R01AI153246

ZBP1 Activation - Project Summary/Abstract

The putative nucleotide sensor ZBP1 can trigger necroptotic cell death or transcriptional responses, and genetic studies indicate that this pathway is required for host defense against an array of viral pathogens. Furthermore, recent studies show that in some circumstances ZBP1 can become activated under sterile conditions, implicating endogenous cellular products as potential ZBP1 ligands. However, despite long study, the ligand responsible for activating ZBP1 and its interplay with other components of the nucleotide sensing machinery remain controversial, with double-stranded RNA, ribonucleoprotein, and viral Z-form nucleic acid species all suggested as ligands.

ZBP1 shares its key nucleotide sensing domain with only one other mammalian protein, ADAR1. ADAR1 inactivates endogenous dsRNA species to limit autoinflammatory pathology, and mutations in ADAR1 in human patients lead to the severe autoimmune disease Aicardi-Goutières Syndrome (AGS). We hypothesize that ADAR1 and ZBP1 compete for a common endogenous ligand, whose inactivation by ADAR1 is required to limit ZBP1 activation. In support of this idea, the pathology observed in a newly-developed mouse model of human ADAR1 mutation was fully rescued by ablation of ZBP1. This finding supports our hypothesis and also implies that autoimmune pathology associated with loss of ADAR1 function is caused by activation of ZBP1-dependent inflammation and cell death.

Using these observations as a starting point, the work proposed here will investigate ZBP1 activation and function by pursuing three aims:

First, we will use ADAR1 mutation and additional new mouse models to facilitate isolation and identification of an endogenous ZBP1 ligand.

Second, we will assess the contribution of necroptosis as well as ZBP1-mediated inflammatory signaling to the pathology of an animal model of human AGS triggered by ADAR1 mutation, and test the ability of necroptosis inhibitors to ameliorate this pathology.

Third, we will investigate the role of other dsRNA sensors, including MDA5 and PKR, in ZBP1 ligand formation and necroptotic pathway activation.

Together, this work will both reveal key aspects of ZBP1 function and identify ZBP1-dependent necroptosis as a potentially treatable target to ameliorate AGS.

University Of Washington

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]

Washington 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 411% from $616,492 to $3,147,333.