R01AI187291

ROLE OF UBIQUITIN LIGASES AND DEUBIQUITINASES IN HOST DEFENSE AGAINST MYCOBACTERIUM TUBERCULOSIS - PROJECT SUMMARY ONE MECHANISM THAT IS CENTRAL TO INNATE IMMUNITY AGAINST INTRACELLULAR PATHOGENS SUCH AS MYCOBACTERIUM TUBERCULOSIS (MTB) IS ENGAGEMENT AND TARGETING OF BACTERIA FOR DEGRADATION BY THE CELLULAR UBIQUITINATION MACHINERY, A PROCESS THAT ALSO DIRECTLY IMPACTS IMMUNE RESPONSES. UBIQUITIN LIGASES EXPRESSED BY HOST INNATE IMMUNE CELLS ATTACH THE PROTEIN UBIQUITIN TO INTRACELLULAR PATHOGENS OR THE ORGANELLES CONTAINING THEM, AND SUCH UBIQUITINATION EVENTS THEN TRIGGER RECRUITMENT OF THE HOST AUTOPHAGY-LYSOSOMAL DEGRADATION MACHINERY TO ENGULF AND DESTROY THE INVADING PATHOGEN. UBIQUITIN LIGASES SUCH AS SMURF1 AND PARKIN TAG MTB-CONTAINING STRUCTURES FOR AUTOPHAGIC DEGRADATION IN A PROCESS TERMED XENOPHAGY. CONVERSELY, HOST DEUBIQUITINATING ENZYMES (DUBS) MAY REMOVE THESE UBIQUITIN TAGS, POTENTIALLY AIDING THE PATHOGEN'S SURVIVAL. A MAJOR GAP IN OUR UNDERSTANDING OF THE CELLULAR MECHANISMS OF XENOPHAGY IS THAT WE DO NOT HAVE A COMPLETE UNDERSTANDING OF THE MECHANISMS OF UBIQUITIN ATTACHMENT AND REMOVAL FROM MTB, AND WE HYPOTHESIZE THAT THE EXTENT OF MTB UBIQUITINATION, MEDIATED BY THE RELATIVE BALANCE BETWEEN THE ACTIVITIES OF UBIQUITIN LIGASES AND DEUBIQUITINASES, DIRECTLY IMPACTS THE OUTCOME OF MTB INFECTION. BRIDGING THE KNOWLEDGE GAP AROUND THE ROLES OF INDIVIDUAL UBIQUITIN LIGASES AND DUBS MAY YIELD NOVEL STRATEGIES FOR HOST-DIRECTED THERAPIES, CRUCIAL IN THE CURRENT CLIMATE OF GROWING ANTIBIOTIC RESISTANCE. HERE, WE WILL APPLY GENETIC, BIOCHEMICAL, IMMUNOLOGIC, TRANSCRIPTOMIC AND ANIMAL APPROACHES TO DETERMINE THE FUNCTIONAL ROLE OF SPECIFIC UBIQUITINATION AND DEUBIQUITINATION MECHANISMS IN THE CONTEXT OF MTB INFECTION. THUS, IN THE PROPOSED RESEARCH WE WILL: (1) ELUCIDATE THE ROLE OF UBIQUITIN LIGASES SMURF1 AND SMURF2 IN TARGETING MTB FOR AUTOPHAGY AND HOW THEY REGULATE INTERFERON-Β PRODUCTION DURING INFECTION. (2) DELINEATE THE ROLES OF K63 AND K48 DEUBIQUITINATION DURING MACROPHAGE INFECTION, FOCUSING ON THE K63-SPECIFIC DUB USP15 AND THE YET UNIDENTIFIED DUBS RESPONSIBLE FOR K48 DEUBIQUITINATION, CRITICAL STEPS THAT NEGATIVELY REGULATE AUTOPHAGY. (3) DETERMINE THE FUNCTION OF LINEAR M1-UBIQUITINATION BY THE LUBAC SYSTEM AND ITS NEGATIVE REGULATION BY THE DUB CYLD IN CELLULAR IMMUNITY TO MTB. THE PROPOSED WORK IS EXPECTED TO IDENTIFY THE MOLECULAR MECHANISMS THAT TARGET MTB FOR DEGRADATION AND HOST PROTEINS WHOSE ACTIVITIES REGULATE PROTECTIVE IMMUNE RESPONSES.

The University Of Texas Southwestern Medical Center

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]

Texas United States

State-Wide

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