R01AI190169

RESOLVING THE MECHANISMS OF IFIH1 RISK VARIANT IN SYSTEMIC LUPUS ERYTHEMATOSUS - ABSTRACT DYSREGULATED TYPE I INTERFERON (IFN I) HAS BEEN ASSOCIATED WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE). BOTH VIRAL INFECTIONS AND DETRIMENTAL SELF-RNA SENSING HAVE BEEN IMPLICATED IN DRIVING THE DYSREGULATED INFLAMMATION ASSOCIATED WITH SLE. HOWEVER, WE LACK A COMPREHENSIVE UNDERSTANDING OF THE MECHANISMS INVOLVED IN DISTINGUISHING SELF- VERSUS NON-SELF RNA AND HOW ALTERED CELLULAR RESPONSES TO SELF-RNA MIGHT PROMOTE AUTOIMMUNITY. NUMEROUS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) WITHIN THE INNATE IMMUNE SIGNALING PATHWAY HAVE BEEN ASSOCIATED WITH SLE PATHOGENESIS. ONE SNP, RS1990760, IS IN INTERFERON-INDUCED HELICASE C DOMAIN- CONTAINING PROTEIN 1 (IFIH1), AND RESULTS IN AN ALANINE TO THREONINE SUBSTITUTION AT AMINO ACID 946 (A946T), WHICH HAS BEEN ASSOCIATED WITH SLE AND IDENTIFIED AS A CRITICAL ALLELE TO DISEASE PATHOGENESIS. OUR PREVIOUS WORK REVEALED THAT HEALTHY INDIVIDUALS EXPRESSING THIS IFIH1 RISK VARIANT (IFIH1T946) EXHIBITED A BASAL INTERFERON- STIMULATED GENE (ISG) SIGNATURE, WHICH WAS RECAPITULATED IN AN IFIH1T946 (IFIH1R) KNOCK-IN MOUSE MODEL. IN AN INDUCED SLE MURINE MODEL, IFIH1R MICE DISPLAYED PERSISTENT ELEVATED ANTI-NUCLEAR AUTOANTIBODIES LINKING THIS TO THE LOW GRADE INTERFERONOPATHY. HOWEVER, THE CELLULAR AND MOLECULAR MECHANISMS BY WHICH IFIH1R PROMOTES SLE REMAIN UNDEFINED. HEREIN, WE WILL FOCUS ON THREE AIMS: 1) EXAMINING HOW IFIH1R ENHANCES INFLAMMATION, 2) DETERMINING IF IFIH1R PROMOTES SLE PATHOGENESIS IN A MURINE MODEL, AND 3) DETERMINING HOW HUMAN IFIH1R ALTERS THE IFN SIGNATURE AND IMMUNE CELL EFFECTOR FUNCTIONS IN HEALTHY INDIVIDUALS AND IN SLE PATIENTS. DATA GENERATED FROM THIS APPLICATION WILL GIVE UNDERSTANDING INTO THE MECHANISMS THAT DRIVE INFLAMMATION THAT PROMOTES SLE PATHOGENESIS, WHICH WILL HELP STRATIFY PATIENTS AND STEER THERAPEUTIC STRATEGIES STEMMING FROM CELLULAR PATHWAYS IN SLE PATHOGENESIS.

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.

93.859 - Biomedical Research and Research Training

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

National Institute of General Medical Sciences (NIGMS) [HHS - NIH]

Oklahoma United States

State-Wide

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

Amendment Since initial award the total obligations have increased 347% from $700,000 to $3,130,679.