# Intracellular nucleic acid detection in autoimmunity

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $610,187

## Abstract

Project Summary/Abstract
Intracellular sensors of nucleic acids are essential for host defense, but they can also cause specific human
autoimmune and autoinflammatory diseases if they are not carefully regulated. Over the past 15 years, a
paradigm has emerged in which thresholds for activation of these sensors are set by cellular enzymes that
metabolize or modify endogenous nucleic acids, thus preventing self-reactivity. The most potent of these
enzymes is ADAR1, an RNA editing enzyme that deaminates adenosines in RNA. Mutations in the human
ADAR gene that encodes ADAR1 cause Aicardi-Goutieres Syndrome, a severe disease characterized by
inappropriate production of type I interferons (IFNs). In previous work, we demonstrated that ADAR1 is an
essential and specific regulator of the MDA5-MAVS pathway of antiviral defense. However, the precise
relationships between ADAR1 RNA, MDA5 activation, and disease remain incompletely understood because of
the lack of tools to study this process in vivo. We have generated three new mouse models to advance our
understanding of ADAR1 biology and the broader regulation of the type I IFN response: a knockin mouse
model of the most common ADAR AGS allele in humans, a MDA5-HA epitope tag knockin mouse to track
MDA5 activation in live cells, and a new Ifnb knockin reporter mouse to enable screens for novel regulators of
the type I IFN response. We will use these tools to define the mechanisms that underlie ADAR1-controlled
disease in vivo, the precise relationship between ADAR1 RNA editing and MDA5 activation, and the scope of
IFN regulation in primary cells. Our studies will uncover fundamental new insights into ADAR1 biology and will
identify novel targets that can be manipulated for therapeutic benefit, with direct relevance to human disease.

## Key facts

- **NIH application ID:** 9971302
- **Project number:** 2R01AI084914-11
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Daniel B Stetson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $610,187
- **Award type:** 2
- **Project period:** 2010-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971302

## Citation

> US National Institutes of Health, RePORTER application 9971302, Intracellular nucleic acid detection in autoimmunity (2R01AI084914-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971302. Licensed CC0.

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