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Molecular Mechanisms of ADAR1-Driven RNA Editing in Immune Modulation

Award Number: R01AI198602
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/08/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Molecular Mechanisms of ADAR1-Driven RNA Editing in Immune Modulation - Adenosine deaminase acting on RNA (ADAR1) plays a pivotal role in regulating RNA-induced immune response. By binding to and editing various endogenous RNAs, ADAR1 can effectively neutralize their immunogenicity, thereby preventing erroneous immune activation. Genetic mutations or imbalanced expression of ADAR1 can lead to pathological immune activation, as exemplified in Aicardi–Goutières Syndrome as well as other autoimmune diseases, cancer, and neurodegeneration. Targeting ADAR1 has emerged as a promising avenue for enhancing anti-tumor immunity in cancer therapy. Furthermore, ADAR1-mediated RNA editing has been repurposed for precision RNA editing technologies for correcting disease-related mutations. However, the molecular and cellular mechanisms governing ADAR1's substrate recognition, catalysis, immunosuppression, and regulation remain poorly understood. In this proposal, we seek to dissect how ADAR1 recognizes and edits diverse immunostimulatory RNAs to modulate their structure and immune-stimulatory potential. Our central hypothesis is that ADAR1 acts in a substrate sequence- and structure-dependent manner through its multiple RNA-binding domains, and its RNA binding and editing activities have distinct and context-dependent roles in immune suppression. We will address this through three integrated aims: in Aim 1, we will define how ADAR1 engages and edits diverse immunostimulatory RNAs, including those varying in length, sequence, and secondary structures. We will use biochemical and cell-based assays, single-molecule imaging, and structural visualization to monitor ADAR1 target searching, binding, and editing of different RNAs; in Aim 2, we will delineate the mechanisms by which ADAR1 suppresses immune activation by the RNA sensors MDA5 and ZBP1, and determine whether ADAR1-mediated suppression requires editing, binding, or both; in Aim 3, we will identify and functionally characterize regulators of ADAR1 by integrating computational screening and experimental validation. Together, these studies will establish a comprehensive mechanistic framework for ADAR1-mediated RNA editing and immune regulation. The anticipated outcomes will not only advance our understanding of RNA-based immune signaling in health and disease but also enable the rational design of ADAR1-based therapeutic and biotechnological tools.


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 = $2,538,587 )
2026	2026	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Allergy and Infectious Diseases Research	000	1	7/8/2026	NEW	$2,538,587
														Subtotal = $2,538,587

Grand Total All Awards = $2,538,587

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Molecular Mechanisms of ADAR1-Driven RNA Editing in Immune Modulation

Award Number: R01AI198602

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/08/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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