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.
ADAR1 is an RNA editing enzyme, mutation of which causes Aicardi-Goutieres Syndrome in humans. We have developed novel mouse models to study the mechanisms of disease and the relationship between RNA editing and innate immunity.
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