R01AI168299

Unraveling the Molecular Mechanisms of Impaired Central Tolerance in COPA Syndrome - Project Summary:

Our lab discovered COPA syndrome, a monogenic autoimmune disorder that involves inflammation of the lungs, joints, and kidneys. We established a mouse model of COPA syndrome by generating COPAE241K/+ knock-in mice that spontaneously developed clinical and immunologic features of patients, including interstitial lung disease (ILD) and increased levels of activated, cytokine-secreting T cells.

We performed bone marrow chimera and thymic transplant experiments to reveal that expression of mutant COPA in the thymic stroma is sufficient to cause a defect in negative selection of CD4+ T cells. Our work revealed that a key step in the initiation of disease in COPA syndrome is a breakdown in central tolerance. The goal of this grant is to unravel the mechanisms by which mutant COPA causes impaired thymic tolerance.

COPA syndrome presents in childhood with inflammatory arthritis of the small and large joints and lung disease that manifests as pulmonary capillaritis or ILD. Patients develop clinical features that are observed in systemic lupus erythematosus (SLE), including high-titer anti-nuclear antibodies, autoantibodies to double-stranded DNA, and immune complex glomerulonephritis. In addition, peripheral blood mononuclear cells from all COPA syndrome subjects exhibit a markedly elevated type I interferon stimulated gene signature, a hallmark of SLE.

We recently demonstrated that activation of type I interferon (IFN) signaling in COPA syndrome is caused by constitutive activation of the innate immune adapter molecule STING, which is missorted at the Golgi by mutant COPA. Mutant COPA-mediated STING activation upregulates IFNs in immune cells of COPAE241K/+ mice, and remarkably, also within the thymic epithelium. Taken together, this suggests STING has a functional role in the thymus with the potential to alter thymocyte selection and/or development.

We hypothesize mutant COPA breaks central tolerance by causing activation of STING in thymic epithelial cells (TEC). We will use our mouse model to determine how activated STING in thymic epithelial cells alters T cell maturation and selection. We will define the cellular and molecular mechanisms by which mutant COPA impairs autophagic flux and determine whether proteins missorted by mutant COPA are involved in STING-induced autophagy. Finally, we will test whether small molecule STING agonists and inhibitors can fine-tune STING signaling in the thymus to alter thymocyte development and selection.

Taken together, our work provides new insight into how activated STING in the thymus shapes the T cell repertoire to cause autoimmunity and immune dysregulation. These findings have important implications for settings in which systemic inflammation causes activation of STING in the thymic stroma, including cancer therapy and infections.

San Francisco Regents Of The University Of California

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]

San Francisco, California 941432156 United States

Single Zip Code

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

Amendment Since initial award the total obligations have increased 379% from $690,613 to $3,307,473.