# Regulatory and Mechanistic Understanding of ADAR-Mediated RNA Editing

> **NIH NIH R35** · STANFORD UNIVERSITY · 2023 · $652,149

## Abstract

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 re-
vealed 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 inves-
tigate 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 fash-
ion. 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.

## Key facts

- **NIH application ID:** 10630935
- **Project number:** 5R35GM144100-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Jin Billy Li
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $652,149
- **Award type:** 5
- **Project period:** 2022-06-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10630935

## Citation

> US National Institutes of Health, RePORTER application 10630935, Regulatory and Mechanistic Understanding of ADAR-Mediated RNA Editing (5R35GM144100-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10630935. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*