R01DE035179

TARGETING SUCCINATE SIGNALING FOR INNOVATIVE PAIN RELIEF IN ORAL CANCER. - CURRENT PAIN MANAGEMENT STRATEGIES FOR PATIENTS WITH ORAL OR HEAD AND NECK CANCER CONDITIONS OFTEN RELY ON HIGH-DOSE OPIOID ANALGESICS, WHICH CAN BE INEFFECTIVE. SUCCINATE IS A DICARBOXYLIC ACID METABOLITE IN THE KREBS CYCLE, AND EMERGING EVIDENCE HIGHLIGHTS ITS PRO-INFLAMMATORY ROLE THROUGH THE ACTIVATION OF ITS G-PROTEIN COUPLED RECEPTOR, SUCNR1. NOTABLY, ORAL CANCER PATIENTS SHOW ELEVATED CIRCULATING SUCCINATE LEVELS AND INCREASED SUCNR1 EXPRESSION IN TUMOR TISSUES. WE HAVE BEEN AT THE FOREFRONT OF INVESTIGATING SUCCINATE/SUCNR1 SIGNALING AND HAVE DEMONSTRATED THAT SUCNR1 ACTIVATION PROMPTS PRO-INFLAMMATORY SIGNALING IN MYELOID CELLS. OUR PRELIMINARY FINDINGS INDICATE THAT PATIENTS WITH ORAL CANCER EXPERIENCING HIGHER PAIN SCORES HAVE ELEVATED PLASMA SUCCINATE LEVELS. ADDITIONALLY, SUCNR1 EXPRESSION HAS BEEN OBSERVED IN BOTH HUMAN AND MOUSE GANGLIA, WITH SUCCINATE INCREASING INFLAMMATION AND NOCICEPTION IN WILDTYPE (WT) MICE BUT NOT IN SUCNR1 KNOCKOUT (KO) MICE. IN AN MOC2 ORTHOTOPIC XENOGRAFT MODEL OF ORAL CANCER, KO MICE EXHIBITED REDUCED FACIAL NOCICEPTION AND FEWER TUMOR- INFILTRATING MYELOID CELLS. WE HYPOTHESIZE THAT INHIBITING SUCNR1 ACTIVATION COULD ALLEVIATE ORAL CANCER PAIN BY REDUCING INFLAMMATION AND NOCICEPTION. TO TEST THIS HYPOTHESIS, WE PROPOSE TWO SPECIFIC AIMS. IN AIM 1, WE WILL INVESTIGATE SUCCINATE SIGNALING AND ASSESS SUCNR1 AS A POTENTIAL TARGET FOR ALLEVIATING ORAL CANCER PAIN USING CLINICAL SAMPLES AND PRECLINICAL MODELS. THE ANALGESIC EFFECTS OF A NOVEL SUCNR1 ANTAGONIST WE HAVE DEVELOPED WILL BE EVALUATED IN 4NQO-INDUCED ORAL CANCER MICE. WE WILL MEASURE TUMOR GROWTH, ORAL FUNCTION, AND REFERRED MECHANICAL AND THERMAL HYPERSENSITIVITIES, ALONG WITH ASSOCIATED COMORBIDITIES. ADDITIONALLY, WE WILL EXPLORE THE DISTRIBUTION AND NEUROMODULATORY FUNCTION OF SUCNR1 IN HUMAN ORAL CANCER TISSUES, AND THE GANGLIA OF BOTH HUMAN AND MOUSE. IN AIM 2, WE WILL EVALUATE THE ROLE OF MYELOID SUCNR1 IN ORAL CANCER PAIN WITH GLOBAL AND MYELOID-SPECIFIC KNOCKOUT MICE, ALONGSIDE THEIR LITTERMATE CONTROLS. THREE ORAL CANCER MODELS—MOC1 AND MOC2 ORTHOTOPIC XENOGRAFTS AND 4NQO-INDUCED ORAL CANCER—WILL BE DEVELOPED IN THESE MICE. WE WILL MEASURE TUMOR GROWTH AND NOCICEPTION WHILE CHARACTERIZING VARIOUS MYELOID POPULATIONS IN TUMOR, PERIPHERAL BLOOD, AND TUMOR- DRAINING LYMPH NODES THROUGH FLOW CYTOMETRY. LASTLY, WE WILL ASSESS SUCCINATE AND CYTOKINE LEVELS IN SERUM, AND TUMOR TISSUES USING SUCCINATE ASSAYS, MESO SCALE DISCOVERY MULTIPLEX IMMUNOASSAYS, AND SEMI- QUANTITATIVE PCR.

Rector & Visitors Of The University Of Virginia

NIDCR EXTRAMURAL RESEARCH PROVIDES RESEARCH FUNDS TO SUPPORT BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH IN DENTAL, ORAL, AND CRANIOFACIAL HEALTH AND DISEASE THROUGH GRANTS, COOPERATIVE AGREEMENTS, AND CONTRACTS THAT SUPPORT SCIENTISTS WORKING IN INSTITUTIONS THROUGHOUT THE UNITED STATES AND INTERNATIONALLY. EXTRAMURAL PROGRAMS PLAN, DEVELOP, AND MANAGE SCIENTIFIC PRIORITIES THROUGH PORTFOLIO ANALYSES AND CONSULTATION WITH STAKEHOLDERS, ENCOURAGING THE MOST PROMISING DISCOVERIES AND EMERGING TECHNOLOGIES FOR RAPID TRANSLATION TO CLINICAL APPLICATIONS. THE INTEGRATIVE BIOLOGY AND INFECTIOUS DISEASES PROGRAMS SUPPORTS BASIC AND TRANSLATIONAL RESEARCH PROGRAMS ON ORAL MICROBIOLOGY, SALIVARY BIOLOGY AND IMMUNOLOGY, ORAL AND SALIVARY GLAND CANCERS, NEUROSCIENCE OF OROFACIAL PAIN AND TEMPOROMANDIBULAR DISORDERS, MINERALIZED TISSUE PHYSIOLOGY, DENTAL BIOMATERIALS, AND TISSUE ENGINEERING AND REGENERATIVE MEDICINE. THE BRANCH AIMS TO ACCELERATE PROGRESS IN BASIC AND TRANSLATIONAL RESEARCH IN THESE AREAS, AND FURTHER STIMULATE THE DISCOVERY PIPELINE BASED ON CLINICAL NEEDS. THE TRANSLATIONAL GENOMICS RESEARCH PROGRAMS SUPPORTS BASIC AND TRANSLATIONAL RESEARCH IN GENETICS, GENOMICS, DEVELOPMENTAL BIOLOGY, AND DATA SCIENCE TOWARD THE GOAL OF IMPROVING DENTAL, ORAL, AND CRANIOFACIAL HEALTH. THE FOCUS IS ON DECIPHERING THE GENETIC, MOLECULAR, AND CELLULAR MECHANISMS UNDERLYING DENTAL, ORAL, AND CRANIOFACIAL DEVELOPMENT AND ANOMALIES. THE BEHAVIORAL AND SOCIAL SCIENCES RESEARCH PROGRAMS SUPPORTS BASIC AND APPLIED RESEARCH TO PROMOTE ORAL HEALTH, TO PREVENT ORAL DISEASES AND RELATED DISABILITIES, AND TO IMPROVE MANAGEMENT OF CRANIOFACIAL CONDITIONS, DISORDERS, AND INJURY. THE PROGRAM PRIORITIZES MECHANISTIC RESEARCH THAT CONTRIBUTES TO A CUMULATIVE SCIENCE OF BEHAVIOR CHANGE, TO MAXIMIZE THE RIGOR, RELEVANCE, AND DISSEMINATION OF EFFICACIOUS BEHAVIOR CHANGE INTERVENTIONS. THE CLINICAL RESEARCH PROGRAMS SUPPORTS PATIENT-ORIENTED, POPULATION, AND COMMUNITY BASED RESEARCH AIMED AT IMPROVING THE DENTAL, ORAL, AND CRANIOFACIAL HEALTH OF THE NATION. THE CENTER FOCUSES ON A VARIETY OF DISEASES AND CONDITIONS THROUGH CLINICAL TRIALS, EPIDEMIOLOGIC STUDIES, PRACTICE-BASED RESEARCH, THE HIV/AIDS AND ORAL HEALTH PROGRAM, AND STUDIES OF ORAL HEALTH DISPARITIES AND INEQUITIES IN ALL AREAS OF NIDCR PROGRAMMATIC INTEREST. THE PROGRAM ENCOURAGES INVESTIGATIONS THAT HAVE THE POTENTIAL TO TRANSLATE FINDINGS INTO EVIDENCE-BASED CLINICAL APPLICATIONS. THE RESEARCH TRAINING AND CAREER DEVELOPMENT EXTRAMURAL PROGRAMS SPAN THE CAREER STAGES OF SCIENTISTS, SUPPORTING RESEARCH TRAINING AND CAREER DEVELOPMENT FOR PHD AND DUAL DEGREE DDS/DMD-PHD STUDENTS, POSTDOCTORAL SCHOLARS, AND EARLY CAREER, MIDCAREER, AND ESTABLISHED INVESTIGATORS. THE PROGRAMS MANAGE SUPPORT FOR FELLOWSHIPS, RESEARCH TRAINING GRANTS, CAREER DEVELOPMENT AND CAREER TRANSITION AWARDS, NIH LOAN REPAYMENT AWARDS, AND DIVERSITY SUPPLEMENTS TO SUPPORT RESEARCH EXPERIENCES FOR HIGH SCHOOL STUDENTS THROUGH INVESTIGATORS. NIDCR PARTICIPATES IN THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAMS. THE SBIR PROGRAM IS INTENDED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.THE STTR PROGRAM IS INTENDED TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. EXTRAMURAL PROGRAMS ARE ACCOUNTABLE FOR THE EFFICIENT AND EFFECTIVE USE OF TAXPAYER FUNDS TO SUPPORT RESEARCH ON DENTAL, ORAL, AND CRANIOFACIAL DISEASES AND DISORDERS AND IMPROVING THE ORAL HEALTH OF ALL AMERICANS. EXTRAMURAL PROGRAMS SUPPORT RESEARCH AND RESEARCH TRAINING TO ESTABLISH THE FOUNDATION FOR SCIENTIFIC DISCOVERIES THAT INCLUDE TRANSPARENT AND RIGOROUS PLANNING, PRIORITY SETTING, CONTINUOUS AND CONSISTENT REVIEWS OF PROGRESS, AND FOCUS ON THE DEVELOPMENT OF A DIVERSE, HIGHLY SKILLED, AND NIMBLE WORKFORCE THAT CAN RAPIDLY RESPOND TO SCIENTIFIC BREAKTHROUGHS AND PUBLIC HEALTH CHALLENGES. EXTRAMURAL PROGRAMS ARE ACCOUNTABLE FOR THE EFFICIENT AND EFFECTIVE USE OF TAXPAYER FUNDS TO SUPPORT RESEARCH ON DENTAL, ORAL, AND CRANIOFACIAL DISEASES AND EMPLOY EVALUATION DOMAINS, FROM NEEDS ASSESSMENT AND STRATEGIC PLANNING TO IMPLEMENTATION AND PROCESS EVALUATION, PERFORMANCE MEASUREMENT, AND OUTCOMES AND IMPACT ANALYSIS TO EVALUATE STRATEGIC OBJECTIVES

93.279 - Drug Abuse and Addiction Research Programs

National Institute of Dental and Craniofacial Research (NIDCR) [HHS - NIH]

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Virginia United States

State-Wide

HEAL Initiative: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed) (RFA-NS-22-034)