R01AI167993

Regulation of Immunity by the CGAS-STING Pathway - Project Summary

The goal of this proposal is to dissect the mechanisms of self-DNA detection by the enzyme cyclic GMP-AMP synthase (CGAS), and to determine the relative contribution of its diverse signaling activities to inflammation in the microenvironment of implantable murine tumors.

CGAS operates in virtually all cell types as a DNA sensory protein, which synthesizes the second messenger cyclic GMP-AMP (cGAMP) upon binding DNA. This second messenger stimulates interferon (IFN) and inflammatory activities via the downstream protein STING.

Because CGAS detects the sugar-phosphate backbone of DNA, a major question relates to how this enzyme is regulated to ensure self-nonself discrimination. This question relates to much fundamental biology and the answer will impact the increasing number of clinical endeavors that target the CGAS-STING pathway.

The CGAS-STING pathway is oft-discussed in the context of antitumor immunity, but the activities of this pathway that are beneficial (or not) to immunity remain unclear. For example, inflammatory activities induced by CGAS-STING in the tumor microenvironment (TME) have been reported to induce protective inflammatory and cytolytic CD8+ T cells. But CGAS-STING signaling events have also been reported to promote tumor growth and disease progression.

A central idea that drives our work is that the ubiquitous presence of the CGAS-STING pathway in most cell types, along with its diverse signaling effectors (cGAMP, IFNs, cytokines), can create a complex TME prone to unpredictable outcomes (e.g. disease resolution or progression). In order to understand each activity of this pathway, new experimental tools are needed to disentangle its effector functions.

Herein, we describe new synthetic biology-based genetic circuits that can dissect the effector functions of CGAS-STING, within cancer cells specifically. Notably, these systems led to the discovery of species-specific differences in the ability of primate and murine CGAS proteins to detect self-DNA. This finding raises questions of the suitability of mice and certain primates as accurate preclinical models for CGAS-STING function, and provide a mandate to define the mechanisms and consequences of CGAS-mediated self-DNA activities.

The work in this proposal is based on the hypothesis that the cGAMP, IFNs, and cytokines induced by the CGAS-STING pathway play differential roles in tissue inflammation and immunity, and that understanding the role of each of these activities, within specific cell types, requires a detailed characterization of the mechanisms of self (and nonself) DNA detection.

To address this hypothesis, we propose to determine how distinct intra-tumoral CGAS activities influence protective T cell immunity (Aim 1). In Aim 2, we propose to determine mechanisms of self-DNA reactivity by human CGAS through comparative analysis of the human, mouse, chimpanzee, and orangutan proteins, each of which display distinct means of self-DNA reactivity.

Children's Hospital Corporation

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]

Boston, Massachusetts 021155724 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 302% from $784,885 to $3,152,902.