R01AI191517

FUNCTIONAL AND MECHANISTIC CHARACTERIZATION OF LUPUS SUSCEPTIBILITY - PROJECT ABSTRACT SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A COMPLEX AUTOIMMUNE DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION AND MULTI-ORGAN INVOLVEMENT, LEADING TO SIGNIFICANT MORBIDITY AND MORTALITY. SLE DISPROPORTIONATELY AFFECTS WOMEN AND INDIVIDUALS OF ASIAN, AFRICAN, AND HISPANIC DESCENT, WITH A HIGHER PREVALENCE AND SEVERITY COMPARED TO OTHER POPULATIONS. DESPITE ADVANCEMENTS IN RESEARCH, THE MOLECULAR MECHANISMS UNDERLYING SLE REMAIN POORLY UNDERSTOOD, AND CURRENT THERAPIES ARE OFTEN INSUFFICIENT DUE TO CLINICAL HETEROGENEITY AND UNPREDICTABLE DISEASE TRAJECTORIES, UNDERSCORING THE URGENT NEED FOR NOVEL INTERVENTIONS. AUTOPHAGY, A CRITICAL CELLULAR MECHANISM FOR MAINTAINING HOMEOSTASIS, HAS EMERGED AS A KEY PLAYER IN SLE PATHOGENESIS. DYSFUNCTIONAL AUTOPHAGY DISRUPTS CELLULAR PROCESSES, INCLUDING LYSOSOMAL FUNCTION, ANTIGEN PRESENTATION, AND CYTOKINE REGULATION, WHICH ARE CENTRAL TO BOTH IMMUNE AND NON-IMMUNE CELL FUNCTIONS. WHILE B AND T CELLS HAVE LONG BEEN IMPLICATED IN SLE, RECENT EVIDENCE HIGHLIGHTS THE ROLE OF CLASSICAL MONOCYTES (CD14++CD16−) AND KIDNEY-RESIDENT PODOCYTES IN DRIVING DISEASE PROGRESSION. IN SLE, MONOCYTES EXHIBIT IMPAIRED AUTOPHAGY, RESULTING IN DEFECTIVE PHAGOCYTOSIS AND HEIGHTENED PRODUCTION OF PRO-INFLAMMATORY CYTOKINES, SUCH AS TNF-Α AND IL-6, FUELING SYSTEMIC INFLAMMATION. SIMILARLY, PODOCYTES RELY ON AUTOPHAGY FOR MAINTAINING STRUCTURAL INTEGRITY AND GLOMERULAR FILTRATION. AUTOPHAGY IMPAIRMENTS IN PODOCYTES LEAD TO CYTOSKELETAL DAMAGE, APOPTOSIS, AND PROTEINURIA, WHICH ARE HALLMARK FEATURES OF LUPUS NEPHRITIS. GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED NUMEROUS SLE SUSCEPTIBILITY LOCI; YET TRANSLATING THESE FINDINGS INTO MECHANISTIC INSIGHTS REMAINS CHALLENGING. OUR STUDY FOCUSES ON FOUR KEY GWAS LOCI LINKED TO GENES INVOLVED IN AUTOPHAGY, LYSOSOMAL FUNCTION, AND APOPTOSIS—PATHWAYS CRUCIAL FOR IMMUNE REGULATION AND TISSUE HOMEOSTASIS. WE HYPOTHESIZE THAT GENETIC VARIANTS WITHIN REGULATORY ELEMENTS OF THESE GENES DISRUPT AUTOPHAGY, EXACERBATING IMMUNE DYSREGULATION AND ORGAN-SPECIFIC DAMAGE IN SLE. AIM 1 INVOLVES FINE-MAPPING SLE SUSCEPTIBILITY LOCI THROUGH IMPUTATION-BASED ANALYSIS OF RESEQUENCING DATA FROM PATIENTS AND CONTROLS. FUNCTIONAL VARIANTS WILL BE PRIORITIZED USING ALLELE-SPECIFIC EXPRESSION, CHROMATIN PROFILING, AND 3D GENOME INTERACTION DATA, FOLLOWED BY GENOTYPING VALIDATION. AIM 2 EVALUATES THE FUNCTIONAL IMPACT OF THESE VARIANTS ON AUTOPHAGY AND CELLULAR PROCESSES USING CRISPR-BASED MODIFICATIONS IN IMMUNE (E.G., THP-1 MONOCYTES) AND NON-IMMUNE (E.G., PODOCYTE) CELL MODELS. COMPLEMENTARY STUDIES IN PRIMARY MONOCYTES FROM SLE PATIENTS AND HEALTHY CONTROLS WILL VALIDATE FINDINGS. BY ELUCIDATING THE ROLE OF AUTOPHAGY-RELATED GENETIC VARIANTS IN SLE, THIS RESEARCH AIMS TO UNCOVER NOVEL MECHANISMS OF DISEASE AND IDENTIFY THERAPEUTIC TARGETS FOR PRECISION MEDICINE APPROACHES.

Oklahoma Medical Research Foundation

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE 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 SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER 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. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Oklahoma United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)