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Elucidating the Mechanisms and Roles of RNA Editing and Sensing

Award Number: R35GM162298
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/06/2026
PERIOD OF PERFORMANCE END DATE: 12/31/2030

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Elucidating the Mechanisms and Roles of RNA Editing and Sensing - PROJECT SUMMARY My research program over the next five years is focused on the regulation and functions of RNA editing and sensing to advance our understanding of RNA-mediated immune regulation, a relatively new field with emerging roles in human immune diseases. ADAR1-mediated Adenosine-to-Inosine (A-to-I) RNA editing is one the most abundant RNA modifications/edits found in humans. The key function of ADAR1 editing is to label endogenous double-stranded RNAs (dsRNAs) as “self” to evade unwanted recognition by dsRNA sensor MDA5 as “non-self”. Loss of ADAR1 editing leads to accumulation of unedited dsRNAs in the cells, which eventually activate MDA5-mediated interferon (IFN) immune response. This unwanted “self-sensing” of endogenous dsRNAs causes rare autoimmune diseases in humans and embryonic lethality in mice. My recent research revealed that insufficient RNA editing can be caused by common genetic variants located in or nearby the dsRNAs, even in the presence of fully functional ADAR1. Surprisingly, a large number of these genetic variants were also found as risk variants in multiple human immune diseases. My analysis showed that, these risk variants collectively reduce RNA editing levels of immunogenic dsRNAs to increase cellular “dsRNA burden” in disease samples, which was coupled with elevated IFN immune responses, presumably through activating MDA5-mediated RNA sensing. While my research uncovered a previously unknown function of RNA editing and sensing in common immune diseases, it remains unclear how RNA editing neutralizes the immunogenicity of various endogenous dsRNA species and how erroneous RNA sensing leads to inflammation and immune diseases. Built on my previous findings, we aim to address these questions by developing new tools to uncover the regulatory mechanisms underlying RNA editing and sensing. On one hand, we have been developing tiling base- editor screens to identify functional protein domains and residues of ADAR1. Using changes in RNA editing and cellular immune responses as the functional readout, we aim to uncover essential functional domains of ADAR1 with their associated endogenous dsRNA species and downstream dsRNA sensors. This functional genomics approach will not only help dissect the multifaceted roles of ADAR1 in immune regulation, but also uncover new functions of ADAR1, hidden immunogenic dsRNA species, and previous unknown dsRNA sensors. On the other hand, we are actively developing novel imaging and sequencing methods to specifically detect RNA sensing activities in cells and tissues. We will utilize post-translational modifications (PTMs) and/or protein- protein interactions unique to the activation of each RNA sensors to guide our assay design, so that we can distinguish between different RNA sensing pathways while still capture any potential synergistic effects. In the long-term, we aim to apply our methods to patient-derived tissues, hoping to uncover the incorrectly activated RNA sensing pathways in patients and the relevant cell types that together contribute to immune diseases. By integrating functional genomics, transcriptomic analysis, and immune profiling, this program aims to bridge the gap of knowledge in RNA editing and sensing. While we focus on elucidating the fundamental mechanisms regulating RNA-mediated immune regulation, our findings will also pave the route for developing novel therapies targeting at RNA editing and sensing pathways to treat cancer and immune disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $446,875 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	4/2/2026	NEW	$446,875
														Subtotal = $446,875

Grand Total All Awards = $446,875

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Elucidating the Mechanisms and Roles of RNA Editing and Sensing

Award Number: R35GM162298

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/06/2026

PERIOD OF PERFORMANCE END DATE: 12/31/2030

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