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The ADAR1–dsRNA–MDA5 axis
We decode how ADAR1-mediated RNA editing shields the cell from its own dsRNA — and how failures in this surveillance drive inflammatory disease, neurodegeneration, and aging.
Projects
Genetic Architecture of dsRNA-Driven Inflammation
Identity and Recognition of Cellular Immunogenic dsRNAs
The ADAR1–dsRNA–MDA5 Axis in Aging and Age-Associated Disease
Dysregulated dsRNA sensing is not limited to rare monogenic disorders — it underlies the genetic risk of a broad spectrum of common inflammatory diseases. We integrate large-scale GWAS with cis-edQTL mapping across human tissues and leverage single-cell and single-nucleus RNA-seq datasets to resolve cell-type-specific editing landscapes and evaluate dsRNA-triggered interferon responses in disease-relevant cell populations. Applying this framework to chronic inflammatory diseases — including psoriasis, inflammatory bowel disease (IBD), Parkinson's disease, Alzheimer's disease, and chronic kidney disease — we aim to quantify and model the cumulative genetic burden of immunogenic dsRNA as a shared molecular driver of chronic inflammation.
Despite the central role of endogenous dsRNA in innate immune activation, the full repertoire of cellular immunogenic dsRNAs remains poorly defined. Although inverted-repeat Alu elements and cis-natural antisense transcripts have emerged as candidate immunogenic substrates, these represent only a fraction of the dsRNA structures present in the cell — a conclusion reinforced by the striking observation that ADAR1 editing-deficient mice are prenatally lethal, yet largely rescued by MDA5 knockout, implying a far broader landscape of MDA5-activating dsRNAs than currently catalogued. We are developing biochemical and biotechnological methods to systematically profile cellular dsRNAs, expand the known immunogenic dsRNA repertoire, and dissect the molecular determinants governing selective MDA5 recognition and filament assembly.
The ADAR1–dsRNA–MDA5 pathway operates across a spectrum of disease severity. At one extreme, rare loss-of-function mutations in ADAR1 or gain-of-function mutations in MDA5 (IFIH1) cause severe monogenic autoimmune syndromes such as Aicardi-Goutières syndrome, revealing the pathway's indispensable role in immune self-tolerance. At the other, we hypothesize that the gradual, age-associated erosion of ADAR1 editing fidelity drives the chronic low-grade interferon signaling characteristic of inflammaging — a state increasingly linked to neurodegenerative diseases, including Parkinson's and Alzheimer's disease. We are dissecting the molecular mechanisms by which progressive dsRNA accumulation during aging shifts the ADAR1–MDA5 axis toward sustained innate immune activation, with the goal of identifying intervention points that could mitigate age-driven inflammation.
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