R35GM144100

Regulatory and Mechanistic Understanding of ADAR-Mediated RNA Editing - Project Summary/Abstract

The innate immunity is well-controlled to respond to pathogenic infection in a timely and sensitive manner, while tolerating "self" molecules in the cell. Defects in the regulation of innate immunity result in various disorders, such as autoimmune diseases or heightened vulnerability to infections.

Previous studies by us and others revealed ADAR1, an RNA editing enzyme that catalyzes adenosine to inosine (A-to-I) editing on dsRNAs, as a key player in the regulation of innate immune response to double-stranded RNAs (dsRNAs). ADAR1 RNA editing and binding activities have been shown to prevent endogenous ("self") dsRNAs from activating the cytosolic dsRNA sensors MDA5 and PKR, but the underlying molecular mechanisms are not well understood.

In addition, the cytoplasmic editing of at least some dsRNAs by the ADAR1 p150 isoform is crucial to suppress the dsRNA-mediated autoimmunity, although the ADAR1 p110 isoform in the nucleus is generally a lot more abundant. How are these dsRNAs edited in the cytoplasm but not in the nucleus?

In this MIRA application, we focus on two projects to address these knowledge gaps. First, we will elucidate the interplay between ADAR1 and other players in the dsRNA innate immunity pathways. Specifically, we will investigate the mechanisms by which ADAR1 regulates the MDA5 and PKR pathways of dsRNA sensing. We propose that ADAR1 regulates dsRNA-mediated innate immunity in both RNA editing-dependent and -independent fashion. We will study how these two modes of action operate in vitro and test their in vivo implications in mouse models.

Second, we will uncover the regulatory mechanisms for cytoplasmic vs. nuclear editing. Specifically, we will perform genetic screens and biochemical assays to identify and characterize the factors responsible for spatial differences in editing.

Taken together, these innovative studies will provide a deep understanding of the molecular mechanisms operating at the interface of dsRNA editing and dsRNA sensing in innate immunity.

The Leland Stanford Junior University

THE NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES (NIGMS) SUPPORTS BASIC RESEARCH THAT INCREASES OUR UNDERSTANDING OF BIOLOGICAL PROCESSES AND LAYS THE FOUNDATION FOR ADVANCES IN DISEASE DIAGNOSIS, TREATMENT, AND PREVENTION. NIGMS ALSO SUPPORTS RESEARCH IN SPECIFIC CLINICAL AREAS THAT AFFECT MULTIPLE ORGAN SYSTEMS: ANESTHESIOLOGY AND PERI-OPERATIVE PAIN; CLINICAL PHARMACOLOGY COMMON TO MULTIPLE DRUGS AND TREATMENTS; AND INJURY, CRITICAL ILLNESS, SEPSIS, AND WOUND HEALING. NIGMS-FUNDED SCIENTISTS INVESTIGATE HOW LIVING SYSTEMS WORK AT A RANGE OF LEVELSFROM MOLECULES AND CELLS TO TISSUES AND ORGANSIN RESEARCH ORGANISMS, HUMANS, AND POPULATIONS. ADDITIONALLY, TO ENSURE THE VITALITY AND CONTINUED PRODUCTIVITY OF THE RESEARCH ENTERPRISE, NIGMS PROVIDES LEADERSHIP IN SUPPORTING THE TRAINING OF FUTURE SCIENTISTS AND DEVELOPING RESEARCH CAPACITY THROUGHOUT THE COUNTRY.

93.859 - Biomedical Research and Research Training

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

Stanford, California 94305 United States

Single Zip Code

Maximizing Investigators' Research Award (R35 - Clinical Trial Optional) (PAR-19-367)

Amendment Since initial award the total obligations have increased 435% from $599,240 to $3,207,836.