# ADAR mediated RNA editing is a causal mechanism in coronary artery disease

> **NIH NIH K08** · STANFORD UNIVERSITY · 2024 · $165,996

## Abstract

PROJECT SUMMARY/ABSTRACT
 Coronary artery disease (CAD) is the leading cause of death worldwide and there remains a crucial need to
discover mechanisms of disease and develop new therapies. Leveraging the power of human genetics and
mechanistic discovery, we are poised to understand causal mechanisms of disease and design critical
therapies. Although there are more than 160 genetic loci discovered which are associated with CAD, outside of
lipid lowering therapies, the promise of these genome wide association studies (GWAS) to identify causal
genes and result in novel mechanisms for treatment has not been fulfilled.
 Recent discoveries have revealed that RNA editing is a fundamental mechanism of inflammation
and disease, a process mediated by ADAR enzymes. In a groundbreaking discovery now accepted in Nature,
the lab of the applicant’s co-mentor, Dr. Jin Billy Li, has discovered that common genetic variation which
decreases RNA editing powerfully increases CAD risk. Preliminary data implicates RNA editing in vascular
smooth muscle cells (SMCs) to have a causal role in CAD. In this proposal, the applicant aims to
elucidate the fundamental mechanisms of ADAR mediated RNA editing, and the potential for targeting the
pivotal downstream double stranded RNA (dsRNA) sensor, MDA5 (encoded by IFIH1), as treatment in CAD.
 Vascular inflammation has long been implicated in the onset and progression of atherosclerosis, but the
specific disease modifying targets remain elusive. Pivotal studies have discovered that endogenous dsRNA is
formed in normal RNA transcription and undergoes RNA editing by ADAR1. If insufficiently edited, dsRNA will
activate a powerful interferon stimulated gene (ISG) response through MDA5 (IFIH1). Common genetic
variation can modify RNA editing frequency — ‘editing-QTLs’ (edQTL) — where edQTLs are not only predictive
of CAD risk, but also other autoinflammatory disorders including lupus and inflammatory bowel disorders.
 In this proposal, the applicant hypothesizes that the ADAR-MDA5 axis plays an important role in the onset
of CAD and that MDA5 is an ideal therapeutic target. However, there is a critical gap in knowledge, and it is
unknown if deficient RNA editing in SMCs accelerates the development of atherosclerosis, and it is imperative
that the ADAR-MDA5 axis is investigated to reveal its potential for therapeutic innovation.
 To address this, the applicant has bred a novel SMC lineage traced atherosclerosis mouse model with
conditional SMC deletion of Adar with and without Ifih1 deletion. Through a one-of-a-kind biobank of primary
HCASMCs, the applicant will further characterize the effect of MDA5 activation from decreased RNA editing.
Further, the applicant will discover the key genes downstream of MDA5 activation through a cutting-edge
genomics approach using epigenetic editing and single cell RNA sequencing (perturb-seq). This work will
advance the applicant’s training and enable the applicant to gain skill sets in bioinformat...

## Key facts

- **NIH application ID:** 10896909
- **Project number:** 5K08HL167699-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Chad S Weldy
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $165,996
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896909

## Citation

> US National Institutes of Health, RePORTER application 10896909, ADAR mediated RNA editing is a causal mechanism in coronary artery disease (5K08HL167699-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10896909. Licensed CC0.

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