CHARACTERIZATION OF A MULTIVALENT KILLED FILOVIRUS/RABIES VACCINE

RETRIEVAL PRACTICE PRINCIPLES: A THEORY OF LEARNING FOR APHASIA REHABILITATION

EXPLOITING EMERGING IDEAS IN G PROTEIN-COUPLED RECEPTOR BIOLOGY AND PHARMACOLOGY TO TREAT ASTHMA - OVERALL PROGRAM ABSTRACT FOR THIS NHLBI PPG WE HAVE ASSEMBLED A HIGHLY COLLABORATIVE TEAM OF EXPERTS IN G PROTEIN-COUPLED RECEPTOR (GPCR) BIOLOGY, AIRWAY SMOOTH MUSCLE (ASM) BIOLOGY, AND ASTHMA BIOLOGY TO PURSUE THE THEME OF “EXPLOITING EMERGING IDEAS IN G PROTEIN-COUPLED RECEPTOR BIOLOGY AND PHARMACOLOGY TO TREAT ASTHMA.” THE PROGRAM EXPECTS TO ACHIEVE THE FOLLOWING GOALS: 1) IDENTIFY NOVEL TARGETS AND TARGETING MOLECULES INVOLVING GPCR REGULATION OF ASM CONTRACTION AND PROLIFERATION; 2) DELINEATE THE MECHANISMS BY WHICH THESE NOVEL TARGETS/TARGETING MOLECULES REGULATE THESE ASM FUNCTIONS; AND 3) ESTABLISH THE THERAPEUTIC UTILITY OF NOVEL TARGETING MOLECULES IN IN VIVO MODELS OF ASTHMA. THESE GOALS WILL BE ACCOMPLISHED ACROSS 4 SCIENTIFIC PROJECTS, TWO SCIENTIFIC CORES, AND AN ADMINISTRATIVE CORE, TO TEST THE CENTRAL HYPOTHESIS THAT NOVEL MODES OF GPCR REGULATION CAN BE TARGETED TO EFFECT SUPERIOR MANAGEMENT OF ASM FUNCTION AND ASTHMA. EACH PROJECT TAKES ADVANTAGE OF A ROBUST EXPERIMENTAL STRATEGY THAT INCORPORATES MULTIPLE CELL, TISSUE, AND IN VIVO MODELS OF ASM FUNCTION, COMPLEMENTED BY CUTTING-EDGE BIOCHEMICAL ANALYSES TO DETAIL MECHANISMS OF ACTION. PROJECT 1 WILL TEST THE ABILITY OF, AND MECHANISMS EFFECTED BY, RECENTLY-DEVELOPED BIASED Β2AR LIGANDS TO MANAGE ASM CONTRACTILITY AND THE ASTHMA PHENOTYPE, WHILE (WITH CORE A) LEVERAGING RECENT INSIGHT IN Β2AR STRUCTURE-ACTIVITY RELATIONSHIP TO DEVELOP NEW LIGANDS SUPERIOR TO IN-HAND LEADS. PROJECT 2 PIVOTS AWAY FROM THE RECEPTOR LOCUS AS A MEANS TO REGULATE GPCR CONTROL OF ASM, TO EXPLORE THE ROLE OF THE CAMP TRANSPORT INHIBITOR ABBC1, POSITING THAT ABBC1- DEPENDENT PATHWAYS INHIBIT Β-AGONIST EFFECTS ON HASM E-C COUPLING, AND ARE UPREGULATED IN ASTHMA PATIENTS. PROJECT 3 SIMILARLY EXPLORES REGULATION OF DOWNSTREAM GQ-COUPLED RECEPTOR SIGNALING BY DIACYLGLYCEROL KINASE (DGK), WHOSE TARGETING EFFECTIVELY INHIBITS PRO-CONTRACTILE AND PRO-MITOGENIC GPCR SIGNALING IN ASM TO CONTROL THE ASTHMA PHENOTYPE. PROJECT 4 BREAKS NEW GROUND IN THE EXPLORATION OF CLASS C GPCRS, CLARIFYING THE ROLES OF GPRC5A AND GPRC5B IN ASM AND ASTHMA BIOLOGY, AND IN COLLABORATION WITH CORE A, DEVELOPING NEW LIGANDS TO SKEW THE SIGNALING COMPETITION BETWEEN THESE 2 RECEPTORS TOWARDS THERAPEUTICALLY BENEFICIAL GPRC5A SIGNALING AND AWAY FROM PATHOGENIC GPRC5B SIGNALING. THE FOUR PROJECTS WILL BE SUPPORTED BY CORE A, WHICH WILL EMPLOY HIGH-THROUGHPUT SCREENING OF DIVERSE LIBRARIES OF ARRAYED AND EXPRESSED SMALL MOLECULES, AND FURTHER EMPLOY STRUCTURAL BIOLOGY, COMPUTATIONAL MODELING AND VIRTUAL SCREENING TO LEVERAGE SCREENING RESULTS, PREDICT AND TEST NOVEL DRUG-LIKE MOLECULES. CORE B WILL PROVIDE ALL DE-IDENTIFIED HUMAN CELL AND TISSUE MODELS TO STUDY NOVEL MECHANISMS REGULATING EC COUPLING IN HASM. CORE C WILL PROVIDE ADMINISTRATIVE SUPPORT FOR THE PROGRAM. EACH PROJECT ALSO COLLABORATES WITH OTHER PROJECTS TO TEST COMBINATION STRATEGIES THAT TARGET RECEPTORS (Β2AR, GPR5A, GPR5B) IN CONJUNCTION WITH DOWNSTREAM REGULATORS (ABCC1, DGK). THE STRENGTHS OF THIS PROGRAM ARE THE COMMON FOCUS ON A SINGLE THEME AND THE PRODUCTIVE WORKING RELATIONSHIP AMONG INVESTIGATORS WITH THE ABILITY TO APPLY CUTTING-EDGE GPCR BIOLOGY TO KEY QUESTIONS IN ASTHMA BIOLOGY AND PHARMACOLOGY.

ALCOHOLIC TISSUE INJURY

VIRUS CLEARANCE FROM THE CENTRAL NERVOUS SYSTEM

BASIC AND TRANSLATIONAL RESEARCH PROGRAM

ORTHROPOXVIRUS PATHOGENESIS AND VACCINES

TARGETING ADIPONECTIN FOR CARDIOPROTECTION IN THE ISCHEMIC HEART

EXPLORING THE EPHB2-NMDA RECEPTOR INTERACTION IN SPINAL CORD INJURY-INDUCED NEUROPATHIC PAIN

MOLECULAR MECHANISMS OF MITOCHONDRIAL TRANSCRIPTION AND REPLICATION

ALTERED PROTEOGLYCAN GENE EXPRESSION AND CANCER

CYSTEINE PROTEASES IN APOPTOSIS

TRMD-TARGETING ACTINOBACTERIAL NATURAL PRODUCTS AS NEXT GENERATION ANTIBIOTICS - PROJECT SUMMARY. DISCOVERING NEW ANTIBIOTICS FOR GRAM-NEGATIVE BACTERIA IS UNIQUELY CHALLENGING, DUE TO THEIR DOUBLE-MEMBRANE STRUCTURE THAT ACTS AS A PERMEABILITY BARRIER TO DRUGS AND AS AN ANCHOR FOR EFFLUX PUMPS. EFFORTS THAT TARGET ONE MEMBRANE PROTEIN OR ONE EFFLUX PUMP AT A TIME ARE INEFFECTIVE, DUE TO RAPID RISE OF RESISTANCE MUTATIONS. WE WILL TARGET THE TRMD-CATALYZED M1G37 METHYLATION OF TRNA TO INHIBIT BIOSYNTHESIS OF MULTIPLE CLASSES OF MEMBRANE PROTEINS, WITH THE POTENTIAL TO ACCELERATE BACTERICIDAL ACTION. TRMD IS A BACTERIA-SPECIFIC S- ADENOSYL-METHIONINE (ADOMET)-DEPENDENT METHYL TRANSFERASE THAT CONTROLS ACCURACY OF THE PROTEIN-SYNTHESIS READING FRAME. LOSS OF TRMD INCREASES +1 FRAMESHIFTING AND CAUSES CELL DEATH. WE HAVE SHOWN THAT GENES FOR MULTIPLE MEMBRANE PROTEINS AND EFFLUX PUMPS IN E. COLI AND IN OTHER GRAM-NEGATIVE BACTERIA CONTAIN TRMD- DEPENDENT CODONS NEAR THE START OF THE READING FRAME. WE HYPOTHESIZE THAT TARGETING TRMD WILL REDUCE PROTEIN SYNTHESIS OF ALL OF THESE GENES, THUS OFFERING A NOVEL SOLUTION TO AN UNMET NEED. WHILE ASTRAZENECA (AZ), GSK, AND ACADEMIC LABS HAVE ATTEMPTED TO TARGET TRMD BY SCREENING SMALL MOLECULAR COMPOUND LIBRARIES, ISOLATED HITS LACK THE CELL-PERMEABILITY NEEDED TO EXHIBIT AN ANTIBACTERIAL EFFECT. HERE, WE PROPOSE TO SCREEN A LARGE COLLECTION OF MICROBIAL EXTRACTS AND FRACTIONS FOR CELL-PERMEABLE AND TRMD-TARGETING NATURAL PRODUCTS (NPS) THAT ARE POTENT AND SELECTIVE OVER THE HUMAN COUNTERPART TRM5. WE WILL USE A CELL-BASED ASSAY, CONSISTING OF A 1:1 MIX OF AN E. COLI (EC) TRMDMCH STRAIN (DEPENDENT ON TRMD FOR SURVIVAL AND EXPRESSING MCH (MCHERRY) AS A FLUORESCENCE MARKER) AND AN EC TRM5YFP STRAIN (DEPENDENT ON TRM5 FOR SURVIVAL AND EXPRESSING YFP), IN A HIGH- THROUGHPUT SCREENING (HTS) CAMPAIGN TO ISOLATE NPS THAT SELECTIVELY INHIBIT THE TRMDMCH STRAIN. WE PERFORM THIS ASSAY IN EC TOLC+ CELLS, WHICH MAINTAIN THE ENTIRE GRAM-NEGATIVE EFFLUX MACHINERY INCLUDING THE MAJOR EFFLUX PUMP ENCODED BY TOLC, TO SCREEN FOR NPS THAT ARE CELL-PERMEABLE AND RESISTANT TO EFFLUX. A PILOT SCREEN WITH THIS TOLC+ CELL-BASED ASSAY HAS IDENTIFIED AN ATTRACTIVE HIT, DEMONSTRATING THE HTS-READINESS OF THE ASSAY. IN AIM 1, WE WILL USE THIS TOLC+ CELL-BASED ASSAY TO SCREEN 74,770 ACTINOBACTERIAL EXTRACTS AND FRACTIONS AVAILABLE AT THE SCRIPPS RESEARCH INSTITUTE (TSRI). WE WILL ASSESS HITS IN SECONDARY ASSAYS, REMOVE FALSE POSITIVES, EVALUATE THEIR ACTIVITY AT THE WHOLE-CELL LEVEL, AND TEST THEM FOR PERMEABILITY AND EFFLUX IN A PANEL OF GRAM-NEGATIVE BACTERIA. IN AIM 2, WE WILL DE-REPLICATE THE TOP 20 HITS TO ISOLATE THE ACTIVE NPS, DETERMINE THEIR STRUCTURES, AND USE A COMBINATION OF GENOME SEQUENCING AND MINING TO IDENTIFY THEIR BIOSYNTHETIC GENE CLUSTERS (BGCS) FOR DEVELOPING BIOTECHNOLOGY PLATFORMS TO SCALE UP THEIR PRODUCTION. IN AIM 3, WE WILL TEST ACTIVE NPS FOR CONFERRING TRMD- DEFICIENT PHENOTYPES IN WHOLE-CELL ASSAYS, DETERMINE THEIR POTENCY, SELECTIVITY, MECHANISM OF ACTION, AND ASSESS THEIR RISK OF RESISTANCE. THESE NPS REPRESENT NOVEL LEADS IN A NEW PARADIGM OF ANTIBIOTIC DISCOVERY THAT ADDRESSES THE MULTI-DRUG RESISTANCE PROBLEM OF GRAM-NEGATIVE BACTERIA.

IMPROVING HIV PREVENTION SERVICES AMONG SOCIOECONOMICALLY DISADVANTAGED CIS-GENDER WOMEN - ABSTRACT NEARLY ONE OUT OF FIVE NEW HIV INFECTIONS IN THE UNITED STATES OCCURS AMONG CISGENDER WOMEN, WITH 85% OF CASES ATTRIBUTED TO HETEROSEXUAL CONTACT. BLACK WOMEN ARE DISPROPORTIONATELY AFFECTED, COMPRISING 60% OF NEW HIV INFECTIONS AMONG WOMEN, ALTHOUGH THEY COMPRISE ONLY 14% OF THE FEMALE POPULATION. CONSISTENT CONDOM USE, DAILY ORAL TENOFOVIR DISOPROXIL FUMARATE 300MG-EMTRICITABINE 200MG (TDF-FTC) AS PRE-EXPOSURE PROPHYLAXIS (PREP), AND MALE PARTNER HIV TESTING ARE EVIDENCE-BASED INTERVENTIONS FOR WOMEN TO REDUCE THEIR RISK OF HIV ACQUISITION. YET, ONLY 1-6% OF WOMEN WHO COULD BENEFIT FROM PREP ARE PRESCRIBED IT. BARRIERS TO PREP UPTAKE ARE MULTIFACTORIAL. PATIENT-LEVEL BARRIERS TO PREP UPTAKE INCLUDE WOMEN WHO MAY NOT THINK PREP IS FOR THEM, GIVEN THAT THE MAJORITY OF PREP CLINICAL TRIALS AND MARKETING STRATEGIES HAVE TARGETED MEN WHO HAVE SEX WITH MEN. ALSO, CISGENDER WOMEN MAY NOT PERCEIVE THEMSELVES AS BEING AT RISK FOR HIV. FURTHER EXACERBATING THE DISCORDANCE BETWEEN RISK PERCEPTION AND ACTUAL RISK IS THAT WOMEN TEND TO BE UNAWARE OF THEIR MALE PARTNERS' HIV SEROSTATUS AND HIV RISK FACTORS. PROVIDER-LEVEL BARRIERS INCLUDE DIFFICULTY IDENTIFYING PATIENTS AT HIGH RISK FOR HIV, DISCOMFORT WITH SEXUAL HISTORY TAKING, AND LACK OF PREP KNOWLEDGE. UNFORTUNATELY, AN ACCURATE HIV RISK ASSESSMENT TOOL DOES NOT EXIST FOR U.S. CISGENDER WOMEN AND MAY NOT EVER EXIST BECAUSE THE HIV INCIDENCE IN U.S. WOMEN IS TOO LOW TO DEVELOP IT. AN ALTERNATIVE EVIDENCE-BASED INTERVENTION IS DESPERATELY NEEDED. WE PLAN TO FILL THIS GAP BY IDENTIFYING AN EFFECTIVE INTERVENTION AND IMPLEMENTATION STRATEGY TO INCREASE PREP UPTAKE IN AN OBGYN CLINICAL SETTING (WHERE WOMEN RECEIVE PRENATAL CARE AND SEXUAL AND REPRODUCTIVE HEALTH SERVICES). SINCE TDF-FTC WAS APPROVED, WOMEN HAVE CONSISTENTLY EXPRESSED A PREFERENCE FOR RECEIVING HIV PREVENTION SERVICES IN CLINICS WHERE THEY RECEIVE OBGYN CARE. OUR MULTI-LEVEL (PATIENT AND PROVIDER-LEVEL), MULTI-COMPONENT INTERVENTION INCLUDES EHR DATA COLLECTION AND EDUCATION USING MULTI-MEDIA TOOLS. OUR CENTRAL HYPOTHESIS IS THAT COMMUNICATING TAILORED HIV RISK MESSAGING IN REAL-TIME IN A RELATABLE AND COMPREHENSIVE MANNER TO PATIENTS AND OBGYN PROVIDERS CAN INCREASE CONVERSATIONS ABOUT HIV PREVENTION. AIM 1A: TO DETERMINE THE MOST EFFECTIVE INTERVENTION AND EVALUATE ITS IMPLEMENTATION IN AN OBGYN CLINICAL SETTING. 1B: TO IDENTIFY MODIFIABLE CONTEXTUAL FACTORS ASSOCIATED WITH EFFECTIVE IMPLEMENTATION USING THE RE-AIM FRAMEWORK. AIM 2: TO EVALUATE THE COST-EFFECTIVENESS, RETURN ON INVESTMENT, BUDGET IMPACT, AND EQUITY IMPACT OF THE MULTI-LEVEL INTERVENTION COMPONENTS AND THE IMPLEMENTATION STRATEGY. IN COLLABORATION WITH OUR LOCAL GOVERNMENT- AND A HRSA-FUNDED IMPLEMENTING PARTNER SITES, WE HOPE TO DEMONSTRATE A SUSTAINABLE AND SCALABLE SOLUTION TO INCREASING PREP COUNSELING BY OBGYN PROVIDERS AND PREP UPTAKE BY PATIENTS.

MITOCHONDRIA-SR TETHERING: ITS ROLE IN CARDIAC BIOENERGETICS AND CA2+ DYNAMICS

TRANSCRIPTIONAL REGULATION BY EPIGENETIC FACTORS

RPE LACTATE TRANSPORTERS: A ROLE IN RETINAL SURVIVAL

BIOCHEMISTRY AND MORPHOLOGY OF CONNECTIVE TISSUE

ENDOGENOUS SUPPRESSION OF INTEGRIN SIGNALING

USING REPORTER HUMAN IPS CELLS TO STUDY FATE, FUNCTION AND PARKINSON'S DISEASE

CCHS-JNMC GLOBAL NETWORK FOR WOMEN'S & CHILDREN'S HEALTH RESEARCH UNIT

OPTIMISE: A SHARED CARE APPROACH FOR IMPROVING COMPREHENSIVE CARE OF CANCER PATIENTS WITH COMORBIDITIES IN A SAFETY-NET SYSTEM - PROJECT SUMMARY. CANCER SURVIVORS HAVE UNIQUE HEALTHCARE NEEDS INCLUDING RISK FOR SERIOUS LATE EFFECTS, ONGOING SURVEILLANCE, LIFESTYLE MODIFICATIONS TO REDUCE SECOND CANCER RISK, AND PSYCHOSOCIAL SUPPORT. NEARLY 70% ARE CONSIDERED “COMPLEX CANCER SURVIVORS” BECAUSE THEY HAVE AT LEAST ONE COMORBID CHRONIC CONDITION IN ADDITION TO CANCER. COMORBIDITIES POSE SIGNIFICANT CHALLENGES TO THE DELIVERY OF QUALITY CANCER CARE BECAUSE THEY ADVERSELY AFFECT AND ARE AFFECTED BY CANCER TREATMENT. MEDICALLY UNDERSERVED PATIENTS HAVE THE HIGHEST BURDEN OF MULTIPLE CHRONIC CONDITIONS AND ARE AT INCREASED RISK FOR POOR OUTCOMES DURING AND AFTER CANCER TREATMENT. AS MEDICALLY UNDERSERVED COMPLEX CANCER PATIENTS MAY LACK HEALTHCARE KNOWLEDGE AND ACCESS TO SUPPORTIVE CARE, THEIR HEALTH OUTCOMES AND CARE TRANSITIONS MIGHT BE IMPROVED BY ENHANCING COMMUNICATION AND COLLABORATION BETWEEN THEIR ONCOLOGISTS AND PRIMARY CARE PROVIDERS (PCPS). THIS STUDY TESTS AND EVALUATES A NOVEL SHARED CARE MODEL FOR COMPLEX CANCER SURVIVORS CALLED OPTIMISE (ONCOLOGY-PRIMARY CARE PARTNERSHIP TO IMPROVE COMPREHENSIVE SURVIVORSHIP CARE) IN THE LARGEST SAFETY-NET HEALTHCARE SYSTEM IN HOUSTON, TX. THREE-HUNDRED NEWLY DIAGNOSED BREAST, GI, AND HEMATOLOGICAL CANCER PATIENTS WHO ARE BEING TREATED WITH CURATIVE INTENT AND WHO HAVE COMORBIDITIES REQUIRING ONGOING MANAGEMENT DURING CANCER TREATMENT WILL COMPLETE BASELINE SURVEYS AND BE RANDOMIZED TO EITHER OPTIMISE OR USUAL MEDICAL CARE (UMC). PATIENTS RECEIVING UMC WILL RECEIVE THEIR CANCER TREATMENT, AS DIRECTED BY THEIR ONCOLOGIST, A SURVIVORSHIP CARE PLAN (SCP) AT THE END OF ACTIVE TREATMENT, AND SURVEILLANCE VISITS WITH THEIR ONCOLOGIST BASED ON NATIONAL GUIDELINES. PATIENTS IN OPTIMISE WILL 1) HAVE AN ONCOLOGY NURSE NAVIGATOR ASSIGNED TO THEIR CARE TEAM AT DIAGNOSIS TO FACILITATE ONCOLOGIST-PCP COMMUNICATION AND CONTINUITY OF CARE; 2) RECEIVE COORDINATED CARE BETWEEN THEIR ONCOLOGIST AND PCP THROUGHOUT CANCER TREATMENT AND SURVEILLANCE FACILITATED BY A STRUCTURED COMMUNICATION AND REFERRAL PROCESS; 3) RECEIVE A SURVIVORSHIP CARE PLAN (SCP) AT THE END OF TREATMENT THAT INCORPORATES COMORBIDITY MANAGEMENT; AND, 4) RECEIVE A RISK-STRATIFIED SHARED CARE MODEL OF POST-TREATMENT SURVEILLANCE WHERE ONE OR MORE ROUTINE ONCOLOGIST FOLLOW- UP VISITS IS REPLACED BY A PCP VISIT. AIM 1 EVALUATES THE IMPACT OF OPTIMISE ON PATIENT CHRONIC DISEASE SELF- MANAGEMENT (PRIMARY OUTCOME) AND QUALITY OF LIFE (SECONDARY OUTCOME). AIM 2 EXPLORES THE EFFECTS OF OPTIMISE ON HEALTHCARE USE AND PATIENT UNMET NEEDS DURING AND AFTER ACTIVE CANCER TREATMENT. AIM 3 EXAMINES THE EFFECTS OF OPTIMISE ON ONCOLOGIST AND PCP ATTITUDES AND COORDINATION OF CARE. AIM 4 SEEKS TO ELUCIDATE PATIENT- AND SYSTEM-LEVEL FACTORS THAT MAY INFLUENCE IMPLEMENTATION OUTCOMES. OPTIMISE SHIFTS THE TIMING OF THINKING ABOUT SURVIVORSHIP TO POINT OF DIAGNOSIS AND SEEKS TO DEVELOP A CLINICAL INFRASTRUCTURE TO SUPPORT CONTINUITY OF CARE FROM CANCER DIAGNOSIS THROUGH POST-TREATMENT SURVIVORSHIP. IF FOUND EFFECTIVE, OPTIMISE COULD BE EXPANDED TO OTHER CANCERS, IGNITING A POTENTIALLY RICH AREA OF RESEARCH. IT MAY ALSO HAVE SIGNIFICANT DOWNSTREAM IMPACT IN OTHER MEDICAL SETTINGS BY ENHANCING CARE TRANSITIONS FROM SPECIALTY TO PRIMARY CARE.

LOW VISION DEPRESSION PREVENTION TRIAL FOR AGE RELATED MACULAR DEGENERATION

FOXD3 UP-REGULATION AND ERBB3 SIGNALING AS AN ADAPTIVE RESPONSE TO RAF INHIBITORS

HEALTH BELIEFS, GLYCEMIC CONTROL, AND PREVENTING COGNITIVE DECLINE IN AFRICAN AMERICANS WITH DIABETES AND MILD COGNITIVE IMPAIRMENT: A RANDOMIZED CLINICAL TRIAL

ROLE OF ARRESTINS IN G PROTEIN-COUPLED RECEPTOR REGULATION

EXOSOME-MEDIATED PROPAGATION OF DISEASE LINKED POLY-DIPEPTIDES IN C9ORF72-FTD/ALS

REGULATION OF ENDOTHELIAL NITRIC OXIDE SYNTHASE MRNA STABILITY

SIDNEY KIMMEL CANCER CENTER LAPS INSTITUTIONAL COLLABORATION

MOLECULAR MECHANISMS OF AXON BRANCHING IN SYNAPTIC DEVELOPMENT

ASK1 A NOVEL REGULATOR OF PLATELET FUNCTION

TARGETED THERAPIES IN MUTANT BRAF MELANOMA

TARGETING VISCERAL PAIN THROUGH INTESTINAL NEUROPOD CELL GUCY2C SIGNALING - VISCERAL HYPERSENSITIVITY (VH) AND PAIN IN DISORDERS OF GUT-BRAIN INTERACTION (DGBI), LIKE CONSTIPATION-TYPE IRRITABLE BOWEL SYNDROME (IBS-C) OR CHRONIC IDIOPATHIC CONSTIPATION (CIC), AFFLICTS >10% OF THE POPULATION WITH REDUCING QUALITY OF LIFE AT A COST OF ~$30B/Y IN THE U.S. THE ETIOLOGY OF VH IN DBGI IS NOT KNOWN. VH REFLECTS RECRUITMENT OF SILENT DORSAL ROOT GANGLIA (DRG) VISCERAL AFFERENTS, REDUCING THEIR THRESHOLD TO FIRE, AND INCREASING THEIR RATE OF FIRING, ACTION POTENTIALS. CURRENT ANALGESICS, INCLUDING NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND OPIATES, ARE INADEQUATE, WITH POOR EFFICACY AND SIDE EFFECTS, HIGHLIGHTING THE CLINICAL NEED FOR NOVEL THERAPEUTICS. THE INTESTINAL RECEPTOR GUANYLYL CYCLASE C (GUCY2C) BINDS COGNATE PEPTIDES AT THE EXTRACELLULAR DOMAIN THAT ACTIVATE AN INTRACELLULAR CATALYTIC DOMAIN, CONVERTING GTP TO CYCLIC GMP, THE DOWNSTREAM EFFECTOR. GUCY2C IS THE RECEPTOR FOR DIARRHEAGENIC BACTERIAL HEAT-STABLE ENTEROTOXINS (STS), AND THE HOMOLOGOUS HORMONE UROGUANYLIN IN SMALL INTESTINE AND THEIR RECEPTOR ACTIVATION INDUCES SECRETION (DIARRHEA FOR STS). THIS SECRETION IS THE BASIS FOR TREATING DBGI CONSTIPATION SYNDROMES WITH LINACLOTIDE (LINZESS™), AN ST ANALOG, OR PLECANATIDE (TRULANCE™), A UROGUANYLIN ANALOG. BEYOND SECRETION, GUCY2C AGONISTS RELIEVE PAIN IN DBGI PATIENTS AND RODENTS, REDUCING VISCERAL NOCICEPTION PRODUCED BY COLORECTAL DISTENSION (CRD). WHILE VISCERAL PAIN RELIEF BY AGONISTS IS MEDIATED BY GUCY2C, MECHANISMS, AND THEIR ROLE IN THE PATHOPHYSIOLOGY OF VH, ARE UNKNOWN. INTERESTINGLY, GUCY2C AGONISTS ARE FORMULATED FOR ACTIVITY CONFINED TO SMALL INTESTINE. OUR RECENT STUDIES REVEALED THAT DBGI PATIENTS WITH VH LOSE UROGUANYLIN, SILENCING GUCY2C IN SMALL INTESTINE. ADDITIONALLY, WE DISCOVERED THAT GUCY2C IS OVER-EXPRESSED BY SMALL INTESTINE NEUROPOD CELLS, WHICH SYNAPSE WITH DRG NEURONS CONTROLLING GUT-SPINAL CORD SIGNALING. SILENCING GUCY2C PRODUCED SPONTANEOUS VH IDENTICAL TO THAT PRODUCED BY INFLAMMATION. IN CLOSE AGREEMENT, NEUROPOD CELLS PRODUCE DRG NEURON HYPEREXCITABILITY WHICH IS ELIMINATED BY GUCY2C SIGNALING. THESE DATA SUGGEST A NOVEL ANATOMICAL HYPOTHESIS IN WHICH NEUROPOD CELLS IN SMALL INTESTINE CONTROL THE EXCITABILITY OF DRG NEURONS AFFERENT TO THE SPINAL CORD WHICH, IN TURN, INHIBIT NOCICEPTIVE SIGNALING FROM CRD. THE PATHOPHYSIOLOGICAL HYPOTHESIS SUGGESTS THAT VH IN DBGI REFLECTS UROGUANYLIN LOSS, SILENCING GUCY2C IN NEUROPOD CELLS IN SMALL INTESTINE, DISRUPTING THE CONTROL OF DRG NEURON EXCITABILITY WHICH AMPLIFIES COLORECTAL NOCICEPTION. THE THERAPEUTIC HYPOTHESIS SUGGESTS THAT GUCY2C-CGMP SIGNALING CAN BE SELECTIVELY AMPLIFIED ONLY IN NEUROPOD, BUT NOT OTHER INTESTINAL, CELLS TO SUPPRESS NEURON EXCITABILITY CONTROLLING VISCERAL PAIN WITHOUT PRODUCING SECRETION AND DIARRHEA, THE MAJOR THERAPEUTIC LIMITATION TO ORAL GUCY2C AGONISTS. PROPOSED STUDIES WILL DEFINE KEY ELEMENTS OF A NEW GUT-SPINAL CORD AXIS IN WHICH GUCY2C DRIVES NEUROTRANSMISSION BY NEUROPOD CELLS IN SMALL INTESTINE TO REGULATE NEURON EXCITABILITY CONTROLLING VISCERAL PAIN IN THE COLORECTUM. THE POTENTIAL TO TRANSLATE THESE INSIGHTS INTO NEW THERAPEUTIC PARADIGMS FOR VH TARGETING NEUROPOD CELLS TO MAXIMIZE ANALGESIA, BUT MINIMIZE DIARRHEA, IS HIGHLIGHTED BY THE AVAILABILITY OF ORAL GUCY2C AGONISTS TO TREAT CONSTIPATION.

THE BIOLOGY OF PERLECAN IN CANCER AND ANGIOGENESIS

PLASMA-BASED THERAPIES FOR BONE INFECTION: A TRIPARTITE USA/NORTHERN IRELAND/REPUBLIC OF IRELAND CONSORTIUM

A PRAGMATIC RANDOMIZED CONTROLLED TRIAL ASSESSING THE IMPACT OF MEDICALLY TAILORED MEALS AND MEDICAL NUTRITION THERAPY VIA TELEHEALTH AMONG PATIENTS WITH POORLY CONTROLLED DIABETES

PROVIDER SUPPORT AND PATIENT OUTREACH IN LUNG CANCER SCREENING - WE PROPOSE TO CONDUCT A MULTI-LEVEL INTERVENTION RANDOMIZED TRIAL IN FOUR HEALTH SYSTEMS (CHRISTIANA CARE HEALTH SYSTEM (CCHS), JEFFERSON HEALTH (JH), LEHIGH VALLEY HEALTH NETWORK (LVHN), AND PENNSTATE HEALTH (PSH)) TO TEST THE COMBINED AND SEPARATE EFFECTS OF A PROVIDER SUPPORT INTERVENTION AND A PATIENT OUTREACH INTERVENTION ON SDM AND LCS IN PRIMARY CARE PRACTICE. USING A MIXED METHODS 2X2 FACTORIAL DESIGN, WE INITIALLY WILL RECRUIT AND RANDOMIZE 28 PRIMARY CARE PRACTICES AND PROVIDERS EITHER TO A PROVIDER SUPPORT GROUP (N=14) OR A CONTROL GROUP (N=14). OVER THREE YEARS, WE WILL ALSO IDENTIFY APPROXIMATELY 4,480 PATIENTS WHO ARE POTENTIALLY ELIGIBLE FOR LCS AND HAVE A SCHEDULED PRIMARY CARE VISIT. ON A WEEKLY BASIS, WE WILL ALLOCATE IDENTIFIED PATIENTS TO COHORTS AND INITIATE TELEPHONE CONTACT WITH EACH COHORT TO VERIFY SCREENING ELIGIBILITY, OBTAIN CONSENT, AND COMPLETE A BASELINE SURVEY. WE WILL RANDOMIZE AT LEAST 672 PATIENT PARTICIPANTS EITHER TO A PATIENT OUTREACH GROUP (N=336) OR A CONTROL GROUP (N=336). THUS, THE TRIAL WILL INVOLVE A PROVIDER SUPPORT + PATIENT OUTREACH GROUP, A PROVIDER SUPPORT GROUP, A PATIENT OUTREACH GROUP, AND A CONTROL GROUP. WE WILL COLLECT HEALTH SYSTEM ELECTRONIC MEDICAL RECORDS (EMRS) DATA, STUDY ADMINISTRATIVE DATA, PHYSICIAN AND PATIENT SURVEY DATA, AND INTERVIEW DATA FROM PHYSICIANS, PRACTICE STAFF, HEALTH SYSTEM CARE COORDINATORS, AND HEALTH SYSTEM LEADERS FOR USE IN ADDRESSING TRIAL AIMS. SPECIFIC AIMS OF THE TRIAL ARE AS FOLLOWS: AIM 1. ASSESS INTERVENTION IMPACT ON LUNG CANCER SCREENING (LCS); AIM 2. ASSESS INTERVENTION IMPACT ON SHARED DECISION MAKING (SDM); AIM 3. IDENTIFY MEDIATORS AND MODERATORS OF SCREENING; AND, AIM 4. ASSESS INTERVENTION IMPLEMENTATION. WE WILL USE HEALTH SYSTEM EMR DATA, STUDY ADMINISTRATIVE DATA, PROVIDER BASELINE AND ENDPOINT SURVEY DATA, AND PATIENT BASELINE AND ENDPOINT SURVEY DATA, FOCUS GROUP DATA, AND HEALTH SYSTEM LEADER INTERVIEW DATA TO IDENTIFY PRACTICE-, PROVIDER- AND PATIENT-LEVEL FACTORS THAT IMPACT INTERVENTION EFFECTS ON SCREENING. IN TERMS OF OVERALL IMPACT, THIS TRIAL WILL IDENTIFY EFFECTIVE STRATEGIES FOR INCREASING SDM AND LCS RATES IN PRIMARY CARE AND FOR IMPLEMENTING EFFECTIVE STRATEGIES IN HEALTH SYSTEMS. WE WILL DISSEMINATE STUDY FINDINGS THROUGH COMMUNICATION CHANNELS IN PARTICIPATING HEALTH SYSTEMS AND MORE BROADLY BY REPORTING RESULTS ON CLINICALTRIALS.GOV, AT HEALTH CARE PROFESSIONAL ORGANIZATION MEETINGS, THROUGH LOCAL, STATE AND REGIONAL CONFERENCES, AND VIA PUBLICATIONS IN PEER-REVIEWED JOURNALS.

MODEL SYSTEMS FOR PXE

GENOMIC PROFILING OF SINGLE CIRCULATING TUMOR CELLS IN THE PRECISION MEDICINE OF METASTATIC PROSTATE CANCER - PROJECT SUMMARY AND ABSTRACT METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC) IS THE MOST LETHAL STATE OF PROSTATE CANCER (PCA) AND REMAINS AS THE MOST CHALLENGING ISSUE IN PCA TREATMENT. THE DEVELOPMENT OF MORE EFFECTIVE TREATMENTS FOR MCRPC IS A SIGNIFICANT UNMET CLINICAL NEED. THERE ARE SUBSTANTIAL HETEROGENEITIES IN TREATMENT RESPONSES OF MCRPC, NECESSITATING THE USE OF MORE PERSONALIZED STRATEGIES IN GUIDING TREATMENT BASED ON THE SPECIFIC GENOMIC CHARACTERISTICS OF INDIVIDUAL PATIENTS. THERE ARE CONSIDERABLE LIMITATIONS IN USING THE TRADITIONAL TISSUE- BASED GENOMIC PROFILING TO GUIDE MCRPC TREATMENT, PARTLY BECAUSE MCRPC IS A BONE-PREDOMINANT METASTATIC DISEASE, THUS TISSUE SAMPLES ARE DIFFICULT TO OBTAIN AND YIELDS ARE GENERALLY LOW. MOREOVER, DURING TREATMENTS, THE GENOMIC PROFILES OF TUMORS MAY CHANGE QUICKLY TO EVADE THERAPEUTIC OR IMMUNE ATTACKS, LEADING TO DRUG RESISTANCE. IN ORDER TO PROMPTLY AND ACCURATELY CAPTURE THESE CHANGES AND ADJUST TREATMENT PLANS, REPEATED TUMOR BIOPSIES WOULD BE NEEDED, WHICH IS DIFFICULT TO PERFORM IN ROUTINE CLINICAL PRACTICES GIVEN THE INVASIVE AND BONE-PREDOMINANT NATURE OF MCRPC. THEREFORE, IN ORDER TO IMPROVE MCRPC PROGNOSIS, IT IS HIGHLY IMPORTANT TO DEVELOP NOVEL, NON-INVASIVE LIQUID BIOPSY APPROACHES TO REAL-TIME MONITOR TREATMENT RESPONSE AND GUIDE THE USE OF DIFFERENT TREATMENTS. CIRCULATING TUMOR CELLS (CTCS) ARE SHED FROM TUMORS INTO BLOOD AND HAVE EXTREMELY HIGH MALIGNANT POTENTIAL, AND ARE ARGUABLY THE MOST IMPORTANT SUBSET OF TUMOR CELLS TO MONITOR AND TREAT. CTCS CAN BE NON-INVASIVELY AND REPEATEDLY ENUMERATED IN REAL-TIME, AND HAVE EXHIBITED PROMISING PROGNOSTIC POTENTIALS, AS EVIDENCED BY THE FDA-APPROVAL OF THE CELLSEARCH PLATFORM FOR CTC ENUMERATIONS AS AN INDEPENDENT PROGNOSTIC FACTOR OF SEVERAL METASTATIC CANCERS INCLUDING MCRPC. HOWEVER, NATIONAL GUIDELINES HAVE NOT UNANIMOUSLY ENDORSED THE USE OF CTC ENUMERATION IN ROUTINE CLINICAL PRACTICES, MOSTLY BECAUSE IT REMAINS UNCLEAR WHAT ACTIONS SHOULD BE TAKEN FOR HIGH-RISK PATIENTS WITH ELEVATED CTCS. THESE FACTS HIGHLIGHT THE IMPORTANCE OF MOVING BEYOND CTC ENUMERATION AND TOWARDS IN-DEPTH GENOMIC CHARACTERIZATIONS OF CTCS. LARGE STUDIES ON SINGLE-CELL CTC ANALYSIS HAVE BEEN RARELY REPORTED, PARTLY DUE TO THE SIGNIFICANT CHALLENGES ON SINGLE-CTC DETECTION, ISOLATION, WHOLE GENOME AMPLIFICATION (WGA), AND SEQUENCING BIAS IDENTIFICATION AND CORRECTION. WE HAVE ESTABLISHED A COMPREHENSIVE PIPELINE ON THE ENRICHMENT, ENUMERATION, ISOLATION, WGA, SEQUENCING, AND DATA ANALYSIS OF SINGLE CTCS. BASED ON THREE PCA PATIENT COHORTS AT THE SIDNEY KIMMEL CANCER CENTER, MD ANDERSON CANCER CENTER, AND GEORGE WASHINGTON UNIVERSITY CANCER CENTER, WE WILL CONDUCT GENOMIC PROFILING OF SINGLE CTCS TO IDENTIFY MARKERS OF TREATMENT RESPONSE AND PROGNOSIS. TO OUR BEST KNOWLEDGE, THIS IS THE FIRST LARGE POPULATION-BASED STUDY OF SINGLE-CTC ANALYSIS IN MCRPC. FINDINGS FROM THIS STUDY WILL SIGNIFICANTLY IMPROVE THE POTENTIAL OF THE CLINICAL APPLICATION OF CTCS IN MCRPC MANAGEMENT, BY PRECISELY TAILORING TREATMENT TO THE GENOMIC MAKE-UP OF INDIVIDUAL CTCS FROM INDIVIDUAL PATIENTS.

PREVENTING SPINAL INFECTION: ULTRASOUND TRIGGERED PROPHYLAXIS

A NEW LCA MODEL BY POLARITY GENE ABLATION

MGLUR5 HYPOACTIVITY IS INTEGRAL TO GLUTAMATERGIC DYSREGULATION IN SCHIZOPHRENIA

ANALYSIS OF A NOVEL CRIMEAN-CONGO HEMORRHAGIC FEVER VACCINE AND ITS MECHANISM OF PROTECTION IN RODENT MODELS - CRIMEAN-CONGO HEMORRHAGIC FEVER VIRUS (CCHFV) CAUSES SEVERE DISEASE IN HUMANS, WITH FATALITY RATES REACHING 40%. CCHFV IS ENDEMIC TO PARTS OF AFRICA, ASIA, THE MIDDLE EAST, AND EUROPE, SPECIFICALLY TO REGIONS WHERE THE TICK VECTOR, SPECIES OF THE HYALOMMA GENUS, IS PRESENT. CLASSIFIED AS AN NIH/NIAID CATEGORY A AND WHO HIGH- PRIORITY PATHOGEN, CCHFV POSES THE HIGHEST POSSIBLE RISK TO NATIONAL SECURITY AND PUBLIC HEALTH. CCHFV IS A NEGATIVE-SENSE SINGLE-STRANDED RNA VIRUS IN THE ORDER BUNYAVIRALES. CCHFV IS AN EMERGING INFECTIOUS DISEASE, POSING A HIGH RISK OF A WIDESPREAD OUTBREAK. AN INACTIVATED WHOLE VIRUS VACCINE WAS THE ONLY CCHFV VACCINE TO BE TESTED IN HUMANS AND WAS INEFFECTIVE. WE PROPOSE THE USE OF INACTIVATED RABIES VIRUS (RABV)- AND VESICULAR STOMATITIS VIRUS (VSV)-BASED CCHFV VACCINES, AS INACTIVATED RHABDOVIRAL VECTORS HAVE NOT YET BEEN EXPLORED. INACTIVATED RHABDOVIRAL-BASED VACCINES ARE SAFE AND EFFECTIVE AT INDUCING IMMUNITY AND PROTECTION AGAINST MULTIPLE HEMORRHAGIC FEVER VIRUSES, AND A VSV-BASED SURROGATE CHALLENGE VIRUS IS AN EFFECTIVE TOOL IN ANOTHER HEMORRHAGIC FEVER MODEL. THE GOAL OF THIS PROJECT IS TWO-FOLD: FIRST, TO COMPARE RABV- AND VSV-BASED CCHFV/RABV BIVALENT VACCINES IN TERMS OF THEIR PRODUCTION, IMMUNOGENICITY; SECOND, TO ESTABLISH A NON-BSL-4 VSV-BASED SURROGATE MOUSE CHALLENGE SYSTEM FOR CCHFV TO DETERMINE MECHANISM OF PROTECTION. WE HYPOTHESIZE THAT INACTIVATED RHABDOVIRAL-BASED CCHFV VACCINES WILL PROTECT AGAINST THE CCHFV CHALLENGE THROUGH NON-NEUTRALIZING ANTIBODIES DIRECTED AGAINST GP38. TOWARD THIS HYPOTHESIS, WE PROPOSE THREE AIMS: AIM 1: CHARACTERIZATION OF RHABDOVIRAL-BASED CCHFV VACCINE CONSTRUCTS. THIS AIM DOES CHARACTERIZE AND TEST THE IMMUNOGENICITY OF RABV- AND VSV-BASED CCHFV VACCINES AND COMPARE THEM TO THE BULGARIA HUMAN VACCINE AND AN MRNA-BASED VACCINE PROVIDED BY COLLABORATORS. AIM 2: DETERMINE RHABDOVIRAL-BASED CCHFV VACCINE MECHANISM OF PROTECTION BY ESTABLISHING A SURROGATE CHALLENGE VIRUS MODEL. THIS AIM AIMS TO DEVELOP A NON-BSL-4-REQUIRING SURROGATE CHALLENGE MODEL FOR CCHFV AND COMPARE IT TO THE ESTABLISHED BSL-4 WT CCHFV MODEL IN VACCINE EFFICACY STUDIES. AIM 3: EVALUATE THE PROTECTIVE EFFICACY OF RHABDOVIRAL-BASED VACCINE CANDIDATES IN A WILDTYPE CCHFV LETHAL CHALLENGE MODEL USING NEEDLE AND TICK CHALLENGE. THE GOAL OF THIS AIM IS TO DETERMINE THE EFFICACY OF OUR RHABDOVIRAL-BASED VACCINES AND CONTROL VACCINES AGAINST WT CCHFV CHALLENGE IN TWO DIFFERENT LETHAL CHALLENGE MODEL.

THE ROLE OF THE DE-CONDENSED STRUCTURE OF NASCENT CHROMATIN DURING T CELL DIFFERENTIATION

BIASED MUSCARINIC ACETYLCHOLINE RECEPTOR SIGNALING IN OBSTRUCTIVE LUNG DISEASE PATHOLOGY AND THERAPY

NOVEL TUMOR-TARGETED IMMUNOTHERAPIES AGAINST METASTATIC UVEAL MELANOMA

MULTIFUNCTIONAL REGULATION OF PROSTATE CANCER METABOLISM BY SIGMA1 MODULATORS

TARGETING CDK6 EXPRESSION/ACTIVITY IN PH+ AND PH1-LIKE ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) - ABSTRACT PHILADELPHIA-POSITIVE ACUTE LYMHOBLASTIC LEUKEMIA (PH+ ALL) AND PH1-LIKE B-ALL ACCOUNT FOR MOST CASES OF “HIGH-RISK” ADULT B-ALL. CURRENT THERAPIES WITH TYROSINE KINASE INHIBITORS (TKIS) HAVE IMPROVED THE OUTCOME OF PH+ ALL, BUT RESISTANCE TO TKIS DEVELOPS RAPIDLY IN MOST PATIENTS. PH1-LIKE B-ALL IS CURRENTLY TREATED WITH INTENSIVE COMBINATION CHEMOTHERAPY BUT DISEASE RELAPSE IS COMMON WITH A 5-YEAR SURVIVAL IN ONLY ~25% OF PATIENTS. AS A RESULT, THE PROGNOSIS OF PH+ ALL AND PH1-LIKE B-ALL REMAINS DISMAL. IN PREVIOUS STUDIES, WE SHOWED THAT PH+ AND PH1-LIKE ALL CELLS EXHIBIT A SELECTIVE REQUIREMENT FOR CDK6 EXPRESSION WHILE CDK4 EXPRESSION IS DISPENSABLE. CDK6 IS THE CATALYTIC SUBUNIT OF THE CYCLIN D/CDK6 COMPLEX WHICH IS ESSENTIAL FOR THE G1 TO S-PHASE CELL CYCLE TRANSITION AND HAS KINASE-INDEPENDENT GROWTH-PROMOTING EFFECTS IN HEMATOLOGICAL MALIGNANCIES. OUR PRELIMINARY STUDIES INDICATE THAT CDK6 SILENCING IS MORE EFFECTIVE THAN CDK6 ENZYMATIC INHIBITION IN SUPPRESSING PH+ ALL IN MICE. TO BLOCK KINASE-DEPENDENT AND INDEPENDENT EFFECTS OF CDK6, WE HAVE DEVELOPED CDK4/6-TARGETED PROTEOLYSIS-TARGETING CHIMERA (PROTACS) THAT INHIBIT CDK4/6 ENZYMATIC ACTIVITY IN VITRO AND PROMOTE THE PREFERENTIAL DEGRADATION OF CDK6 OVER CDK4 IN PH+ AND PH1-LIKE ALL CELLS, PROVIDING DURABLE SUPPRESSION OF CDK6 FUNCTION. IN THIS PROPOSAL, WE WILL ASSESS THE REQUIREMENT OF CDK6 IN PH+ AND PH1-LIKE ALL BY COMPARING THE EFFECTS OF CDK6 DEGRADATION BY PROTAC YX-2-107 AND PHARMACOLOGICAL INHIBITION USING PALBOCICLIB, AN FDA-APPROVED CDK4/6 INHIBITOR (AIM 1.1). WE WILL ALSO DETERMINE WHETHER THE MORE POTENT LEUKEMIA SUPPRESSION INDUCED BY CDK6 DOWN-REGULATION IN COMPARISON TO CDK6 ENZYMATIC INHIBITION CAN BE EXPLAINED BY CHANGES IN GENE EXPRESSION INDUCED SELECTIVELY BY CDK6 SILENCING. SUCH CHANGES INVOLVE THE HISTONE DEACETYLASE 1(HDAC1) GENE AND SEVERAL OTHERS INVOLVED IN MITOCHONDRIAL METABOLIC PATHWAYS (AIMS 1.2 AND 1.3). ALTHOUGH WE HAVE BEEN ABLE TO ACHIEVE HIGH SPECIFICITY OF CDK6 VERSUS CDK4 TARGETING AND BIOLOGICAL/THERAPEUTIC EFFECTS COMPARABLE/SUPERIOR TO PALBOCICLIB EX VIVO AND IN PDXS OF PH+ ALL, WE WILL CONTINUE TO IMPROVE OUR LEAD COMPOUND PROTAC YX-2-107 BY MEDICINAL CHEMISTRY APPROACHES IN ORDER TO DEVELOP DERIVATIVES WITH ENHANCED IN VIVO EFFICACY. IN AIM 2, WE WILL ASSESS METABOLIC PROPERTIES OF SELECT CDK6-DEGRADING PROTACS AND TEST THEIR BIOLOGICAL/THERAPEUTIC EFFECTS IN PH+ AND PH1-LIKE ALL CELLS EX VIVO AND IN MICE INJECTED WITH DE NOVO OR RELAPSED/TKI-RESISTANT PATIENT-DERIVED PH+/PH1-LIKE ALL CELLS. COLLECTIVELY, OUR PROTAC-BASED APPROACH WHICH LEVERAGES THE EXPERTISE IN CANCER BIOLOGY AND MEDICINAL CHEMISTRY OF THE CALABRETTA AND SALVINO'S LABORATORIES HOLDS PROMISE TO DEVELOP NOVEL AND MORE EFFECTIVE THERAPEUTIC AGENTS FOR THE TREATMENT OF CDK6-DEPENDENT HIGH-RISK B-ALL IN PRE-CLINICAL PDX MODELS AND, POTENTIALLY, IN THE CLINIC.

OCCULT COLORECTAL CANCER ELIMINATION BY GUCY2C-DIRECTED IMMUNOTHERAPY

TRAINING IN TISSUE ENGINEERING AND REGENERATIVE MEDICINE

MOLECULAR COMPOSITION OF THE MITOCHONDRIAL CALCIUM UNIPORTER AND CARDIAC PATHOPHYSIOLOGY

NONINVASIVE, UNIPLEX, MOLECULAR, PATHOMIC URINARY ASSAY FOR DETECTION OF PROSTATE CANCER

PYRIMIDINE METABOLISM IN THE DEVELOPMENT OF AUTOREACTIVE B CELLS AND SLE - PROJECT SUMMARY SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A FEMALE-BIASED DEBILITATING AUTOIMMUNE DISEASE THAT AFFECTS MILLIONS IN AMERICA AND WORLDWIDE. ANTIBODY-FORMING CELLS (AFCS) AND GERMINAL CENTERS (GCS) PROMOTE THE DEVELOPMENT OF AUTOREACTIVE PLASMA CELLS (PCS) AND THE RELEASE OF PATHOGENIC AUTOANTIBODIES (AUTOABS) THAT ARE CRITICAL FOR THE INITIATION AND PROGRESSION OF DISEASE MANIFESTATIONS INCLUDING LUPUS NEPHRITIS. MECHANISMS THAT PROMOTE THE DEVELOPMENT OF AUTOREACTIVE B CELLS WHICH DRIVE SLE PATHOGENESIS ARE INCOMPLETELY UNDERSTOOD. HOWEVER, SUCH KNOWLEDGE IS INSTRUMENTAL FOR DEVELOPING MUCH NEEDED THERAPEUTICS THAT ARE PREFERABLE TO CURRENT SLE TREATMENT OPTIONS THAT GLOBALLY SUPPRESS THE IMMUNE SYSTEM AND INCREASE DISEASE-ASSOCIATED MORBIDITY AND MORTALITY. METABOLIC REPROGRAMMING HAS EMERGED AS A CRITICAL MECHANISM THAT UNDERPINS SLE AUTOIMMUNE RESPONSES AND DISEASE PROGRESSION. VARIOUS METABOLIC PATHWAYS ARE IMPLICATED IN AUTOIMMUNE RESPONSES IN SLE. ALTHOUGH THE IMPORTANCE OF NUCLEOTIDE METABOLISM HAS BEEN DESCRIBED IN CANCER AND PURINES SUCH AS ATP ARE ESSENTIAL FOR CELLULAR METABOLISM, THE ROLE OF PYRIMIDINES IN B CELL METABOLIC REPROGRAMMING AND RESPONSES IN SLE IS UNKNOWN. IMPORTANTLY, DRUGS TARGETING THE PYRIMIDINE PATHWAY ARE FDA APPROVED FOR THE TREATMENT OF CANCER AND RHEUMATOID ARTHRITIS. DRUGS TARGETING THE PYRIMIDINE PATHWAY IS ALSO CONSIDERED FOR MAINTENANCE THERAPY FOR LUPUS NEPHRITIS WITH NO MAJOR TOXICITY. HOWEVER, THE ROLE OF PYRIMIDINE METABOLISM IN AUTOREACTIVE B CELL DEVELOPMENT AND PATHOGENIC AUTOANTIBODY (AUTOAB) PRODUCTION IN AFC AND GC PATHWAYS IN SLE IS NOT KNOWN. THIS GRANT WILL FOCUS ON DELINEATING THE MECHANISMS BY WHICH PYRIMIDINE SYNTHESIS PROMOTES SYSTEMIC AUTOIMMUNITY. THE KNOWLEDGE GAINED WILL BE BENEFICIAL FOR DISSECTING MECHANISMS CRITICAL FOR B CELL DEVELOPMENT AND FUNCTION AND MAY LEAD TO NOVEL THERAPIES FOR SLE AND OTHER B CELL-MEDIATED DISEASES. OUR PRELIMINARY DATA HIGHLIGHTED THE SIGNIFICANCE OF DE NOVO PYRIMIDINE SYNTHESIS IN AUTOREACTIVE B CELL RESPONSES IN A SLE MOUSE MODEL. OUR DATA ALSO INDICATED AN INTERPLAY OF PYRIMIDINE METABOLISM AND B CELL METABOLIC REPROGRAMMING IN SLE-PRONE B CELLS. ADDITIONAL DATA POINTED TO A ROLE FOR MTORC1, A MASTER REGULATOR OF METABOLISM, IN ACTIVATING THE PYRIMIDINE PATHWAY IN SLE-PRONE B CELLS. WE HYPOTHESIZE THAT B CELL-INTRINSIC PYRIMIDINE METABOLISM AND AN INTERPLAY OF DE NOVO PYRIMIDINE SYNTHESIS AND METABOLIC NETWORKS PROMOTE AUTOREACTIVE B CELL DEVELOPMENT IN AFC AND GC PATHWAYS, LEADING TO AUTOAB PRODUCTION AND SLE. THIS HYPOTHESIS WILL BE TESTED BY THREE SPECIFIC AIMS. AIM-1 WILL, FOR THE FIRST TIME, IDENTIFY THE CELL-INTRINSIC MECHANISMS OF PYRIMIDINE METABOLISM IN AUTOREACTIVE B CELL RESPONSES THAT PROMOTE THE FORMATION OF AUTOAB-PRODUCING PLASMA CELLS AND AUTOABS IN SLE. AIM-2 WILL DETERMINE THE INTERPLAY OF PYRIMIDINE SYNTHESIS AND B CELL METABOLIC NETWORKS THAT PROMOTE AUTOREACTIVE B CELL DEVELOPMENT IN SLE. AIM-3 WILL FOCUS ON THE MECHANISM BY WHICH MTORC1 SIGNALING DRIVES THE ACTIVATION OF DE NOVO PYRIMIDINE SYNTHESIS PATHWAY IN SLE-PRONE B CELLS.

TARGETING CELL SENESCENCE IN A NOVEL MODEL OF SPONTANEOUS DISC DEGENERATION - INTERVERTEBRAL DISC DEGENERATION IS THE MAJOR RISK FACTOR ASSOCIATED WITH CHRONIC NECK AND LOW BACK PAIN, UBIQUITOUS HEALTH CONDITIONS THAT AFFECTS MILLIONS OF PEOPLE WORLD-WIDE. THERE IS AN INCOMPLETE UNDERSTANDING OF THE PATHOGENESIS OF DISC DEGENERATION PARTIALLY DUE TO LACK OF AN APPROPRIATE ANIMAL MODEL. CURRENT ANIMAL MODELS PRIMARILY USE TRAUMATIC INSULTS TO PROMOTE DEGENERATION DIFFERING FROM MOST HUMAN CASES OF DISC DEGENERATION. WHILE, A FEW ANIMAL MODELS OF SPONTANEOUS DISC DEGENERATION ARE REPORTED, SEVERAL LIMITATIONS PREVENT THEIR WIDE-SPREAD USE. THUS, THERE IS A GREAT NEED FOR SMALL ANIMAL MODELS THAT ARE MORE REPRESENTATIVE OF HUMAN DISC PATHOLOGY. PREVIOUS STUDIES HAVE INVESTIGATED INBRED STRAINS OF MICE INCLUDING SM/J AND LG/J FOR THEIR REGENERATIVE ABILITY. IN CONTRAST TO LG/J, A “SUPER HEALER” STRAIN, SM/J WAS FOUND TO BE A “POOR HEALER”. HOWEVER, THERE NO STUDIES HAVE INVESTIGATED THE DISC HEALTH STATUS IN THESE STRAINS OF MICE. WE SHOW FOR THE FIRST TIME THAT SM/J MICE EXHIBIT SPONTANEOUS DISC DEGENERATION THAT CAPTURES IMPORTANT FEATURES OF HUMAN DISC PATHOLOGY. BASED ON OUR NOVEL PILOT DATA, WE HYPOTHESIZE THAT THIS DEGENERATIVE PHENOTYPE HAS A STRONG GENETIC BASIS AND DRIVEN BY EARLY CHANGES IN CELL PHENOTYPE, METABOLISM AND SENESCENCE. WE WILL INVESTIGATE THE CELLULAR AND GENETIC MECHANISMS THAT UNDERLIE DISC DEGENERATION IN SM/J MICE IN THREE AIMS. IN AIM 1 WE WILL TEST THE HYPOTHESIS THAT DISC DEGENERATION IN SM/J MICE IS CHARACTERIZED BY COMPROMISED CELL SURVIVAL, ALTERED CELL PHENOTYPE, METABOLISM AND SENESCENCE. WE WILL PERFORM RNA-SEQ AND CHIP-SEQ ANALYSIS OF NP TISSUE OF SM/J AND LG/J MICE. WE WILL ALSO PERFORM METABOLOMICS TO DETERMINE METABOLIC STATUS OF CELLS. THESE STUDIES WILL PROVIDE UNBIASED INSIGHTS INTO TEMPORAL ALTERATIONS IN TRANSCRIPTOME AND METABOLISM TO DELINEATE PATHWAYS AND MECHANISMS CENTRAL TO THE PATHOGENESIS OF DISC DEGENERATION IN SM/J MICE. IN AIM 2 WE WILL TEST THE HYPOTHESIS THAT REMOVAL OF SENESCENT CELLS FROM THE INTERVERTEBRAL DISC SLOWS DOWN THE PROGRESSION OF DISC DEGENERATION IN SM/J MICE. PILOT STUDIES HAVE SHOWN THAT THERE IS AN ACCUMULATION OF SENESCENT CELLS IN SM/J DISCS. WE WILL TREAT EX VIVO ORGAN CULTURED DISCS AND SM/J MICE IN VIVO DURING EARLY AND ESTABLISHED STAGES OF DISC DEGENERATION WITH WELL-CHARACTERIZED SENOLYTIC DRUGS AND ANALYZE METABOLIC, HISTOPATHOLOGICAL AND GENETIC CHANGES. LASTLY IN AIM 3 WE WILL DELINEATE THE GENETIC MECHANISMS THAT CONTRIBUTE TO CELL SENESCENCE AND DISC DEGENERATION IN SM/J MICE. WE WILL PERFORM A GENOME-WIDE ASSOCIATION STUDY (GWAS) USING LG/J X SM/J ADVANCED INTERCROSS LINES (AILS) TO DISCOVER REGIONS OF THE MOUSE GENOME CONTRIBUTING TO DIFFERENCES IN DISC DEGENERATION. FOR THIS PURPOSE, AIL MICE WILL BE GENOTYPED AT 143,000 GIGAMUGA CHIP SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AND DISCS FROM SEVERAL MICE WILL BE USED FOR RNA-SEQ ANALYSIS. TOGETHER, THESE DATA WILL BE USED TO IDENTIFY HIGH-RESOLUTION QUANTITATIVE TRAIT LOCI (QTL) FOR DISC TRAITS ~5 GENES PER SUPPORT INTERVAL. THE GENES RESPONSIBLE FOR THESE QTL WILL BE IDENTIFIED. THIS AIM WILL GENERATE CANDIDATE GENES LIKELY CONTRIBUTING TO VARIATION IN THE SENESCENCE AND DISC DEGENERATION BETWEEN LG/J AND SM/J STRAINS.

PROSTATE CANCER DIAGNOSIS BY MULTIPARAMETRIC ULTRASOUND

PROMOTING REGENERATIVE REPAIR OF AGED CARTILAGE - PROJECT SUMMARY/ABSTRACT AGE IS THE NUMBER ONE RISK FACTOR FOR OSTEOARTHRITIS (OA), HOWEVER, THE MECHANISMS THAT DRIVE AGE-ASSOCIATED JOINT CHANGES AND HOW THESE CONTRIBUTE TO CARTILAGE DAMAGE ARE NOT WELL DEFINED. AS OA JOINT TISSUES AGE, IT IS WELL ESTABLISHED THAT CARTILAGE-FORMING STEM CELLS (CSCS) DISPLAY A SIGNIFICANT DECLINE IN THEIR ABILITY TO DIFFERENTIATE, AND THE JOINT ENVIRONMENT BECOMES MORE INFLAMMATORY. BOTH OF THESE FACTORS TOGETHER UNDERMINE THE ABILITY TO RECOVER FROM INJURIES AND ALSO CONTRIBUTES TO THE FAILURE OF AUTOLOGOUS STEM CELL THERAPIES. THUS, WE PROPOSE AN INNOVATIVE DUAL STRATEGY WHICH WILL ADDRESS BOTH. WE HYPOTHESIZE THAT ACTIVATION OF SIRTUIN 6 (SIRT6) WILL REJUVENATE OLDER CSCS, AND APOPTOSIS SIGNAL REGULATING KINASE 1 (ASK1) INHIBITION WILL REESTABLISH A REGENERATIVE ENVIRONMENT IN THE JOINT. TOGETHER, THIS NOVEL SOLUTION HAS THE POTENTIAL TO GREATLY AUGMENT THE ABILITY FOR CSC DIFFERENTIATION AND CARTILAGE REPAIR IN THE AGED POPULATION. WE WILL TEST THIS HYPOTHESIS AND DETERMINE THE EPIGENETIC MECHANISMS THAT SIRT6 REGULATE IN THE FOLLOWING THREE AIMS. IN AIM 1, WE WILL DETERMINE THE MECHANISMS BY WHICH (A) SIRT6 ACTIVATION AND (B) ASK1 INHIBITION ENHANCE THE CARTILAGE-FORMING DIFFERENTIATION AND PRO-SURVIVAL ACTIVITIES OF AGED CSCS. IN AIM 2, WE WILL DETERMINE THE EFFICACY OF SIRT6 ACTIVATION, IN THE PRESENCE OF ASK1 INHIBITION TO STIMULATE CARTILAGE FORMATION IN AGED, MALE AND FEMALE RODENTS. FINALLY, IN AIM 3, WE WILL DETERMINE THE EFFICACY OF SIRT6 ACTIVATION AND ASK1 INHIBITION TO PROMOTE CARTILAGE REGENERATION AND REPAIR IN RESPONSE TO CHONDRAL INJURY IN A PRE-CLINICAL AGED MINIPIG MODEL. THESE AIMS WILL BE ACHIEVED THROUGH COMPREHENSIVE IN VITRO ANALYSIS OF YOUNG AND OLD (MALE AND FEMALE) CSCS AND MACROPHAGES, IN PROOF-OF-CONCEPT AGING RODENT MODELS (MICE AND RATS), AND A CLINICALLY RELEVANT LARGE ANIMAL CHONDRAL DEFECT MODEL (AGED MINIPIG). IMPORTANTLY, THE FINDINGS FROM THIS PROPOSAL ARE LIKELY TO GIVE UNIQUE AND IMPORTANT INSIGHTS INTO THE ROLE OF EPIGENETIC REGULATION OF AGED CELLS AND THE ROLE OF THE SURROUNDING ENVIRONMENT IN OTHER AGING AND DISEASED TISSUES. IF SUCCESSFUL, THE OVERALL IMPACT OF THIS NOVEL PRO-REGENERATIVE THERAPY TO AMELIORATE THE RAVAGES OF AGING AND JOINT INJURY WOULD REPRESENT A SIGNIFICANT ADVANCEMENT IN THE TREATMENT OF AGE-ASSOCIATED DISEASES, SUCH AS OA. ADDITIONALLY, IT WILL LEAD TO THE DISCOVERY OF NEW DISEASE-MODIFYING TREATMENTS FOR OTHER ORGAN SYSTEMS AND INCREASE THE ABILITY OF THE AGED POPULATION TO LIVE A HEALTHY, MOBILE LIFE.

MONITORING NEOADJUVANT CHEMOTHERAPY OF BREAST CANCER USING 3D SUBHARMONIC AIDED PRESSURE ESTIMATION

MECHANISM OF LUNG CANCER RESISTANCE TO TYROSINE KINASE INHIBITOR AND RADIATION TREATMENTS

ANDROGEN EFFECT ON MOTOR/COGNITIVE OUTCOME IN KLINEFELTER SYNDROME

PHILADELPHIA AUTOIMMUNITY CENTER OF EXCELLENCE

MULTISCALE MODEL OF THE VAGAL OUTFLOW TO THE HEART

PHARMACOLOGICAL JAK2 INHIBITION TO OVERCOME ANDROGEN RECEPTOR ABERRATIONS IN PROSTATE CANCER - THERE IS AN UNMET MEDICAL NEED FOR DEVELOPMENT OF MORE EFFICACIOUS THERAPIES FOR CASTRATE-RESISTANT (CR) PROSTATE CANCER (PC). THE CASTRATE RESISTANT STATE OF PC IS INCURABLE AND RESULTS FROM A FAILURE OF ANDROGEN DEPRIVATION THERAPY (ADT), WHICH TARGETS ANDROGEN RECEPTOR (AR) ACTIVITY IN PC CELLS. THIS HAS LED TO DEVELOPMENT OF SECOND-GENERATION AR-TARGETED THERAPIES THAT MORE EFFECTIVELY ANTAGONIZE THE AR LIGAND BINDING DOMAIN (ENZALUTAMIDE) OR REDUCE ANDROGEN SYNTHESIS (ABIRATERONE ACETATE). HOWEVER, AFTER AR-TARGETING THERAPIES, AR AND ITS SPLICE VARIANTS ARE STILL EXPRESSED AT HIGH LEVELS AND REMAIN TRANSCRIPTIONALLY ACTIVE IN CRPC AND DRIVE CASTRATE-RESISTANT GROWTH, ULTIMATELY CAUSING PATIENT DEATH. A MAJOR GAP IN THE FIELD IS THE LACK OF UNDERSTANDING OF TARGETABLE MECHANISMS THAT INDUCE PERSISTENT AR EXPRESSION AND TRANSCRIPTIONAL ACTIVITY IN CRPC. IN THIS MPI PROPOSAL, WE WILL INTERROGATE THE NOVEL CONCEPT THAT JAK2-STAT5 SIGNALING REPRESENTS A CRITICAL DRIVER OF AR GENE EXPRESSION IN PC AND, THEREFORE, PHARMACOLOGICAL TARGETING OF JAK2 SIGNALING BY THE NEW-GENERATION JAK2 INHIBITORS REPRESENTS A NOVEL THERAPEUTIC STRATEGY TO ELIMINATE AR IN CRPC. THIS IS SUPPORTED BY OUR RIGOROUS PRELIMINARY DATA SHOWING THAT ACTIVATION OF JAK2-STAT5 SIGNALING IS A STRONG INDUCER OF THE AR GENE TRANSCRIPTION LEADING TO HIGH AR MRNA AND PROTEIN LEVELS IN PC. LIKEWISE, INHIBITION OF JAK2-STAT5 SIGNALING BLOCKS EXPRESSION OF AR AND AR-VS IN PC CELL LINES, PC XENOGRAFT TUMORS IN VIVO AND IN PATIENT-DERIVED CLINICAL PCS GROWN AS EXPLANT CULTURES EX VIVO. COLLECTIVELY, THESE FINDINGS SUPPORT THE HYPOTHESIS THAT ACTIVATION OF JAK2-STAT5 CRITICALLY PROMOTES CRPC PROGRESSION BY SUSTAINING EXPRESSION OF AR AND CONSTITUTIVELY ACTIVE AR VARIANTS. WE WILL PURSUE TWO AIMS:1) DETERMINE THE MECHANISMS UNDERLYING CONTROL OF AR AND AR VARIANT MRNA EXPRESSION BY JAK2 SIGNALING IN PC, AND THE OVERLAP OF THE JAK2-STAT5 AND AR TRANSCRIPTOMES; 2) DETERMINE THE EFFICACY OF THE NEW-GENERATION JAK2-INHIBITORS FEDRATINIB (FED) AND PACRITINIB (PAC) IN ELIMINATING AR-FL/V7/V9 MRNA AND PROTEIN EXPRESSION IN CRPC AND SUPPRESSING GROWTH OF CRPC IN VITRO AND IN VIVO. THE PROPOSED WORK IS SIGNIFICANT BECAUSE IT WILL DETERMINE THE MECHANISMS BY WHICH JAK2-SIGNALING DRIVES PERSISTENT AR EXPRESSION IN CRPC. MOREOVER, THE PROPOSED WORK WILL ESTABLISH WHETHER JAK2 INHIBITION BY PAC AND FED CAN BLOCK AR EXPRESSION AND GROWTH OF PC RESISTANT TO AR-TARGETED THERAPY. THE NOVELTY OF THE PROPOSED CONCEPT IS THAT JAK2 REGULATION OF AR OPENS AN ENTIRELY NEW AVENUE TO DIRECTLY CONTROL AR LEVELS AND PC GROWTH THROUGH PHARMACOLOGICAL SUPPRESSION WITH NEW-GENERATION JAK2 INHIBITORS CURRENTLY FDA-APPROVED OR IN CLINICAL DEVELOPMENT FOR OTHER PURPOSES. THESE FIRST-IN-THE-FIELD STUDIES WILL HAVE NEAR-TERM IMPACT FOR THERAPY DEVELOPMENT FOR CRPC PATIENTS BECAUSE THEY ARE EXPECTED TO ESTABLISH PAC AND FED AS NOVEL AGENTS TO TARGET AR IN PC, AND TRANSLATE TO A PHASE I/II CLINICAL STUDY IN CRPC.

OPTIMIZING ULTRASOUND ENHANCED DELIVERY OF THERAPEUTICS

MECHANISMS OF PROTECTIVE MEMORY CD8 T-CELL INDUCTION BY MRNA-LNP VACCINES - SUMMARY CD8 T-CELLS RECOGNIZE AND KILL VIRUS-INFECTED CELLS DISPLAYING AT THE CELL SURFACE SHORT VIRAL PEPTIDES BOUND TO MAJOR HISTOCOMPATIBILITY (MHC) CLASS I MOLECULES (MHC-I). CD8 T-CELLS CONTRIBUTE TO THE CLEARANCE OF MANY VIRAL INFECTIONS. AFTER AN INFECTION SUBSIDES, AN EXPANDED POPULATION OF “MEMORY” CD8 T-CELLS (M CD8 T-CELLS) MAY CONTRIBUTE TO MORE RAPIDLY CONTROLLING A SECONDARY INFECTION WITH THE VIRUS. VACCINES CAN MIMIC THIS PROCESS. MODIFIED MRNA (MMRNA) ENCAPSULATED IN LIPID NANOPARTICLES (MMRNA-LNP) HAVE EMERGED AS A POWERFUL VACCINE PLATFORM. MMRNA-LNPS HAVE MANY ADVANTAGES AS VACCINES: 1) THEY CAN BE FOCUSED ON THE ANTIGEN OF INTEREST. 2) THEY ARE HIGHLY IMMUNOGENIC. 3) THEY ARE EASY TO MAKE. 4) THEY CAN BE MASS-PRODUCED RAPIDLY. 5) THEY ARE RELATIVELY INEXPENSIVE. THE SWIFT DEVELOPMENT AND APPROVAL OF THE MMRNA-LNP VACCINES TO COMBAT SARS-COV-2 ATTEST TO THEIR POTENTIAL. WHILE IT IS KNOWN THAT MMRNA-LNPS INDUCE CD8 T-CELL RESPONSES, MOST OF THE WORK ON THEIR PROTECTION MECHANISMS HAS FOCUSED ON ABS. THE MCD8 T-CELLS INDUCED BY MMRNA- LNP CAN POTENTIALLY COMPLEMENT AB PROTECTION OR MAY PROVIDE MOST OF THE PROTECTION FOR VIRUSES THAT ARE REFRACTORY TO AB-MEDIATED CONTROL. MMRNA-LNPS COULD ALSO BE USED TO INDUCE CD8 T-CELLS AGAINST CANCER. WE HAVE PUBLISHED THAT THE MCD8 T-CELL RESPONSES INDUCED BY MMRNA-LNPS PROTECT MICE FROM HIGHLY LETHAL MOUSEPOX, A SYSTEMIC VIRAL DISEASE OF THE MOUSE CAUSED BY THE ORTHOPOXVIRUS (OPV) ECTROMELIA VIRUS (ECTV). ECTV IS AN OUTSTANDING MODEL FOR SYSTEMIC VIRAL INFECTIONS IN GENERAL AND FOR OPVS THAT CAN INFECT HUMANS, SUCH AS THE ERADICATED VARIOLA VIRUS (VIRUS OF SMALLPOX) AND FOR MONKEYPOX VIRUS (MPXV), WHICH RECENTLY CAUSED A MAJOR OUTBREAK. IN STILL UNPUBLISHED EXPERIMENTS, WE ALSO FOUND THAT M CD8 T-CELLS INDUCED BY A MINI- MMRNA VACCINE ENCODING FOR ONLY THE MINIMAL, HIGHLY CONSERVED CD8 T-CELL EPITOPE VNFNFNGL OF THE SARS- COV-2 SPIKE PROTEIN PROTECTS WILD-TYPE MICE FROM LETHAL RESPIRATORY INFECTION WITH THE MOUSE-ADAPTED SARS- COV-2 STRAIN MA30, AN OUTSTANDING MODEL FOR SARS-COV-2 AND OTHER GRAVE RESPIRATORY INFECTIONS. HERE WE PROPOSE ELUCIDATING THE MECHANISMS WHEREBY MMRNA-LNPS INDUCE PROTECTIVE MCD8 T-CELLS USING THE ECTV SYSTEMIC AND THE MA30 SARS-COV-2 RESPIRATORY MOUSE MODELS. OUR SPECIFIC AIMS ARE TO: A) SPECIFIC AIM 1. INVESTIGATE THE MECHANISMS OF MHC-I ANTIGEN PRESENTATION AFTER MMRNA-LNP VACCINATION. B) SPECIFIC AIM 2. INVESTIGATE THE ROLES OF TYPE I INTERFERON (IFN-I) AND OTHER PROINFLAMMATORY CYTOKINES IN PROTECTIVE M CD8 T-CELL DEVELOPMENT AFTER MRNA-LNP VACCINATION.

MIR-152/PKM2/SLC7A5 AXIS IN BREAST CANCER DEVELOPMENT, CHEMO- AND RADIATION-TREATMENT RESPONSE - BREAST CANCER (BCA) IS THE LEADING CAUSE OF WOMEN CANCER MORTALITY WORLDWIDE, AND TRIPLE NEGATIVE BREAST CANCER (TNBC) CELLS ACCOUNTS FOR 15-20% BCA. HOWEVER, HIGHER THERAPEUTIC RESISTANCE AND LOWER SURVIVAL OF TNBC PATIENTS REMAIN THE MAJOR HINDER OF BCA TREATMENT. DOXORUBICIN (DOX) AND RADIATION ARE COMMONLY USED FOR TNBC TREATMENT. IN OUR PRELIMINARY STUDY, WE FOUND THAT TNBC SHOWED MUCH LOWER EXPRESSION LEVELS OF MIR-152. HIGHER EXPRESSION LEVELS OF ZESTE HOMOLOGUE 2 (EZH2) AND DNA HYPERMETHYLATION WERE INVOLVED IN MIR-152 SUPPRESSION IN TNBC CELLS. TO UNDERSTAND MECHANISM OF MIR-152 SUPPRESSION, AND ROLE AND MECHANISM OF MIR-152 IN REGULATING CANCER DEVELOPMENT AND DOX- AND RADIATION-INDUCED RESISTANCE, WE PERFORMED A LOT OF PRELIMINARY EXPERIMENTS TO IDENTIFY WHAT MOLECULES THAT WERE POTENTIAL MIR-152 DIRECT TARGETS AS WELL AS THAT WERE UPREGULATED IN DOX-RESISTANT TNBC OR PDX TUMOR TISSUES. WE FOUND THAT PYRUVATE KINASE MUSCLE 2 (PKM2), SOLUTE CARRIER FAMILY 7 MEMBER 5 (SLC7A5), AND POLYPYRIMIDINE TRACT-BINDING PROTEIN (PTBP1) AS DIRECT TARGETS OF MIR-152 WITH POTENTIAL ABILITY TO CONVERSE DOX-MEDIATED RESISTANCE. PKM2, SLC7A5 AND PTBP1 LEVELS WERE INCREASED WHEN MIR-152 EXPRESSION WAS SUPPRESSED IN TNBC CELLS AND PDX MODEL. WE FOUND THAT MIR-152 SUPPRESSION PLAYED AN IMPORTANT ROLE IN MEDIATING TNBC METABOLIC REPROGRAMMING, WARBURG EFFECT SWITCH, TUMOR GROWTH AND DOX RESISTANCE THROUGH PKM2/SLC7A5/PTBP1. WE SHOWED THAT OVEREXPRESSION OF MIR-152 OR PKM2 KNOCKDOWN RENDERED TNBC CELLS MORE SENSITIVE TO RADIATION TREATMENT. THESE NEW FINDINGS CREATE NEW OPPORTUNITY TO INVESTIGATE MECHANISM OF TNBC THERAPEUTIC RESISTANCE. WE HYPOTHESIZE THAT RESISTANCE TO CHEMOTHERAPY AND RADIATION TREATMENT, METABOLIC REPROGRAMMING, AND TNBC DEVELOPMENT ARE INDUCED BY MIR-152 SUPPRESSION AND UPREGULATION OF PKM2, SLC7A5, AND PTBP1. TO TEST THIS CENTRAL HYPOTHESIS, WE WILL PERFORM EXPERIMENTS THROUGH THREE AIMS. IN AIM 1, WE WILL INVESTIGATE ROLE AND MECHANISM OF MIR-152 SUPPRESSION IN TNBC CELLS IN DOXORUBICIN- AND RADIATION-INDUCED RESISTANCE; AND ROLE AND MECHANISM OF PKM2 SWITCH AND INDUCTION VIA ALTERNATIVE SPLICING BY MIR-152 SUPPRESSION TO INDUCE WARBURG EFFECT, THERAPEUTIC RESISTANCE, AND TUMOR GROWTH. IN AIM 2, WE WILL DETERMINE ROLE AND MECHANISM OF MIR- 152/SLC7A5/PTBP1 PATHWAY IN REGULATING METABOLIC REPROGRAMMING AND WARBURG EFFECT SWITCH, AND IN MEDIATING DOXORUBICIN- AND RADIATION-INDUCED THERAPEUTIC RESISTANCE. IN AIM 3, WE WILL DETERMINE WHETHER MIR-152 SUPPRESSION AND PKM2 INDUCTION REGULATE TUMOR ANGIOGENESIS THROUGH CXCL8 EXPRESSION USING A HUMANIZED CHIMERIC TUMOR MODEL; AND WHETHER LEVELS OF MIR-152, PKM2, HIF-1A, HNRNPA3, SLC7A5, AND PTBP1 ARE CORRELATED EACH OTHER, AND ARE CORRELATED WITH THERAPEUTIC RESPONSES AND WITH THE CANCER STAGES AND SURVIVAL. THIS R01 PROJECT WILL IDENTIFY MECHANISMS OF THERAPEUTIC RESISTANCE, AND METABOLIC REPROGRAMMING; AND PROVIDE INFORMATION FOR DEVELOPING NEW TREATMENT OPTION OF TNBC IN THE FUTURE.

PIRNA BIOGENESIS RULED BY PIWI-TUDOR INTERACTION

A MOBILE TXT-BASED INTERVENTION TO IMPROVE ADHERENCE TO ADJUVANT HORMONE THERAPY AND SYMPTOM MANAGEMENT FOR BCA SURVIVORS

TARGETING LATEXIN SIGNALING FOR ENDOTHELIAL BARRIER DYSFUNCTION IN INFLAMMATORY LUNG INJURY - PROJECT SUMMARY THE ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) IS A COMMON CAUSE OF RESPIRATORY FAILURE IN THE CRITICALLY ILL, ACCOUNTING FOR ~75000 DEATHS/YEAR AND 3.6 MILLION HOSPITAL DAYS. THE EXISTING PARADIGM IS THAT THE ARDS RESULTS FROM WIDESPREAD DYSFUNCTION OF THE PULMONARY ENDOTHELIUM, LEADING TO MICROVASCULAR THROMBOSIS, INTERSTITIAL EDEMA, ALVEOLAR FLOODING AND RESPIRATORY FAILURE, ALTHOUGH THE MECHANISMS LEADING TO ENDOTHELIAL DYSFUNCTION REMAIN UNKNOWN. THIS PROPOSAL ARISES FROM NOVEL OBSERVATIONS LINKING THE UPREGULATION OF LATEXIN TO ENDOTHELIAL DYSFUNCTION IN THE LUNG. WE FOUND THAT HEALTHY LUNG ENDOTHELIUM EXPRESSES LOW LEVELS OF LATEXIN WHEREAS LEVELS MARKEDLY INCREASE IN RESPONSE TO TURBULENT FLOW OR BACTERIAL LPS. FURTHER, WE FOUND THAT ENDOTHELIAL BARRIER FUNCTION WAS ENHANCED BY REDUCING LATEXIN EXPRESSION IN LPS-EXPOSED LUNG ENDOTHELIAL CELLS AND THAT GLOBAL DEFICIENCY OF LATEXIN IN MICE REDUCED LPS-INDUCED PULMONARY EDEMA, LUNG INFLAMMATION AND MORTALITY. MECHANISTICALLY, WE FOUND THAT LATEXIN MEDIATED ITS EFFECTS THROUGH COMPLEX MECHANISMS, INCLUDING BINDING TO THE ENZYME SRC KINASE AND FACILITATING ITS MEMBRANE TRANSLOCATION AND PHOSPHORYLATION OF VE-CADHERIN AT ADHERENS JUNCTIONS (AJ). ADDITIONALLY, MASS SPECTROSCOPY REVEALED THAT LATEXIN PHYSICALLY INTERACTS WITH SEVERAL OTHER PROTEINS, INCLUDING CLATHRIN AND AP2, SUGGESTING A ROLE IN ENDOCYTIC TRAFFICKING, AND SYNTAXIN-3 AND SNAP3, SUGGESTING A ROLE IN EXOCYTOSIS. CONSISTENT WITH THIS LATTER MECHANISM, WE FOUND THAT LATEXIN DEFICIENCY REDUCED VON WILLENBRAND FACTOR SECRETION FROM LUNG ENDOTHELIUM. TAKEN TOGETHER, THESE OBSERVATIONS LEAD US TO PROPOSE THE FOLLOWING CENTRAL HYPOTHESIS REGARDING THE ROLE OF LATEXIN IN LUNG ENDOTHELIAL BIOLOGY AND THE PATHOGENESIS OF ENDOTHELIAL DYSFUNCTION IN ARDS. WE HYPOTHESIZE THAT LATEXIN PLAYS A PATHOGENIC ROLE IN DRIVING AGONIST- INDUCED ENDOTHELIAL DYSFUNCTION IN THE LUNG AND THAT INHIBITING ITS INTERACTIONS WITH OTHER KEY PROTEINS WILL REDUCE THE SEVERITY OF PULMONARY EDEMA, LUNG INFLAMMATION AND MICROVASCULAR THROMBOTIC COMPLICATIONS IN EXPERIMENTALLY-INDUCED ARDS. TO TEST THIS HYPOTHESIS, WE PROPOSE 3 INDEPENDENT BUT MECHANISTICALLY LINKED SPECIFIC AIMS. IN AIM 1, WE WILL ESTABLISH THAT ENDOTHELIAL-SPECIFIC DELETION OF LATEXIN ENHANCES ENDOTHELIAL BARRIER PROTECTION AND REDUCES MICROVASCULAR THROMBOSIS AND MORTALITY TO LPS IN MICE. IN AIM 2, WE WILL DELINEATE THE MOLECULAR MECHANISMS BY WHICH LATEXIN REGULATES VE-CADHERIN MEMBRANE BIOAVAILABILITY AT ENDOTHELIAL AJS BY PERFORMING VARIOUS IN VITRO AND IN VIVO LOSS- AND GAIN-OF-FUNCTION STUDIES FOR GENES LINKED TO SRC-MEDIATED VE-CADHERIN PHOSPHORYLATION AND CLATHRIN-MEDIATED ENDOCYTOSIS IN ECS. IN AIM 3, WE WILL DELINEATE THE MOLECULAR MECHANISMS BY WHICH LATEXIN MEDIATES VWF SECRETION FROM ENDOTHELIAL CELLS, FOCUSING ON ITS ROLE IN SNARE COMPLEX FORMATION. IN TOTO, THIS PROPOSAL WILL ESTABLISH THE MECHANISMS BY WHICH LATEXIN REGULATES KEY PATHOLOGICAL BEHAVIORS IN LUNG ENDOTHELIUM AND PROVIDE DIRECTION FOR DEVELOPING NOVEL THERAPEUTIC APPROACHES FOR INFLAMMATORY VASCULAR DISEASES OF THE LUNG, SUCH AS THE ARDS.

NRSA FOR PRIMARY MEDICAL CARE

CHROMATIN BIOLOGY OF THE AFRICAN TRYPANOSOME - PROJECT SUMMARY PROTOZOAN PARASITES OF THE GROUP KINETOPLASTIDS ARE RESPONSIBLE FOR MAJOR HUMAN MALADIES SUCH AS FATAL SLEEPING SICKNESS (TRYPANOSOMA BRUCEI, ALSO TERMED THE AFRICAN TRYPANOSOME), CHAGAS DISEASE (T. CRUZI), AND LEISHMANIASIS (LEISHMANIA SPECIES). DUE TO THE LACK OF INEXPENSIVE AND SAFE DRUGS, RISING RESISTANCE AGAINST CURRENT DRUGS, AND LIMITED DRUG DISCOVERY EFFORTS, NOVEL APPROACHES ARE URGENTLY NEEDED TO COMBAT THESE NEGLECTED TROPICAL DISEASES. BECAUSE KINETOPLASTIDS CONSTITUTE ONE OF THE EARLIEST-BRANCHING ORGANISMS IN THE EUKARYOTIC TREE OF LIFE, THEY EXHIBIT NUMEROUS MOLECULAR AND CELLULAR FEATURES THAT ARE DISTINCT FROM METAZOA AND FUNGI, AND THAT CAN BE EXPLOITED FOR PHARMACOLOGICAL INTERVENTION. BY COMBINING STRUCTURAL, BIOCHEMICAL, AND IN VIVO APPROACHES, WE SEEK TO ADDRESS FUNDAMENTAL QUESTIONS IN CHROMATIN BIOLOGY AND GENE REGULATION IN THE MODEL KINETOPLASTID T. BRUCEI. WE ARE PARTICULARLY INTERESTED IN THE STRUCTURE AND MECHANISM OF THE CLOSELY RELATED DOT1A AND DOT1B ENZYMES THAT ARE KEY REGULATORS OF ESSENTIAL FUNCTIONS IN T. BRUCEI AND THAT CATALYZE THE METHYLATION OF HISTONE H3 LYSINE 76 (H3K76) IN THE GLOBULAR NUCLEOSOME CORE REGION. WHILE DOT1A REGULATES CELL-CYCLE PROGRESSION, DOT1B IN ANTIGENIC VARIATION, AN ESSENTIAL MECHANISM FOR THE PARASITE TO EVADE THE HOST’S IMMUNE SYSTEM. DUE TO SIGNIFICANT MECHANISTIC DIFFERENCES OF TRYPANOSOME DOT1A/B TO HUMAN AND YEAST DOT1 ENZYMES, THE MOLECULAR MECHANISMS OF HOW THEY METHYLATE CHROMATIN AND HOW THEY ARE REGULATED REMAIN POORLY UNDERSTOOD. IN AIM 1, WE WILL THEREFORE INVESTIGATE THE MECHANISM OF DOT1A-NUCLEOSOME SUBSTRATE RECOGNITION AND ITS IMPACT ON CELL CYCLE CONTROL. IN AIM 2, WE WILL DECIPHER THE REGULATORY MECHANISM OF DOT1A GOVERNED BY RNASEH2, AN ENZYME THAT IS KNOWN TO CLEAVE RNA IN RNA/DNA HYBRIDS AND THAT HAS BEEN IMPLICATED IN BOTH DNA REPLICATION AND TRANSCRIPTIONAL REGULATION. OUR GOAL IS TO DEFINE THE IMPACT OF RNASEH2 ON DOT1A ACTIVITY, PROVIDE A STRUCTURAL BASIS FOR ITS REGULATORY FUNCTION, AND ELUCIDATE THE MECHANISM OF HOW DOT1A ACTIVITY IS COORDINATED WITH THE CELL CYCLE. THE INTERACTION OF RNASEH2 WITH DOT1A/B IS SPECIFIC TO TRYPANOSOMES, SUGGESTING A NOVEL REGULATORY MECHANISM OF DOT1 ENZYMES. COLLECTIVELY, OUR STUDIES WILL ILLUMINATE THE LONG- STANDING QUESTION OF HOW DOT1A IS RECRUITED TO CHROMATIN AND HOW IT IS REGULATED IN A SPATIOTEMPORAL MANNER. OUR STUDIES WILL YIELD THE FIRST ATOMIC STRUCTURES OF THE FUNDAMENTAL UNIT OF CHROMATIN, THE NUCLEOSOME, OF THE VAST GROUP OF PROTOZOA, WHICH ARE MEDICALLY, ECOLOGICALLY, EVOLUTIONARILY, AND SCIENTIFICALLY IMPORTANT EUKARYOTES. DUE TO THE NOVEL REGULATORY FUNCTION OF RNASEH2, OUR RESULTS WILL BROADEN OUR MECHANISTIC UNDERSTANDING OF DOT1A AND RNASEH2 ENZYMES. BECAUSE T. BRUCEI DOT1-REGULATED PROCESSES ARE ESSENTIAL FOR THE PARASITE, THIS RESEARCH MAY ULTIMATELY HAVE A LARGE IMPACT ON GLOBAL HEALTH BY EXPLOITING THE UNIQUE ATTRIBUTES OF PROTOZOAN DOT1 STRUCTURE AND REGULATION TO INFORM NOVEL THERAPIES FOR SLEEPING SICKNESS AND OTHER DISEASES CAUSED BY KINETOPLASTIDS THAT AFFECT HALF A BILLION OF PEOPLE.

NATIONAL INSTITUTE ON DISABILITY AND REHABILITATION RESEARCH - SPINAL CORD INJURY MODEL DEMONSTRATIONS

REDUCING EMERGENCY DIABETES CARE FOR OLDER AFRICAN AMERICANS

LOCAL?IMMUNE?TOLERANCE?IN?THE?LARGE?INTESTINE?MEDIATED?BY?GPR15

G PROTEIN-COUPLED RECEPTOR KINASES

CAV-3 IN DIABETIC MYOCARDIAL INJURY FOLLOWING ISCHEMIA/REPERFUSION

SUPPORTING WOMEN AND CHILDREN IN SUBSTANCE ABUSE RECOVERY - A FAMILY UNIT APPROACH

MIR-21 REGULATION OF AUTOREACTIVE B CELL AND LUPUS NEPHRITIS DEVELOPMENT - PROJECT SUMMARY MICRORNAS (MIRNAS) ARE CRITICAL POST-TRANSCRIPTIONAL REGULATORS OF GENE EXPRESSION IN IMMUNITY AND AUTOIMMUNITY, ALTHOUGH MANY MIRNAS REMAIN POORLY CHARACTERIZED. ONE SUCH MIRNA, MIRNA-21 (MIR-21), IS UPREGULATED IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) PATIENTS AND PROMOTES VARIOUS DISEASES IN MOUSE MODELS. THESE INCLUDE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE), ASTHMA, CANCER, AND OUR FINDINGS ON ITS ROLE IN TOLL-LIKE RECEPTOR 7 (TLR7)-DRIVEN SLE IN MICE. WE FOUND THAT TLR7 OVEREXPRESSING SLE-PRONE B6.SLE1BYAA MICE DEFICIENT IN MIR-21 (SLE1BYAAMIR-21-/-) HAD REDUCED GERMINAL CENTER (GC) B CELL, T FOLLICULAR HELPER (TFH) CELL AND PLASMA CELL (PC) RESPONSES. THESE RESPONSES IN SLE1BYAAMIR-21-/- MICE WERE STRONGLY ASSOCIATED WITH REDUCED AUTOANTIBODY, AND SPLENIC AND BONE MARROW AUTOANTIBODY-PRODUCING ANTIBODY FORMING CELL (AFC) RESPONSES. THESE DATA SUBSTANTIATE A ROLE FOR MIR-21 IN THE LOSS OF B CELL TOLERANCE AND AUTOIMMUNITY, WHICH NECESSITATES IDENTIFICATION OF MECHANISMS (FOCUS OF THE GRANT) BY WHICH MIR-21 PROMOTES AUTOANTIBODY PRODUCTION AND SLE. THIS WILL FILL GAPS IN KNOWLEDGE AND MAY HELP DISCOVER AN URGENTLY NEEDED TARGETED THERAPY FOR SLE, A DEBILITATING DISEASE THAT AFFECTS MILLIONS OF AMERICANS AND PEOPLE WORLD-WIDE. TLR SIGNALING, ESPECIALLY TLR7, PROMOTES SLE IN HUMANS AND MURINE MODELS, AND AN ATTRACTIVE THERAPEUTIC TARGET. TLR7 SIGNALING ACTIVATES THE NF-KB INFLAMMATORY SIGNALING PATHWAY. TLR7 UPREGULATES MIR-21 EXPRESSION IN B CELLS WHICH CAN TARGET THE NEGATIVE REGULATOR OF NF-KB SIGNALING, PELI1, ALTHOUGH THE ROLE OF MIR-21 IN REGULATING NF- KB SIGNALING IN SLE-PRONE B CELLS BY TARGETING PELI1 IS UNKNOWN. PRELIMINARY DATA SHOWED THAT B CELLS FROM SLE1BYAAMIR-21-/- MICE HAVE INCREASED PELI1 EXPRESSION COMPARED TO CONTROL SLE1BYAA B CELLS. IN ADDITION, PREVIOUS STUDIES IMPLICATED TLR SIGNALING IN METABOLIC REPROGRAMMING, PRIMARILY THROUGH THE ACTIVATION OF THE PI3K/AKT/MTOR PATHWAY IN VARIOUS IMMUNE CONDITIONS, ALTHOUGH THE ROLE OF THIS PATHWAY IN TLR7-MEDIATED METABOLIC REPROGRAMING IN B CELLS IN SLE IS NOT CLEAR. MIR-21 WAS ALSO SHOWN TO REGULATE THE PI3K/AKT/MTOR PATHWAY IN VARIOUS MODELS; HOWEVER, ITS ROLE IN REGULATING B CELL METABOLISM IN TLR7-DRIVEN SLE IS NOT KNOWN. INTERESTINGLY, OUR RNA-SEQ ANALYSIS OF B CELLS FROM A TLR7-INDUCED MODEL SHOWED NEGATIVELY ENRICHED GENES IN THE PI3K/AKT/MTOR PATHWAY IN THE ABSENCE OF MIR-21. ADDITIONAL PRELIMINARY DATA SHOWED INCREASED EXTRACELLULAR ACIDIFICATION (ECAR) AND OXYGEN CONSUMPTION (OCR) RATES IN SLE1BYAA B CELLS OVEREXPRESSING TLR7 COMPARED TO SLE1B B CELLS, INDICATING A MORE ENERGETIC PHENOTYPE IN RESPONSE TO TLR7 SIGNALING. CONVERSELY, SLE1BYAAMIR-21-/- B CELLS EXHIBITED REDUCED ECAR AND OCR COMPARED TO SLE1BYAA B CELLS. WE HYPOTHESIZE THAT MIR-21 PROMOTES TLR7-DRIVEN SYSTEMIC AUTOIMMUNE RESPONSES AND SLE DISEASE BY REGULATING TLR7-NF-KB SIGNALING AND METABOLIC REPROGRAMMING IN B CELLS. PROPOSED HYPOTHESIS AND SPECIFIC AIMS WILL HELP DELINEATE THE MECHANISM BY WHICH MIR-21 DRIVES AUTOIMMUNE RESPONSES AND LUPUS NEPHRITIS AND WILL INFORM US WHETHER MIR-21 OR MIR-21 REGULATED PATHWAY(S) CAN BE A THERAPEUTIC TARGET FOR SLE.

T CELL CONTROL OF MCMV AND TISSUE-LOCALIZED IMMUNE SUPPRESSION

IMPACT OF TBI TUMOR SUPPRESSOR PATHWAY ON DAN CHECK POINTS AND THERAPEUTIC RESPONSE

A POPULATION-BASED APPROACH TO SINGLE CTC ANALYSIS IN METASTATIC BREAST CANCER OUTCOME