UNIVERSITY OF NEW ENGLAND

UNE CENTER FOR CELL SIGNALING RESEARCH - CELLULAR SYSTEMS SUCH AS THE NERVOUS, IMMUNE, VASCULAR SYSTEMS AND BONE DO NOT WORK IN ISOLATION, BUT ARE FUNCTIONALLY INTEGRATED AND COMMUNICATE EXTENSIVELY BOTH IN HEALTH AND DISEASE STATES. DEFECTS OR DYSFUNCTION IN CELL SIGNALING ARE FUNDAMENTAL DRIVERS OF HUMAN DISEASE, AND OUR ABILITY TO MEET CONTEMPORARY CLINICAL CHALLENGES, INCLUDING NEURODEGENERATIVE AND METABOLIC DISEASE, CHRONIC PAIN AND OPTIMIZING HEALTHY AGING, REQUIRES A BROADER UNDERSTANDING OF MECHANISMS OF INTERCELLULAR AND INTRACELLULAR COMMUNICATION. THE PROPOSED UNE CENTER FOR CELL SIGNALING RESEARCH (CCSR) WILL BUILD A CRITICAL MASS OF TALENTED INVESTIGATORS WITH A BROAD RESEARCH EMPHASIS ON CELLULAR METABOLISM, INFLAMMATION AND AGING. THE INITIAL RESEARCH PROJECT LEADERS (RPLS), SELECTED THROUGH A COMPETITIVE PROCESS, BRING DIVERSE AND COMPLEMENTARY EXPERTISE FROM ACROSS UNE COLLEGES AND DEPARTMENTS. THEIR RESEARCH PROJECTS ADDRESS DISCRETE CLINICAL CHALLENGES BY INVESTIGATING FUNDAMENTAL CELL BIOLOGICAL MECHANISMS THAT MAY HAVE BROAD RAMIFICATIONS FOR HUMAN DISEASE. NEW FACULTY RECRUITMENT AND SUPPORT OF A PILOT PROJECT PROGRAM WILL ENSURE A CONTINUED PIPELINE OF RPLS AND FURTHER GROW THE CENTER. INVESTIGATORS WILL BE PROVIDED WITH A STRUCTURED MENTORSHIP PROGRAM TO SUPPORT BOTH THEIR PROFESSIONAL AND RESEARCH PROGRAM DEVELOPMENT IN THEIR PROGRESSION TO INDEPENDENT FUNDING AND BEYOND. THE PROPOSED CENTER WILL ALSO EXPAND THE RESEARCH INFRASTRUCTURE AT UNE TO SUPPORT THE INNOVATIVE RESEARCH PROGRAMS OF INVESTIGATORS IN CELL SIGNALING. THE PROPOSED IN VITRO ANALYTICAL CORE WILL SUPPORT THE RESEARCH OF THE RPLS WITH OUTSTANDING INSTRUMENTATION AND INNOVATIVE SERVICES THAT ARE NOT BROADLY AVAILABLE ELSEWHERE IN THE REGION, INCLUDING PRIMARY CELL AND CELL LINE CULTURING, TRANSFECTION AND ANALYSIS THROUGH FUNCTIONAL IMAGING AS WELL AS TRANSCRIPTIONAL AND PROTEIN-BASED ANALYSIS. THE CORE WILL BE HOUSED IN NEWLY RENOVATED RESEARCH SPACE THAT WILL BE CONTIGUOUS WITH AN EXISTING UNE HISTOLOGY AND IMAGING CORE, PROVIDING A UNIQUE SUITE OF RESOURCES TO SUPPORT RESEARCH AT UNE. INSTITUTIONAL COMMITMENTS INCLUDE ADDITIONAL PROTECTED RESEARCH TIME FOR RPLS AND INSTITUTIONAL MATCHING FUNDS FOR THE PILOT PROJECT PROGRAM. IN ADDITION, THE UNIVERSITY HAS COMMITTED TO HIRING 3 ADDITIONAL INVESTIGATORS WHOSE RESEARCH PROGRAMS WILL COMPLEMENT THOSE OF THE EXISTING FACULTY. THE CENTER WILL ALSO BENEFIT FROM STRONG CONTINUED INSTITUTIONAL INVESTMENT INTO RESEARCH INFRASTRUCTURE, AS WELL AS WELL-ESTABLISHED COLLABORATIONS WITH NEIGHBORING IDEA STATE PROGRAMS IN MAINE AND NEW HAMPSHIRE. RESEARCH INFRASTRUCTURE WILL BE ENHANCED BY LABORATORY RENOVATIONS, PURCHASING NEW INSTRUMENTATION, AND KEY SUPPORT FOR PERSONNEL. ADDITIONAL INSTITUTIONAL SUPPORT HAS BEEN COMMITTED FOR EACH OF THESE. WITH SOUND FINANCIAL AND ADMINISTRATIVE MANAGEMENT AND REGULAR ASSESSMENTS OF PERFORMANCE WITH SPECIFIED BENCH MARKS, THE CCSR WILL BE WELL- POSITIONED TO MAKE A SIGNIFICANT IMPACT IN OPTIMIZING HEALTHY, PAIN-FREE AGING AND IN FINDING NEW TREATMENTS FOR NEURODEGENERATIVE AND METABOLIC DISEASES.

INTERDISCIPLINARY CENTER OF EXCELLENCE FOR THE STUDY OF PAIN AND SENSORY FUNCTION - CHRONIC PAIN CONTINUES TO BE A CRITICAL HEALTH, SOCIAL AND ECONOMIC ISSUE THROUGHOUT THE WORLD. PATIENT RELIEF IS UNDERMINED BY MODEST EFFICACY AND/OR SERIOUS, SELF-LIMITING SIDE EFFECTS OF ALL CURRENT PAIN PHARMACEUTICALS. MOREOVER, THE OPIOID EPIDEMIC, THAT HAS ONLY INCREASED IN SEVERITY AS A CONSEQUENCE OF COVID-19, LENDS URGENCY TO THE SEARCH FOR ALTERNATIVE TREATMENTS FOR MODERATE TO SEVERE PAIN. THROUGH PHASE 1 AND 2 COBRE FUNDING AND LEVERAGED INSTITUTIONAL SUPPORT, THE UNIVERSITY OF NEW ENGLAND (UNE) CENTER FOR THE STUDY OF PAIN AND SENSORY FUNCTION WAS SUCCESSFUL IN RENOVATING NEW LABORATORY SPACE, ESTABLISHING TWO RESEARCH CORE FACILITIES, AND RECRUITING A CRITICAL MASS OF INVESTIGATORS STUDYING PAIN AND ITS TREATMENT. PROVIDED WITH MENTORSHIP AND CAREER DEVELOPMENT SUPPORT, RESEARCH PROJECT FUNDING, AND ACCESS TO STATE-OF-THE-ART RESEARCH CORE FACILITIES, COBRE INVESTIGATORS HAVE MADE MAJOR SCIENTIFIC ADVANCES IN THE DISCOVERY OF NOVEL TARGETS FOR THE TREATMENT OF CHRONIC PAIN AND SECURED ALMOST $14 MILLION IN EXTRAMURAL RESEARCH FUNDING. THE RESEARCH CORES HAVE ALREADY SUPPORTED SBIR AND STTR PROJECTS THAT HAVE LED TO THE SUBMISSION OF ONE COMPOUND TO THE FDA FOR APPROVAL OF PHASE 1 CLINICAL TRIALS. THIS INCREASE IN RESEARCH ACTIVITY SEEDED BY COBRE FUNDS WAS LARGELY RESPONSIBLE FOR UNE’S RECENT PROMOTION TO R2 STATUS (DENOTED AS HIGH RESEARCH ACTIVITY) BY THE CARNEGIE CLASSIFICATION OF INSTITUTIONS OF HIGHER EDUCATION. COBRE PHASE 3 WILL BUILD ON ITS PREVIOUS SUCCESSES TO SECURE THE CENTER’S LONG-TERM VIABILITY. STRONG INSTITUTIONAL SUPPORT WILL CONTINUE TO BE PROVIDED IN THE FORM OF DEDICATED CORE SPACE, EQUIPMENT MAINTENANCE, INTERNAL FUNDING FOR A RESEARCH CORE VOUCHER PROGRAM, RELEASE TIME FOR CORE DIRECTORS AND GUARANTEE OF CORE STAFF SALARY BEYOND PHASE 3. FOR AIM 1, THE COBRE TEAM WILL CONTINUE TO INCREASE RESEARCH CAPACITY THROUGH CAREER DEVELOPMENT PROGRAMMING AND DIRECT FINANCIAL SUPPORT FOR PILOT RESEARCH PROJECTS. THE PILOT PROJECT PROGRAM WILL ACCEPT APPLICATIONS FROM FACULTY AT UNE AND REGIONAL PARTNER INSTITUTIONS TO SUPPORT PROJECTS THAT UTILIZE THE CORE FACILITIES AND HAVE THE POTENTIAL TO LEAD TO EXTRAMURAL FUNDING. THIS APPROACH WILL INCREASE THE RESEARCH CORE USER BASE AND ASSIST IN AIM 2, TRANSITIONING THE RESEARCH CORES INTO SUSTAINABLE RESOURCES THAT PROVIDE EXPERTISE, TRAINING, AND STATE- OF-THE-ART INSTRUMENTATION TO THE UNE AND BROADER SCIENTIFIC COMMUNITIES FOR CONDUCTING CUTTING-EDGE BIOMEDICAL RESEARCH. THE RESEARCH CORES WILL BECOME SUSTAINABLE THROUGH COLLABORATIONS WITH REGIONAL COBRES AND MAINE INBRE PARTNERS, THE COMBINED EFFORTS OF THE EXTERNAL ADVISORY AND STEERING COMMITTEES, STRONG INSTITUTIONAL SUPPORT, AND AN AGGRESSIVE BUSINESS STRATEGIC PLANNING AND MARKETING APPROACH. COBRE PHASES 1 AND 2 PROFOUNDLY TRANSFORMED THE RESEARCH ENVIRONMENT AT UNE. AT THE TIME OF PHASE 1 SUBMISSION, CORE RESEARCH FACILITIES WERE NONEXISTENT. THE INCREASE IN RESEARCH CAPACITY CREATED THROUGH THE COBRE PROGRAM HAS LED TO THE RECRUITMENT AND FUNDING OF A CRITICAL MASS OF INVESTIGATORS, TRAINING OF A SKILLED WORKFORCE, AND DEVELOPMENT OF SUSTAINABLE CORE RESEARCH FACILITIES THAT CAN SUPPORT HIGH-QUALITY RESEARCH FOR UNE FACULTY AND STUDENTS, AS WELL AS EXTERNAL ACADEMIC AND INDUSTRY PARTNERS. WITH CONTINUED INSTITUTIONAL INVESTMENT AND ADDITIONAL SUPPORT PROVIDED THROUGH PHASE 3 FUNDING, WE WILL BUILD ON THIS EARLY SUCCESS AND ESTABLISH OUR CENTER AS A LEADER IN PAIN RESEARCH FOR MANY YEARS TO COME.

CENTRAL AND PERIPHERAL MECHANISMS OF CORNEAL PAIN - THE CORNEA IS THE MOST DENSELY INNERVATED TISSUE IN THE BODY, AND PAIN IS THE PRIMARY EXPERIENCE RESULTING FROM CORNEAL STIMULATION. WHILE PHYSIOLOGICAL CORNEAL PAIN (NOCICEPTIVE PAIN) PROTECTS THE EYE FROM INJURY, INFLAMMATION AND/OR NERVE DAMAGE CAN RESULT IN PROLONGED OR CHRONIC CORNEAL PAIN. CORNEAL AFFERENTS REPRESENT A DIVERSE POPULATION OF NEURONS, WITH SPECIALIZED PROPERTIES RELATED TO MAINTAINING OCULAR HEALTH. THE FULL DIVERSITY OF THESE NEURONS, AND THEIR RESPONSES TO INJURY ARE UNKNOWN. THE FIRST SET OF EXPERIMENTS WILL DETERMINE THE MRNA TRANSCRIPT SIGNATURES OF MOUSE CORNEAL NEURONS IN THE TRIGEMINAL GANGLION (TG) AND THEIR TRANSCRIPTIONAL RESPONSES TO CORNEAL INJURY AND COMPARE WITH CELL-TYPE-SPECIFIC TRANSCRIPTIONAL AND EPIGENOMIC SIGNATURES OF HUMAN TG NEURONS. CORNEAL AFFERENTS ARE KNOWN TO PROJECT TO TWO MAIN REGIONS IN THE SPINAL TRIGEMINAL NUCLEUS (VSP), EACH WITH DISTINCT ROLES IN NOCICEPTION AND MAINTAINING CORNEAL HOMEOSTASIS. WE HAVE PRELIMINARY DATA DEMONSTRATING AN ADDITIONAL PROJECTION TO THE LATERAL PARABRACHIAL NUCLEUS (LPBN), A REGION CRITICAL IN REGULATING COMPLEX MOTIVATIONAL-AFFECTIVE RESPONSES TO AVERSIVE STIMULI. ITS CONTRIBUTION TO CORNEAL PAIN IS UNKNOWN. THE SECOND SET OF EXPERIMENTS WILL EXAMINE CENTRAL PROCESSING OF CORNEAL INPUT IN THE LPBN. WE WILL DETERMINE THE CONTRIBUTION OF CORNEAL->LPBN PRIMARY AFFERENT PROJECTIONS TO CORNEAL NOCICEPTIVE RESPONSES AND THE FUNCTION OF LPBN NEURONS IN CORNEAL NOCICEPTIVE AND CHRONIC PAIN BEHAVIORS. ADDITIONAL STUDIES WILL PERFORM SINGLE-NUCLEUS TRANSCRIPTOME ANALYSIS TO IDENTIFY MOLECULAR PROFILES OF CORNEAL-ACTIVATED BRAINSTEM NEURONS, FOLLOWED BY MULTIPLEX IN SITU HYBRIDIZATION TO PROVIDE SPATIAL RESOLUTION IN REGIONS THAT RECEIVE DIRECT CORNEAL AFFERENT INPUT. THE CORNEA IS ALSO ENDOWED WITH RESIDENT CORNEAL LEUKOCYTES (RCLS) RESIDING IN CLOSE PROXIMITY TO CORNEAL NERVES, SUGGESTING THE POSSIBILITY OF NEURO-IMMUNE CROSSTALK IN THE CORNEA. HOWEVER, CURRENT KNOWLEDGE IS LIMITED ON POSSIBLE DIRECT REGULATION OF RCLS THROUGH CORNEAL NERVES, OR THE INFLUENCE OF RCLS ON CORNEAL NERVE FUNCTION. THE THIRD SET OF EXPERIMENTS WILL CHARACTERIZE THE CELL POPULATIONS AND MOLECULAR MECHANISMS INVOLVED IN NEUROIMMUNE CROSSTALK RESULTING IN PERIPHERAL NERVE SENSITIZATION IN THE CORNEA. CORNEAL SINGLE CELL MRNA TRANSCRIPT SIGNATURES ASSOCIATED IN MURINE CORNEAL PAIN MODELS WILL BE USED TO IDENTIFY TRANSCRIPTIONAL CHANGES THAT UNDERLY NOCICEPTOR SENSITIZATION. CROSSING THESE IMMUNE CELL TRANSCRIPTS WITH TRANSCRIPT PROFILES OF CORNEAL AFFERENTS WILL PROVIDE EVIDENCE FOR LIGAND-RECEPTOR PAIRS. IN VITRO STUDIES WILL CONFIRM THE ABILITY OF THE IDENTIFIED MODULATORS TO SENSITIZE TG NEURONS, AND THE FUNCTIONAL SIGNIFICANCE WILL BE ASSESSED USING BEHAVIOR AND EX VIVO ELECTROPHYSIOLOGY. EMPLOYING A MULTIDISCIPLINARY APPROACH, THESE EXPERIMENTS WILL PROVIDE A COMPREHENSIVE ANALYSIS OF CELLULAR AND MOLECULAR MECHANISMS OF NOCICEPTIVE AND CHRONIC CORNEAL PAIN, LEADING TO THE IDENTIFICATION NOVEL PATHWAYS AND TREATMENTS.

ADVANCED NURSE EDUCATION-SEXUAL NURSE ASSAULT EXAMINER PROGRAM

LEADERSHIP EDUCATION IN NEURODEVELOPMENTAL AND RELATED DISORDERS TRAINING PROGRAM

MODEL STATE-SUPPORTED AHEC PROGRAM

GRANT PROGRAM

GERIATRICS WORKFORCE ENHANCEMENT PROGRAM

RNA-PROTEIN INTERACTIONS IN NOCICEPTION - ABSTRACT PERSISTENT AND CHRONIC PAIN ARE FACILITATED BY PLASTICITY OF SENSORY AFFERENTS. RECENT ADVANCES DEMONSTRATE THIS PLASTICITY IS INITIATED AND MAINTAINED BY DE NOVO TRANSLATION OF PRO-NOCICEPTIVE GENES. IN ANIMAL MODELS, PHARMACOLOGICAL AND GENETIC PERTURBATIONS OF PROTEIN TRANSLATION HAVE SHOWN THERAPEUTIC EFFICACY. THEREFORE, DISCOVERY OF PROTEINS THAT SELECTIVELY REGULATE PRO-NOCICEPTIVE MRNA TRANSLATION IN SENSORY NEURONS WOULD PROVIDE OPPORTUNITIES FOR THE DEVELOPMENT OF NOVEL TARGETED THERAPEUTICS. MRNA TRANSLATION IS REGULATED BY RNA-BINDING PROTEINS (RBPS). OUR ANALYSES OF SINGLE CELL RNA-SEQ DATA CONFIRMED BY HISTOLOGICAL ASSESSMENTS REVEALED THE PRESENCE OF A RBP RESTRICTED TO SUBPOPULATIONS OF DORSAL ROOT GANGLION (DRG) NOCICEPTIVE NEURONS. PREVIOUS STUDIES INDICATE THAT THIS RBP BINDS TO AND INHIBITS TRANSLATION OF MRNA TRANSCRIPTS ASSOCIATED WITH NEURONAL EXCITABILITY. OUR COMPUTATIONAL ANALYSES PREDICTED THAT THIS NOCICEPTOR- RESTRICTED RBP WOULD SUPPRESS A CONSTELLATION OF ION CHANNELS, NEUROPEPTIDES AND OTHER “PAIN GENES”, THEREBY FORMING A PUTATIVE ANTI-NOCICEPTIVE REGULON. THIS PROPOSAL WILL TEST THE HYPOTHESIS THAT THIS IDENTIFIED RBP TONICALLY SUPPRESSES NOCICEPTIVE TRANSMISSION BY BINDING TO AND INHIBITING TRANSLATION OF PRO-NOCICEPTIVE MRNAS. THIS PROPOSAL WILL DETERMINE IF ENHANCING THE FUNCTION OF THIS RBP IS A VIABLE STRATEGY TO DEVELOP INTERVENTIONS THAT NORMALIZE PAIN THRESHOLDS AND REVERSE CHRONIC PAIN. IN DOING SO THESE INVESTIGATIONS WILL DEMONSTRATE A NOVEL ANTI-NOCICEPTIVE REGULON THAT SCALES THE THRESHOLD FOR PAIN PERCEPTION AND VALIDATE USE OF A TOOL TO DISCOVER FACTORS RESPONSIBLE FOR THE TRANSITION

PRIMARY CARE TRAINING AND ENHANCEMENT: PHYSICIAN ASSISTANT RURAL TRAINING PROGRAM

MITOCHONDRIAL REGULATION OF NOCICEPTOR FUNCTION - CHRONIC PAIN AFFECTS MORE THAN 50 MILLION AMERICANS PER YEAR, RESULTING IN EXTRAORDINARY PERSONAL AND SOCIETAL COSTS. ADDING TO THE DILEMMA, DEATHS INVOLVING PRESCRIPTION OPIATE ANALGESICS HAVE ALMOST QUADRUPLED IN THE LAST TEN YEARS. THE CLINICAL CHALLENGE OF PAIN MANAGEMENT IS UNDERSCORED BY EVIDENCE THAT CHRONIC PAIN IS MECHANISTICALLY DISTINCT FROM ACUTE PAIN, THEREFORE A THOROUGH UNDERSTANDING OF THE MOLECULAR AND CELLULAR MECHANISMS UNDERLYING THE TRANSITION TO CHRONIC PAIN IS FUNDAMENTAL TO IMPROVING AND EXPANDING TREATMENT OPTIONS. HYPERALGESIC PRIMING IS A COMPELLING MODEL OF THE TRANSITION TO CHRONIC PAIN IN WHICH AN INITIAL INJURY RESOLVES, BUT LEAVES THE ANIMAL IN A PRIMED STATE IN WHICH A SECOND INSULT INDUCES A GREATLY PROLONGED PAIN RESPONSE. EXPERIMENTS PROPOSED HERE WILL EXAMINE THE IMPACT OF MITOCHONDRIAL DYNAMICS ON THE DEVELOPMENT OF ACUTE AND CHRONIC INFLAMMATORY PAIN COMPARED TO A NERVE INJURY MODEL OF NEUROPATHIC PAIN, AND WILL EXPLORE MOLECULAR MECHANISMS MEDIATING PROPOSED ANTI-NOCICEPTIVE ACTIONS OF ENDOGENOUS UNCOUPLING MECHANISMS AND MITOCHONDRIAL UNCOUPLING DRUGS. SPECIFIC AIM 1 WILL EXAMINE THE HOW MITOCHONDRIAL FUNCTION CHANGES IN RESPONSE TO NOXIOUS INSULT AND THE IMPACT OF MITOCHONDRIAL REGULATION ON ACUTE HYPERALGESIA IN SENSORY GANGLIA. SPECIFIC AIM 2 WILL USE PATCH CLAMP ELECTROPHYSIOLOGY TO DEMONSTRATE CHANGES IN ELECTRICAL PROPERTIES OF SENSORY NEURONS IN RESPONSE TO MANIPULATION OF MITOCHONDRIAL FUNCTION, AND WILL IDENTIFY CELL SIGNALING PATHWAYS THAT MEDIATE MITOCHONDRIAL EFFECTS ON NEURONAL EXCITABILITY. SPECIFIC AIM 3 WILL CHARACTERIZE CHANGES IN MITOCHONDRIAL FUNCTION UNIQUE TO THE TRANSITION TO CHRONIC PAIN, AND WILL ELUCIDATE CELL SIGNALING PATHWAYS MODULATING THE IMPACT OF MITOCHONDRIAL FUNCTION ON INFLAMMATORY AND NEUROPATHIC PAIN CHRONIFICATION. THIS PROPOSAL WILL USE INNOVATIVE APPROACHES TO EXPLORE NOVEL MECHANISMS BY WHICH MITOCHONDRIA INFLUENCE THE MANIFESTATION OF ACUTE AND CHRONIC PAIN, AND TEST THE THERAPEUTIC POTENTIAL OF TARGETING THESE MECHANISMS FOR PAIN RELIEF.

NOVEL EXPRESSION OF MHC CLASS II ON DRG NEURONS AND ITS ROLE IN PROMOTING ANTINOCICEPTIVE CD4+ T CELLS IN FEMALES DURING CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY - PROJECT SUMMARY/ABSTRACT CHEMOTHERAPEUTIC AGENTS ARE OFTEN DOSE LIMITING DUE TO THE EMERGENCE OF A DEBILITATING AND PAINFUL NEUROPATHY, POSING A MAJOR CHALLENGE TO THE SUCCESSFUL TREATMENT OF CANCER. RECENT REPORTS DEMONSTRATE THAT MALE MICE LACKING T CELLS HAVE PROLONGED MECHANICAL HYPERSENSITIVITY AFTER TREATMENT WITH PACLITAXEL (PTX), AND ONLY THE INTRAVENOUS TRANSFER OF CD8+, BUT NOT CD4+, T CELLS REDUCED THE HYPERSENSITIVITY. OUR PRELIMINARY IN VIVO DATA DEMONSTRATES FEMALE MICE HAVE 2-FOLD MORE CD4+ T CELLS IN THE DRG THAN MALE AND OVARIECTOMIZED (OVX) FEMALE MICE, AND NEURONAL INJURY INDUCED BY PTX ROBUSTLY INCREASES ANTI-INFLAMMATORY CD4+ T CELLS IN THE DRG ONLY IN ESTROGEN-COMPETENT FEMALE MICE. CD4+ T CELL DEPLETION IN FEMALE MICE PRIOR TO PTX RESULTS IN AN INCREASE IN MECHANICAL HYPERSENSITIVITY 3 DAYS POST-PTX. OUR RESULTS SUGGEST A PREVIOUSLY UNEXPLORED HORMONE AND SEX DIFFERENCE IN CD4+ T CELLS AND THE SEVERITY OF CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY (CIPN). PTX IS PRIMARILY USED TO TREAT OVARIAN, BREAST, AND NON-SMALL CELL LUNG CANCER WITH POST- MENOPAUSAL PATIENTS AT AN INCREASED RISK OF CIPN; THEREFORE, PREVENTATIVE MEASURES WOULD BE INVALUABLE FOR WOMEN. THE MECHANISM BY WHICH CD4+ T CELLS REDUCE THE SEVERITY OF PIPN IS UNKNOWN. IN OUR PRELIMINARY STUDIES, DRG NEURONS FROM FEMALE MICE HAVE THE CAPACITY TO ACTIVATE CD4+ T CELLS TO SECRETE ANTI- INFLAMMATORY CYTOKINES. PUBLISHED RNA-SEQ DATASETS OF DRG NEURONS SHOW THAT DRG NEURONS EXPRESS MHCII, A PROTEIN DIRECTLY INVOLVED IN T CELL ACTIVATION. OUR CENTRAL HYPOTHESIS IS THAT PTX ADMINISTRATION IN FEMALE MICE INCREASES MHCII ON SENSORY NEURONS TO STIMULATE THE PARACRINE RELEASE OF ANTI-INFLAMMATORY CYTOKINES BY RESIDENT CD4+ T CELLS TO SUPPRESS CIPN. IN AIM 1, WE WILL DETERMINE THE EXTENT TO WHICH ESTROGEN- DRIVEN CD4+ T CELLS REDUCE THE SEVERITY OF PTX-INDUCED PERIPHERAL NEUROPATHY. ESTROGEN IS KNOWN TO INDUCE PROLIFERATION OF BLOOD CD4+ T CELLS, BUT IT IS UNKNOWN IF THIS OCCURS IN THE DRG. WE PREDICT THAT ESTROGEN SIGNALING IN CD4+ T CELLS WILL INCREASE THE NUMBER OF RESIDENT CD4+ T CELLS IN THE DRG TO SECRETE ANTI- INFLAMMATORY CYTOKINES IN RESPONSE TO PTX. WE EXPECT CD4+ T CELLS TO AMELIORATE CIPN IN FEMALE, BUT NOT MALE MICE. IN AIM 2, WE WILL QUANTIFY THE EXTENT PTX CAN ENHANCE MHCII ON DRG NEURONS TO INDUCE ANTI- INFLAMMATORY CD4+ T CELL CYTOKINE PRODUCTION. WE PREDICT PTX-INDUCED INFLAMMATION WILL INCREASE NEURONAL MHCII TO ELICIT AN ANTI-INFLAMMATORY CD4+ T CELL RESPONSE IN THE DRG OF FEMALE, BUT NOT MALE MICE. IN AIM 3, WE WILL DETERMINE THE DEGREE IN VIVO ACTIVATION OF NEUROPROTECTIVE CD4+ T CELLS CAN REDUCE AND REVERSE PTX- INDUCED PERIPHERAL NEUROPATHY. WE PREDICT THAT ACTIVATED CD4+ T CELLS WILL DAMPEN AND REVERSE CIPN IN FEMALE, BUT NOT MALE MICE, UNLESS PRE-TREATED WITH ESTROGEN. COMPLETION OF THESE AIMS WILL PROVIDE COMPELLING EVIDENCE THAT CD4+ T CELLS IN THE DRG OF FEMALES ARE NEUROPROTECTIVE AND ANTI-NOCICEPTIVE, AND CAN BE EXPLOITED TO PREVENT OR RESOLVE CIPN. NEURONAL MHCII-DEPENDENT ACTIVATION OF CD4+ T CELLS REPRESENTS A NOVEL MECHANISM FOR NEURO-IMMUNE COMMUNICATION THAT COULD BE UTILIZED FOR THERAPEUTIC INTERVENTION.

** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** FEW AMERICANS MEET DIETARY RECOMMENDATIONS. POOR DIET IS A MAJOR CONTRIBUTOR TO INCREASING PREVALENCE OF DIABETES AND OBESITY, WHICH ARE NEGATIVELY IMPACTING LONG TERM HEALTH, QUALITY OF LIFE, AND HEALTHCARE COSTS, PARTICULARLY AMONG LOW-INCOME, RACIAL AND ETHNIC MINORITY, AND RURAL POPULATIONS IN THE U.S. TO HELP ADDRESS THESE INEQUITIES, PRODUCE PRESCRIPTION PROGRAMS ARE BEING IMPLEMENTED IN MANY HEALTH CARE SETTINGS. HOWEVER, KEY RESEARCH GAPS AND PROGRAMMATIC BARRIERS REMAIN. IN THE PROPOSED PROJECT, WE WILL USE RESEARCH, EDUCATION, AND EXTENSION TO IMPROVE NUTRITION SECURITY IN RURAL UNDERSERVED COMMUNITIES AND DELIVER SCIENCE-BASED KNOWLEDGE TO CONSUMERS, ALLOWING THEM TO MAKE INFORMED, PRACTICAL DECISIONS THAT CAN IMPROVE HEALTH EQUITY. OUR PROJECT GOAL IS TO IMPLEMENT AND RIGOROUSLY EVALUATE AN INNOVATIVE PRIMARY-CARE BASED HEALTHY FOOD PRESCRIPTION THAT IS PAIRED WITH INCENTIVES TO USE THE LOCAL SUPERMARKET'S ESTABLISHED HEALTHY FOOD SHELF-TAG LABELING SYSTEM TO INCREASE HEALTHY FOOD CHOICES AT THE POINT OF PURCHASE. WE WILL: 1) ASSESS THE PROGRAM'S IMPACT ON PARTICIPANTS' FOOD AND NUTRITION SECURITY, 2) ASSESS THE PROGRAM'S IMPACT ON PARTICIPANTS' SUPERMARKET PURCHASES AND DIET, AND EXPLORE THE PROGRAM'S IMPACT ON HEALTH, AND 3) USE THE RESEARCH FINDINGS TO ENGAGE HEALTH SYSTEMS, NUTRITION EDUCATORS, AND COMMUNITIES IN EVIDENCE-BASED STRATEGIES TO IMPROVE NUTRITION SECURITY. THE PROGRAM HAS THE POTENTIAL TO SUSTAINABLY ENCOURAGE HEALTHY FOOD CHOICES WHERE DECISIONS MATTER--IN THE SUPERMARKET, USING EXISTING SUPERMARKET RESOURCES. IMPROVING PURCHASING PATTERNS BY INCREASING SALES OF LESS PROCESSED AND WHOLE FOODS, COULD ALSO POSITIVELY AFFECT INDUSTRY OFFERINGS AND SUSTAINABILITY OF THE AGRICULTURAL SYSTEM AS A WHOLE.

HIV TAT-ASSOCIATED SENSORY NEUROPATHY AND THE CONTRIBUTION OF TOLL-LIKE RECEPTOR PATHWAY - SUMMARY PERIPHERAL NEUROPATHIES ARE THE MOST FREQUENT NEUROLOGICAL COMPLICATIONS ASSOCIATED WITH HIV, WITHIN WHICH HIV SENSORY NEUROPATHY (HIV-SN) IS THE MOST COMMON FORM, AFFECTING NEARLY HALF OF HIV/AIDS PATIENTS WITH THE PREVALENCE RANGING FROM 1.2 – 69.4%. HIV-SN FREQUENTLY MANIFESTS WITH HARD-TO-MANAGE PAIN AND IS OFTEN UNDER-DIAGNOSED AND/OR UNDER-TREATED, YET, THE LARGE VARIATION IN PREVALENCE DOES NOT ALLOW FOR DETECTION OF SIGNIFICANT DIFFERENCES IN PREVALENCE BETWEEN HAART-EXPOSED VS. HAART-NON-EXPOSED INDIVIDUALS. THERE IS NO SPECIFIC FDA-APPROVED TREATMENT FOR HIV-SN. TAT, TRANS-ACTIVATOR OF TRANSCRIPTION, A REGULATORY PROTEIN AMONG THE FIRST PROTEINS EXPRESSED FOLLOWING HIV INFECTION, IS A KEY ACTIVATOR OF HIV TRANSCRIPTION AND CAN AFFECT BOTH HIV INFECTED CELLS AND NON-INFECTED NEIGHBORING CELLS VIA ITS SECRETION BY INFECTED CELLS. ALTHOUGH HUMAN STUDIES ARE LACKING, RECENT ANIMAL STUDIES USING TWO MODELS OF DOXYCYCLINE-INDUCIBLE HIV-1 TAT TRANSGENIC (ITAT) MICE FROM OUR LAB AND OTHERS PROVIDED CONVINCING EVIDENCE THAT HIV TAT CONTRIBUTES TO THE DEVELOPMENT OF HIV-SN. THEREFORE, IN THIS PROPOSAL, WE WILL FURTHER INVESTIGATE THE UNDERLYING MECHANISMS OF TAT-ASSOCIATED SN. OUR PRELIMINARY STUDY IDENTIFIED POTENTIAL REGULATION OF TAT OF TOLL-LIKE RECEPTOR (TLR) SIGNALING PATHWAY. GIVEN THE WIDELY ACCEPTED INVOLVEMENT OF TLR PATHWAY IN NEUROPATHIC PAIN AND SURPRISING LACK OF STUDIES EXPLORING THE ROLE OF TLR PATHWAY IN HIV-SN, WE WILL FOCUS ON TLR PATHWAY IN TAT-ASSOCIATED SN IN THIS STUDY. WE WILL TAKE ADVANTAGE OF BIOINFORMATIC TOOLS TO IDENTIFY FDA-APPROVED DRUGS WITHOUT SIGNIFICANT INTERACTIONS WITH EXISTING ANTIRETROVIRAL DRUGS THAT COULD POTENTIALLY REVERSE TAT-INDUCED CHANGES IN TLR PATHWAY, AND THEN TEST THEIR EFFECTIVENESS IN TREATING TAT-ASSOCIATED SN IN VIVO. ALTOGETHER, WE HYPOTHESIZE THAT TLR SIGNALING PATHWAY IS INVOLVED IN THE DEVELOPMENT OF HIV-TAT-ASSOCIATED SN AND IT IS POSSIBLE TO IDENTIFY POTENTIAL TREATMENT FOR HIV-SN BY EXAMINING EXISTING DRUGS VIA A COMBINED BIOINFORMATICS AND PRE-CLINICAL MODEL APPROACH. THIS WILL BE TESTED THROUGH 2 SPECIFIC AIMS. AIM 1 WILL DETERMINE THE CONTRIBUTION OF TOLLIP (A KEY REGULATOR OF TLR PATHWAY)-REGULATED TLR PATHWAYS IN HIV TAT-ASSOCIATED SN USING GENETICALLY MODIFIED ANIMAL MODELS IN COMBINATION WITH BEHAVIORAL AND PHYSIOLOGICAL TESTS. AIM 2 WILL IDENTIFY POTENTIAL DRUGS FOR HIV-SN BY TARGETING TLR PATHWAY VIA A COMBINED BIOINFORMATICS AND PRE-CLINICAL MODEL APPROACH. IF SUCCESSFUL, WE WILL FILL IN THE KNOWLEDGE GAPS REGARDING TAT-ASSOCIATED SN AND TLRS’ ROLE IN HIV-SN. OUR COMPREHENSIVE COMBINATION DRUG DISCOVERY STRATEGY WILL HELP IDENTIFY POTENTIAL DRUGS FOR HIV-SN, WHICH CAN BE FURTHER TESTED IN OTHER ANIMAL MODELS BEFORE CLINICAL ASSESSMENT. THROUGHOUT THE PROCESS, WE WILL PRIORITIZE DRUG CANDIDATES THAT ARE MECHANISTICALLY-SOUND, AND POTENTIALLY EASILY ACCESSIBLE TO ALL PATIENTS.

THE RURAL DOMESTIC VIOLENCE, DATING VIOLENCE, SEXUAL ASSAULT, AND STALKING PROGRAM (RURAL PROGRAM) IS AUTHORIZED BY 34 U.S.C. 12341. RURAL PROGRAM FUNDS ARE USED TO SUPPORT PROGRAMS THAT: 1) IDENTIFY, ASSESS, AND APPROPRIATELY RESPOND TO CHILD, YOUTH, AND ADULT VICTIMS OF DOMESTIC VIOLENCE, SEXUAL ASSAULT, DATING VIOLENCE, AND STALKING IN RURAL COMMUNITIES; 2) ESTABLISH AND EXPAND VICTIM SERVICES IN RURAL COMMUNITIES TO CHILD, YOUTH, AND ADULT VICTIMS; 3) INCREASE THE SAFETY AND WELL-BEING OF WOMEN AND CHILDREN IN RURAL COMMUNITIES, BY (A) DEALING DIRECTLY AND IMMEDIATELY WITH DOMESTIC VIOLENCE, SEXUAL ASSAULT, DATING VIOLENCE, AND STALKING; AND (B) CREATING AND IMPLEMENTING STRATEGIES TO INCREASE AWARENESS AND PREVENT THESE CRIMES; AND 4) DEVELOP, EXPAND, IMPLEMENT, AND IMPROVE THE QUALITY OF SEXUAL ASSAULT FORENSIC MEDICAL EXAMINATION OR SEXUAL ASSAULT NURSE EXAMINER PROGRAMS. GRANTEES MUST USE AT LEAST ONE OF THE FOLLOWING STRATEGIES IN IMPLEMENTING THEIR PROJECTS: 1) IMPLEMENT, EXPAND, AND ESTABLISH COOPERATIVE EFFORTS AND PROJECTS AMONG LAW ENFORCEMENT OFFICERS, PROSECUTORS, VICTIM SERVICE PROVIDERS, AND OTHER RELATED PARTIES TO INVESTIGATE AND PROSECUTE INCIDENTS OF DOMESTIC VIOLENCE, DATING VIOLENCE, SEXUAL ASSAULT, AND STALKING; 2) PROVIDE TREATMENT, COUNSELING, ADVOCACY, LEGAL ASSISTANCE, AND OTHER LONG-TERM AND SHORT-TERM VICTIM AND POPULATION SPECIFIC SERVICES TO ADULT AND MINOR VICTIMS OF DOMESTIC VIOLENCE, DATING VIOLENCE, SEXUAL ASSAULT, AND STALKING IN RURAL COMMUNITIES; 3) WORK IN COOPERATION WITH THE COMMUNITY TO DEVELOP EDUCATION AND PREVENTION STRATEGIES DIRECTED TOWARD SUCH ISSUES; 4) DEVELOP, ENLARGE, OR STRENGTHEN PROGRAMS ADDRESSING SEXUAL ASSAULT; AND 5) DEVELOP PROGRAMS AND STRATEGIES THAT FOCUS ON THE SPECIFIC NEEDS OF VICTIMS OF WHO RESIDE IN REMOTE RURAL AND GEOGRAPHICALLY ISOLATED AREAS. WITH THIS NEW RURAL DOMESTIC VIOLENCE, DATING VIOLENCE, SEXUAL ASSAULT, AND STALKING GRANT AWARD, UNIVERSITY OF NEW ENGLAND, IN PARTNERSHIP WITH THE WABANAKI WOMENS COALITION AND WABANAKI PUBLIC HEALTH AND WELLNESS, WILL IMPLEMENT A SANE/SART PROJECT FOR THE MAINE COUNTIES OF AROOSTOOK, PENOBSCOT, AND WASHINGTON COUNTIES AND TRIBAL LANDS OF THE HOULTON BAND OF MALISEET INDIANS, THE MIKMAQ NATION, THE PASSAMAQUODDY TRIBE AT INDIAN TOWNSHIP, THE PASSAMAQUODDY TRIBE AT PLEASANT POINT, AND THE PENOBSCOT NATION (PENOBSCOT COUNTY). SPECIFIC ACTIVITIES TARGETINGINDIGENOUS SURVIVORS WILL INCLUDE: 1) FORMING AN ADVISORY GROUP TO GUIDE PROJECT ACTIVITIES; 2) DELIVERING TRAININGS ON CULTURAL RESPONSIVENESS AND ITS RELATION TO SERVING VICTIMS OF SEXUAL VIOLENCE; 3) DELIVERING TRAININGS ON THE CARE OF AND RESPONSE TO SEXUAL ASSAULT SURVIVORS FOR TRIBAL HEALTH PROVIDERS AND NON-HEALTH CARE PROVIDER STAKEHOLDERS; 4) CONDUCTING AN ASSESSMENT OF TRIBAL HEALTH CLINIC CAPACITY TO OFFER MEDICAL FORENSIC EXAMS; 5) DELIVERING ADULT/ADOLESCENT (A/A) ANE SANE AND PEDIATRIC SANE TRAININGS FOR TRIBAL HEALTH CLINIC AND LOCAL HOSPITAL STAFFS SERVING THE TRIBES; 6) DELIVERING SIMULATION TRAINING; 7) PILOTING AND IMPLEMENTING MEDICAL FORENSIC EXAMS AT A TRIBAL HEALTH CENTER; AND 8) IMPLEMENTING ONGOING CASE REVIEW. DELIVERABLES WILL INCLUDE A TRAINING CURRICULUM, TRAINING-RELATED BROCHURES, AND OTHER MARKETING MATERIAL. THE TIMING FOR PERFORMANCE OF THIS AWARD IS 36 MONTHS.

PROJECT ALLIANCE - DRUG FREE COMMUNITIES

CAREER: INTEGRIN-MEDIATED MECHANOTRANSDUCTION OF ARTICULAR CHONDROCYTES -THIS FACULTY EARLY CAREER DEVELOPMENT (CAREER) AWARD WILL FOCUS ON ELUCIDATING THE MOLECULAR MECHANISMS ASSOCIATED WITH THE DEVELOPMENT OF OSTEOARTHRITIS. OSTEOARTHRITIS IS THE TYPE OF ARTHRITIS THAT OCCURS WITH AGE OR INJURY. MECHANICAL FORCE IS A KEY CONTRIBUTING FACTOR TO THE DEVELOPMENT OF OSTEOARTHRITIS. HOWEVER, SUBSTANTIAL GAPS REMAIN IN OUR UNDERSTANDING OF THE MECHANISMS BY WHICH MECHANICAL FORCES LEAD TO BIOLOGICAL BEHAVIORS CAN LEAD TO OSTEOARTHRITIS. THIS WORK WILL FOCUS SPECIFICALLY ON CELLS IN CARTILAGE, WHICH ARE CALLED CHONDROCYTES. THIS PROJECT WILL ELUCIDATE MOLECULAR MECHANISMS BY WHICH ARTICULAR CHONDROCYTES DETERMINE CARTILAGE TISSUE HEALTH. SPECIFICALLY, THIS WORK WILL EXAMINE THE RELATION OF MECHANICAL INPUTS TO BIOLOGICAL OUTPUTS MEDIATED THROUGH THE TRANSMISSION OF FORCES ACROSS SPECIFIC MECHANORECEPTORS THAT CONNECT THE FIBROUS ENVIRONMENT OUTSIDE THE CELL WITH THE STRUCTURAL COMPONENTS INSIDE THE CELL. THIS RESEARCH WILL HAVE EVENTUAL APPLICATION TO FUTURE BIOMECHANICAL OR PHARMACEUTICAL INTERVENTIONS TO PREVENT OR REVERSE OSTEOARTHRITIS. THE RESEARCH FROM THIS PROJECT WILL ALSO BE INTEGRATED INTO AN EDUCATIONAL AND OUTREACH PROGRAM BASED ON GRADUATE AND UNDERGRADUATE CURRICULUM DEVELOPMENT, PROMOTION OF GRADUATE AND UNDERGRADUATE RESEARCH OPPORTUNITIES, AND K-12 AND REGIONAL UNDERREPRESENTED MINORITY OUTREACH THROUGH THE DEVELOPMENT OF EDUCATIONAL STORY BOOKS AND HANDS-ON SUMMER CAMP ACTIVITIES. THE SPECIFIC GOAL OF THE RESEARCH IS TO DETERMINE THE INTEGRIN-MEDIATED MECHANOTRANSDUCTION MECHANISMS BY WHICH ARTICULAR CHONDROCYTES REGULATE CARTILAGE HOMEOSTASIS, AND THUS TO ADVANCE UNDERSTANDING OF THE PATHOGENESIS OF OSTEOARTHRITIS. THE RESEARCH OBJECTIVES INCLUDE: (1) ESTABLISHING A BASELINE CATABOLIC THRESHOLD FOR TENSILE FORCE APPLIED TO CHONDROCYTE INTEGRINS, (2) DETERMINING THE DEGREE TO WHICH ACTIN DYNAMICS DRIVES CHONDROCYTE PREFERENCE FOR DYNAMIC FORCE, AND (3) ESTABLISHING SURFACE GLYCOPROTEINS AS MODULATORS OF CHONDROCYTE INTEGRIN TENSION DYNAMICS VIA APPLICATION OF PRESTRESS. THE OVERARCHING FOCUS WILL BE ON LEVERAGING MECHANICAL CONCEPTS DEVELOPED INITIALLY FOR CIVIL AND MECHANICAL ENGINEERING TO INVESTIGATE MECHANISMS OF OUTSIDE-IN MECHANOTRANSDUCTION, INSIDE-OUT MECHANOTRANSDUCTION, AND MOLECULAR TENSEGRITY TO OBTAIN A BETTER UNDERSTANDING OF INTEGRIN-MEDIATED MECHANOTRANSDUCTION IN ARTICULAR CHONDROCYTES. EDUCATION AND OUTREACH COMPONENTS WILL INTEGRATE RESEARCH RESULTS INTO GRADUATE AND UNDERGRADUATE COURSEWORK AND RESEARCH OPPORTUNITIES, STORYBOOKS INTRODUCING NATIVE AMERICAN ELEMENTARY STUDENTS TO PRINCIPLES OF CELLULAR MECHANOBIOLOGY, AND HANDS-ON SUMMER CAMP ACTIVITIES FOR MIDDLE AND HIGH SCHOOL STUDENTS. THIS PROJECT WILL ADVANCE THE KNOWLEDGE BASE IN CELLULAR VIBRATIONAL ANALYSIS, MOLECULAR TENSEGRITY, AND CELLULAR MECHANOBIOLOGY AND ESTABLISH HIS LONG-TERM CAREER AT THE INTERSECTION OF NANOSCIENCE, NANOENGINEERING, AND BIOMEDICAL ENGINEERING. THIS PROJECT IS JOINTLY FUNDED BY THE BIOMECHANICS AND MECHANOBIOLOGY PROGRAM AND THE ESTABLISHED PROGRAM TO STIMULATE COMPETITIVE RESEARCH (EPSCOR). THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.- SUBAWARDS ARE NOT PLANNED FOR THIS AWARD.

THE IMPACT OF DISRUPTING SENSORY INNERVATION ON TIBIAL BONE MASS - PROJECT SUMMARY TIBIA AND FIBULA FRACTURES ACCOUNT FOR 10% OF ANNUAL OSTEOPOROTIC FRACTURES LEADING TO SIGNIFICANT MORBIDITY WITH A 10% MORTALITY RATE WITHIN 12 MONTHS OF FRACTURE. LOW BONE MINERAL DENSITY CAN DRAMATICALLY INCREASE FRACTURE RISK RESULTING FROM A DECREASE IN BONE FORMATION BY THE OSTEOBLAST, AN INCREASE IN BONE RESORPTION BY THE OSTEOCLAST, OR BOTH. A GREATER UNDERSTANDING OF FACTORS REGULATING TIBIAL BONE MINERAL DENSITY WILL HELP PREVENT TIBIAL FRACTURE THROUGH IDENTIFICATION OF AT-RISK INDIVIDUALS AND TREATMENT OF LOW TIBIAL BONE MINERAL DENSITY. SENSORY NERVES SIGNAL TO AND FROM BONE. BOTH SIGNALING DIRECTIONS ARE CRITICAL ASPECTS OF BONE HOMEOSTASIS AND BONE HEALTH. SENSORY NERVE COMMUNICATION WITH BONE HAS BEEN LINKED TO AN INCREASE IN BONE MINERAL DENSITY THROUGH DIRECT AND INDIRECT COMMUNICATION BETWEEN SENSORY NERVES AND BOTH OSTEOBLAST AND OSTEOCLASTS WHILE DENERVATION IS LINKED TO REDUCED BONE MASS. HOWEVER, IT IS UNCLEAR WHAT IMPACT LONG-TERM DISRUPTION OF THESE SIGNALING PATHWAYS HAS ON BONE HEALTH. THE SAPHENOUS NERVE IS PRIMARILY A SENSORY NERVE WITH NO KNOWN MOTOR FUNCTION. INJURY TO THE SAPHENOUS NERVE RESULTS IN PAIN, NUMBNESS, AND DENERVATION OF THE NERVE ITSELF. PRELIMINARY STUDIES HAVE DEMONSTRATED THAT THE SAPHENOUS NERVE INNERVATES THE TIBIA IN MICE. PRELIMINARY DATA HAS SHOWN THAT TRANSECTION OF THE SAPHENOUS NERVE REDUCES TIBIAL NERVE FIBER DENSITY BY 45-60% IN THE PROXIMAL, LATERAL-MOST PERIOSTEUM OF THE TIBIA. HOWEVER, THE IMPACT OF SAPHENOUS NERVE INJURY ON TIBIAL BONE MINERAL DENSITY IS UNKNOWN. WE HYPOTHESIZE THAT SAPHENOUS NERVE DENERVATION WILL ALTER BONE REMODELING WITHIN THE TIBIA RESULTING IN REDUCED BONE MASS. IN ORDER TO TEST THIS HYPOTHESIS, AIM 1 WILL CHARACTERIZE THE IMPACT OF SAPHENOUS NERVE TRANSECTION ON TIBIAL BONE MASS AND INNERVATION. THESE DATA WILL DETERMINE WHETHER DENERVATION OF THE TIBIA WILL RESULT IN A DECREASED BONE MINERAL DENSITY, MICROARCHITECTURE, CELL NUMBER, AND TURNOVER. IT WILL ALSO FURTHER IDENTIFY REGIONS OF INNERVATION LOSS WITHIN THE TIBIA FOLLOWING SAPHENOUS NERVE INJURY. IN AN EFFORT TO DELINEATE THE MECHANISM OF SENSORY REGULATION OF BONE, AIM 2 WILL ASSESS THE RELATIVE CONTRIBUTION OF SENSORY NERVE FIBER SUBTYPES ON TIBIAL BONE MASS THROUGH CHEMICAL ABLATION OF PEPTIDERGIC AND NON-PEPTIDERGIC SENSORY NEURONS USING RESINIFERATOXIN AND IB4-SAPORIN, RESPECTIVELY. AS CGRP HAS BEEN DEMONSTRATED TO PROMOTE BONE ANABOLISM, WE HYPOTHESIZE THAT SELECTIVE ABLATION OF PEPTIDERGIC SENSORY FIBERS WILL RESULT IN BONE LOSS WHEREAS SELECTIVE ABLATION OF NON-PEPTIDERGIC SENSORY FIBERS WILL NOT ALTER BONE REMODELING OR BONE MASS. THESE DATA WILL REVEAL THE SENSORY NERVE FIBER SUBTYPE NECESSARY FOR MAINTAINING BONE MINERAL DENSITY. THE PROPOSED STUDIES WILL DEFINE THE SAPHENOUS NERVE AS AN IMPORTANT REGULATOR OF BONE HOMEOSTASIS IN THE TIBIA. A GREATER UNDERSTANDING OF THE IMPACT OF NERVE INJURY ON BONE MASS WILL AID IN ELUCIDATING NEW RISK FACTORS PREDISPOSING INDIVIDUALS TO TIBIAL FRACTURE.

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ONTOGENY OF SEX DIFFERENCES IN AMYGDALA AND HYPOTHALAMUS AFTER NEONATAL TRAUMA - EARLY LIFE MEDICAL INTERVENTION, SUCH AS OCCURS IN THE NEONATAL INTENSIVE CARE UNIT, SAVES INFANT LIVES, BUT ALSO IS A SIGNIFICANT RISK FACTOR FOR SUBSEQUENT EMOTIONAL, MOOD AND SENSORY DYSFUNCTION, INCLUDING CHRONIC PAIN. CRITICALLY, THERE IS MOUNTING EVIDENCE OF SIGNIFICANT SEX DIFFERENCES IN NICU OUTCOMES, WITH GREATER MORTALITY AND GROSS NEUROLOGICAL DYSFUNCTION IN MALES AND GREATER RISK OF INTERNALIZING DISORDERS IN FEMALES. HOWEVER, THE MECHANISMS UNDERLYING THESE SEX DIFFERENCES ARE LARGELY UNKNOWN, A KEY GAP IN THE LITERATURE. OUR LONG- TERM GOAL IS TO UNDERSTAND THE NEUROLOGICAL SUBSTRATES THAT UNDERLIE THE DIFFERENT EFFECTS OF NEONATAL PAIN AND STRESS ON VULNERABILITY TO NEGATIVE AFFECT DISORDERS, INCLUDING CHRONIC PAIN, DURING THE JUVENILE PERIOD IN MALE AND FEMALE RATS. TO ACCOMPLISH THIS, WE WILL EXPOSE NEONATAL RATS TO NICU-LIKE TREATMENT INCLUDING A SERIES OF REPETITIVE PAW PRICKS WHICH RESULTS IN A LATENT VULNERABILITY. OUR CENTRAL HYPOTHESIS IS THAT THE UNDERLYING NEURO/ENDOCRINE MECHANISMS DIFFER BETWEEN THE SEXES. FOR EXAMPLE, WE HAVE PREVIOUSLY DEMONSTRATED THAT EXPOSURE TO A SUBSEQUENT “ACTIVATING” STRESSOR DURING THE JUVENILE PERIOD UNMASKS ALTERATIONS TO NEGATIVE AFFECTIVE BEHAVIOR AND PAIN THRESHOLDS IN BOTH SEXES FOLLOWING NEONATAL PAIN. HOWEVER, THE NEUROBIOLOGY UNDERLYING THESE CHANGES DIFFER. FOR EXAMPLE, CORTICOTROPIN RELEASING FACTOR (CRF)-CONTAINING CELLS WITHIN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA) ARE PARTICULARLY RESPONSIVE DURING NEONATAL TRAUMA AND ARE REDUCED IN NUMBER LATER IN LIFE, BUT ONLY IN MALE RATS. FEMALES, ALTHOUGH ALSO AFFECTED BY NEONATAL PAIN, DO NOT APPEAR TO UNDERGO THE SAME CHANGES IN THE AMYGDALAR CRF SYSTEM. IMPORTANTLY, HOWEVER, INTRA-AMYGDALA CRF1 ANTAGONISTS CAN REVERSE THE HYPERSENSITIVITY IN BOTH SEXES. THUS, WHILE CRF-EXPRESSING CELLS IN THE CEA ARE ONLY INVOLVED IN MALE RATS, CRF RECEPTORS ARE INVOLVED IN BOTH SEXES, SUGGESTING INVOLVEMENT OF A NON- AMYGDALA SOURCE OF CRF IN FEMALES. PRELIMINARY DATA POINT TO THE HYPOTHALAMUS. TO BETTER UNDERSTAND THESE DIFFERENCES, WE PROPOSE A SERIES OF INNOVATIVE EXPERIMENTS TO IDENTIFY THE BEHAVIORAL AND BRAIN CHANGES UNDERLYING THE DIFFERENT EFFECTS OF NEONATAL PAIN IN MALE AND FEMALE RATS. SPECIFIC AIM 1 PROPOSES HI-PLEX IN SITU HYBRIDIZATION AND FLORESCENT IMMUNOHISTOCHEMISTRY DESIGNED TO ASSESS CHANGES IN NEUROPEPTIDE GENE EXPRESSION AND CELLULAR PHENOTYPES IN THE AMYGDALA AND HYPOTHALAMUS TO EXAMINE DIFFERENCES BETWEEN MALE AND FEMALE RATS EXPOSED TO NICU-LIKE EXPERIENCES. WHILE THE FUNCTION OF SOME INDIVIDUAL GENES AND BIOMARKERS HAVE BEEN ESTABLISHED, MANY CELLS CO-EXPRESS SEVERAL NEUROPEPTIDES AND THE VARIOUS OVERLAPPING EXPRESSION PATTERNS OF THESE NEUROPEPTIDES HAS NOT BEEN STUDIED. SPECIFIC AIM 2 LOOKS FOR CHANGES IN NEURONAL ACTIVATION PATTERNS IN IDENTIFIED CELL TYPES IN THE AMYGDALA AND HYPOTHALAMUS AND CORRELATES THIS WITH CHANGES IN BEHAVIOR, USING IMMEDIATE EARLY GENE SIGNALING AS A PROXY FOR NEURONAL ACTIVATION. TOGETHER, THESE EXPERIMENTS WILL FILL IN CRITICAL GAPS IN OUR KNOWLEDGE REGARDING SEX DIFFERENCES IN THE LASTING CONSEQUENCES OF NEONATAL PAIN.

INVESTIGATION OF ARMADILLO/?-CATENIN MECHANISMS INFLUENCING NOCICEPTIVE SENSITIVITY IN DROSOPHILA - PROJECT SUMMARY NORMAL PAIN PROMOTES HEALTH BY WARNING US OF POTENTIAL TISSUE DAMAGE, BUT ABNORMAL PAIN REDUCES THE QUALITY OF LIFE FOR MILLIONS AROUND THE WORLD. AVAILABLE TREATMENT FOR PAIN IS CURRENTLY INADEQUATE, IN PART BECAUSE OF THE DELETERIOUS SIDE EFFECTS OF OUR BEST ANALGESICS, THE OPIOIDS. BETTER TREATMENTS FOR ABNORMAL PAIN ARE BADLY NEEDED. WE PROPOSE TO REVEAL NOVEL TARGETS FOR PAIN MEDICATIONS BY EXPLOITING THE POWERFUL GENETIC TOOLKIT OF THE DROSOPHILA MODEL. FRUIT FLY LARVAE REACT TO NOXIOUS STIMULI USING AN ESCAPE BEHAVIOR CONSISTING OF AN UNMISTAKABLE CORKSCREW ROLL. THIS MODEL SYSTEM HAS BEEN USED TO IDENTIFY DOZENS OF COMPONENTS THAT REGULATE NOCICEPTIVE SENSITIVITY. MANY SIGNALING COMPONENTS IDENTIFIED IN THE FLY ARE VERY SIMILAR TO THEIR MAMMALIAN COUNTERPARTS. PRELIMINARY RESULTS INDICATE THAT THE FLY HOMOLOG OF B-CATENIN, CALLED ARMADILLO (ARM) REGULATES NOCICEPTIVE SENSITIVITY BUT THE MECHANISM OF THIS REGULATION IS CURRENTLY UNCLEAR. AIM 1 WILL TEST THE HYPOTHESIS THAT ARM REGULATES SENSITIVITY BY EXERTING ITS INFLUENCE IN THE WELL-KNOWN WNT/WG TRANSCRIPTIONAL CONTROL PATHWAY. THIS TESTING WILL BE ACCOMPLISHED BY TARGETING RNAI SILENCING AND/OR OVEREXPRESSION CONSTRUCTS OF KEY PATHWAY GENES SPECIFICALLY TO THE NOCICEPTOR NEURONS USING THE GAL4/UAS SYSTEM. ANY RESULTING CHANGES TO NOCICEPTIVE SENSITIVITY WILL BE OBSERVED IN THERMO- AND MECHANONOCICEPTION ASSAYS THAT FOCUS ON THE ESCAPE BEHAVIOR. AIM 2 WILL TEST THE INDEPENDENT HYPOTHESIS THAT ARM AND RELATED COMPONENTS REGULATE NOCICEPTIVE SENSITIVITY THROUGH ARM'S CELL ADHESION FUNCTION. WE WILL CAUSE THE NOCICEPTORS TO EXPRESS TAGGED FORMS OF ARM AND OTHER COMPONENTS THAT CAN BE ANALYZED BY IMMUNOFLUORESCENT MICROSCOPY TO STUDY NEURONAL ARM'S CONTRIBUTION TO NEURONAL-EPIDERMAL ADHESIVE JUNCTIONS CALLED SHEATHS AND TO SYNAPSES WITH CNS INTERNEURONS. WE WILL UNDER- AND OVEREXPRESS ARM AND OTHER COMPONENTS AND CORRELATE ANY CHANGES IN SHEATH OR SYNAPSE FORMATION WITH NOCICEPTIVE SENSITIVITY USING OUR BEHAVIORAL ASSAYS. THE PROPOSED STUDIES HAVE THE POTENTIAL TO IDENTIFY NOVEL MECHANISMS AND COMPONENTS THAT AFFECT NOCICEPTIVE SENSITIVITY. BECAUSE OF THE HIGH DEGREE OF FUNCTIONAL CONSERVATION BETWEEN FLY AND MAMMALIAN SIGNALING MOLECULES, COMPONENTS IDENTIFIED BY THESE EXPERIMENTS MAY REPRESENT TARGETS FOR NOVEL MEDICATIONS FOR THE TREATMENT OF ABNORMAL PAIN IN HUMANS.

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RURAL COMMUNITIES OPIOID RESPONSE PROGRAM ? NORTHERN BORDER RURAL WORKFORCE - RURAL COMMUNITIES OPIOID RESPONSE PROGRAM – NORTHERN BORDER RURAL WORKFORCE

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IGF::OT::IGF TUITION AND FEES

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ME, UNIVERSITY OF NEW ENGLAND FALL 1301262739

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ME, UNIVERSITY OF NEW ENGLAND SPR 1301316928

IGF::OT::IGF TUITION AND FEES

MECHANISMS UNDERLYING SEX DIFFERENCES IN EMERGENCE OF ADVANCED OSTEOARTHRITIS PAIN - ABSTRACT OA PAIN IS HETEROGENEOUS WITH DISTINCT MECHANISMS ACROSS PAIN PHENOTYPES THAT ARE POORLY UNDERSTOOD AND THAT LIKELY UNDERLIE THE VARIABILITY IN THERAPEUTIC EFFICACY ACROSS OA PAIN PATIENTS. MANY OA PATIENTS REPORT MID- STAGE OA PAIN THAT OCCURS DURING JOINT USE AND DISSIPATES DURING REST. OTHERS DEVELOP ADVANCED OA PAIN CHARACTERIZED BY PERSISTENT JOINT PAIN THAT DOES NOT DISSIPATE DURING REST AND THAT IS RESISTANT TO CURRENT TREATMENTS. FEMALES HAVE A HIGHER INCIDENCE OF OA PAIN AND REPORT MORE SEVERE PAIN COMPARED TO MALES. THIS GRANT APPLICATION USES AN INNOVATIVE MOUSE MODEL OF MID- AND ADVANCED OA PAIN THAT ALLOWS ANALYSIS OF MECHANISMS UNDERLYING THE TRANSITION BETWEEN MID-STAGE AND ADVANCED OA PAIN. FEMALE MICE DEVELOP ADVANCED OA PAIN WITH LESS JOINT DAMAGE COMPARED TO MALES ALLOWING ANALYSIS OF SEX DIFFERENCES THAT UNDERLIE ENHANCED SUSCEPTIBILITY FOR FEMALES TO DEVELOP ADVANCED OA PAIN COMPARED TO MALES. THE PROPOSED STUDIES WILL INVESTIGATE PATHOLOGICAL CHANGES IN INNERVATION OF THE JOINT AND ADJACENT MUSCLE BY COMPARING CONTROLS TO MID-STAGE AND ADVANCED OA PAIN. THE SPECIFIC AIMS WILL EXPLORE THE HYPOTHESIS THAT MICE WITH ADVANCED OA HAVE SENSORY NERVE SPROUTING INTO JOINT TISSUES AND ADJACENT MUSCLE AS WELL AS SENSORY NERVE DAMAGE AND THAT FEMALES DEVELOP NERVE SPROUTING AND NERVE INJURY IN THE CONTEXT OF LESS JOINT TISSUE DAMAGE COMPARED TO MALES. AIM 1 WILL DETERMINE PATHOLOGICAL SPROUTING OF SENSORY NERVES IN THE KNEE JOINT AND SURROUNDING MUSCLE OF MALE AND FEMALE MICE WITH MID-STAGE AND ADVANCED OA PAIN. THIS AIM WILL EXAMINE WHETHER MALES AND FEMALES WITH ADVANCED OA DEVELOP PATHOLOGICAL SPROUTING OF SMALL DIAMETER CGRP POSITIVE FIBERS AND NF-200 POSITIVE MYELINATED FIBERS INTO JOINT TISSUES AND ADJACENT MUSCLE, AND WHETHER FEMALES WITH ADVANCED OA PAIN SHOW PATHOLOGICAL SPROUTING IN THE CONTEXT OF LESS JOINT TISSUE DAMAGE. AIM 2 WILL DETERMINE POTENTIAL DIFFERENCES IN AXONAL NERVE INJURY THROUGH INDUCTION OF ATF3 IN SENSORY NEURON CELL BODIES OF MALE AND FEMALE MICE WITH MID-STAGE AND ADVANCED OA PAIN. RETROGRADE LABELING FROM THE KNEE JOINT OR TIBIALIS ANTERIOR MUSCLE WILL BE USED TO EXAMINE WHETHER THERE ARE DIFFERENCES IN ATF3 WITHIN SENSORY NEURONS INNERVATING THE JOINT COMPARED TO THE ADJACENT MUSCLE. CO-LABELING OF ATF3 WITH CGRP AND NF200 WILL BE USED TO ANALYZE WHETHER THERE ARE DIFFERENCES IN NERVE INJURY ACROSS THE DIFFERENT POPULATIONS OF SENSORY FIBERS. THESE TECHNIQUES WILL ELUCIDATE WHETHER NERVE INJURY OCCURS SPECIFICALLY IN THE CONTEXT OF ADVANCED OA PAIN AND WHETHER IT IS OBSERVED IN FEMALES WITH LESS JOINT PATHOLOGY COMPARED TO MALES. IMPROVED UNDERSTANDING OF THE PATHOPHYSIOLOGICAL CHANGES WITHIN THE JOINT THAT DIFFER BETWEEN MID-STAGE AND ADVANCED OA PAIN IS A CRITICAL STEP IN IMPROVING PAIN MANAGEMENT ACROSS THIS HETEROGENEOUS PAIN CONDITION. DIRECT ANALYSIS OF SEXUAL DIMORPHISM IN THESE CHANGES WILL PROVIDE INSIGHTS INTO POTENTIAL INCREASE SUSCEPTIBILITY FOR FEMALES TO DEVELOP NEUROPATHIC PAIN AND REQUIRE DIFFERENT THERAPEUTIC TREATMENT STRATEGIES COMPARED TO MALES.

THE ROLE OF THE VENTROMEDIAL NUCLEUS OF THE HYPOTHALAMUS IN EPILEPTOGENESIS - PROJECT SUMMARY/ABSTRACT GENERALIZED EPILEPSY TREATMENTS FOCUS ON SEIZURE SUPPRESSION, RATHER THAN HALTING THE UNDERLYING PATHOGENESIS THAT IS INITIATED BY SEIZURE-ASSOCIATED CHANGES IN BRAIN PLASTICITY. MECHANISMS CONTRIBUTING TO EPILEPTOGENESIS ARE DIFFICULT TO IDENTIFY IN HUMANS DUE TO GENETIC AND ENVIRONMENTAL DIVERSITY, AND AS SUCH, PRECLINICAL MODELS PROVIDE ADVANTAGES FOR ELUCIDATING EPILEPTOGENIC PROCESSES. OUR FOS ACTIVATION PATHWAY AND LESION ANALYSES SUGGEST THAT THE VENTROMEDIAL NUCLEUS OF THE HYPOTHALAMUS (VMH) IS A CRITICAL ANATOMICAL NODE FOR THE PROPAGATION OF SEIZURE DISCHARGE FROM THE FOREBRAIN SEIZURE NETWORK TO THE BRAINSTEM SEIZURE NETWORK. OUR PRELIMINARY DATA FURTHER SUPPORT THIS HYPOTHESIS AS LOSS OF GLUTAMATE TRANSPORT INTO PRESYNAPTIC VESICLES BY DELETION OF THE VESICULAR GLUTAMATE TRANSPORTER GENE, VGLUT2, SOLELY IN THE VMH CAN BLOCK SEIZURE PROPAGATION INTO THE BRAINSTEM SEIZURE NETWORK, WHICH CONTAINS CARDIO-RESPIRATORY CENTERS. ACCESS OF SEIZURE DISCHARGE INTO THE BRAINSTEM RESULTS IN BOTH BRAINSTEM-TONIC SEIZURES AND INCREASES THE PROBABILITY OF SUDDEN UNEXPLAINED DEATH IN EPILEPSY (SUDEP). THESE DATA SUGGEST THE HYPOTHESIS THAT THE VMH IS A CRITICAL ANATOMICAL NODE FOR SEIZURE-INDUCED PLASTICITY. IT ALSO INDICATES A VMH NEUROANATOMICAL PATHWAY, WHICH MAY BE IMPORTANT IN SUDEP, SINCE PREVENTING SEIZURE DISCHARGE FROM PROPAGATING INTO BRAINSTEM CARDIO-RESPIRATORY CENTERS COULD PREVENT SUDEP. OUR LONG-TERM GOAL IS TO IDENTIFY NEUROANATOMICAL SUBSTRATES AND SIGNALING PATHWAYS CRITICAL FOR EPILEPTOGENESIS, SO THAT THERAPEUTIC TREATMENTS AND PREVENTATIVE STRATEGIES CAN BE DEVELOPED FOR EPILEPSY AND SUDEP IN HUMANS. THE OVERALL OBJECTIVES OF THIS PROPOSAL BUILD UPON OUR PREVIOUS WORK AND PRELIMINARY DATA LEADING TO THE FOLLOWING AIMS/OBJECTIVES: 1) ELUCIDATE THE MECHANISMS BY WHICH THE VMH IS INVOLVED IN THE EPILEPTOGENIC PROCESS FOR ALLOWING ICTAL DISCHARGE PROPAGATION FROM THE FOREBRAIN SEIZURE NETWORK INTO THE BRAINSTEM SEIZURE NETWORK AND 2) DETERMINE THE GENOMIC LANDSCAPE IN THE VMH USING SPATIAL TRANSCRIPTOMICS BEFORE AND DURING EPILEPTOGENESIS. IN AIM 1, WE WILL ASSESS VMH REORGANIZATIONAL PROCESS USING 1) MICE WITH VMH-TARGETED DELETION OF GENES (I.E., VGLUT2, TRKB, BDNF) IN OUR REPEATED FLUROTHYL MODEL TO ASSESS SEIZURE OUTCOMES AND 2) ASSESS CHANGES IN AFFERENT AND EFFERENT CONNECTIVITY TO THE VMH VIA TIMM’S STAINING (FIBER SPROUTING) AND TRACT TRACING. FOR AIM 2, WE WILL UTILIZE THE NOVEL APPROACH OF SPATIAL TRANSCRIPTOMICS TO PERFORM CELL-TYPE AND REGIONAL WHOLE TRANSCRIPTOME ANALYSIS USING A NANOSTRING GEOMX DIGITAL SPATIAL PROFILER AND ILLUMINA SEQUENCING TO DETERMINE GENE EXPRESSION CHANGES IN DIFFERENT POPULATIONS OF VMH NEURONS. EXPRESSION DIFFERENCES WILL BE CONFIRMED BY QRT-PCR AND/OR IMMUNOLABELING. OVERALL, OUR PROPOSAL WILL ELUCIDATE SEIZURE RESPONSE MECHANISMS THAT INITIATE AND CONTRIBUTE TO EPILEPTOGENESIS AND PROVIDE A FRAMEWORK OF TRANSCRIPTIONAL NETWORKS CONTRIBUTING TO EPILEPTOGENESIS THAT COULD BE TARGETED FOR THERAPEUTIC INTERVENTION FOR EPILEPSY AND/OR SUDEP.

TUITION AND FEES

TUITION AND FEES

TUITION AND FEES

TUITION AND FEES

TUITION AND FEES

TUITION AND FEES

ME, UNIV OF NEW ENGLAND SPR 1301226068 TUITION AND FEES