# Project 3 Genes to Omics-Informed Drugs: Drug Repositioning and Testing to Prevent AF Progressions

> **NIH NIH P01** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $608,924

## Abstract

PROJECT 3 - Genes to Omics-Informed Drugs: Drug Repositioning and Functional Testing to Prevent
AF Progression
PROJECT SUMMARY
An important clinical problem in atrial fibrillation (AF) is preventing AF from progressing to more persistent
forms. After an initial episode, AF recurs with increase in burden occurring in ~50% and progression to
persistent or permanent AF occurring in 25% within 5 years of diagnosis. Compared to paroxysmal AF,
prognosis is poorer and outcomes after medical or ablation therapy are worse for patients with persistent or
permanent AF. While many processes and pathways have been implicated in AF development and to a lesser
extent progression, the precise molecular drivers, their interactions and context in which they act are not fully
understood. Genetic risk factors for development of AF may differ from those promoting progression of AF,
which may also be impacted by environmental, comorbid or cellular stressors. We hypothesize that an
interplay between AF progression and gene regulatory and interactome networks can be identified and that
understanding these mechanisms is essential to informing therapeutic discovery for AF progression. Our goal
is to identify AF progression genes, pathways and modules that will enable identification and then validation of
repurposable drugs for the prevention of AF and AF progression. To find drugs to target progression of AF, we
must first better understand the molecular components of AF progression. This project builds upon our prior
RNA sequencing (RNASeq) data in human left atrial (LA) appendage (LAA) tissues that showed altered,
inadequate or overwhelmed transcriptomic responses to cell stress pathways occur with progression to
persistent AF. We propose to integrate single-nucleus transcriptomics (snRNASeq) in human LA tissue to
identify master transcription factor (TF)- and interactome-mediated gene regulatory networks and cell types
underlying AF disease progression, overcoming a limitation of bulk RNASeq data that cannot resolve changes
from differing cell composition, such as fibroblasts, which may increase with AF progression. snRNASeq will
yield further insights into AF progression and specific cell types related to progression. We will also use human
interactome network approaches to identify novel risk genes and disease modules that change with AF
progression. We will then integrate interactome, genetic, and AF progression genomic, proteomic and
metabolomics data using artificial intelligence (AI) approaches to identify therapeutic targets for AF progression
and repurposable drugs and drug combinations targeting AF progression. ‘Omic data from other projects in the
Program will also be integrated that may yield potential gene or pathway specific candidate drugs. Candidate
drugs and combinations will then be functionally tested in human engineered heart tissues (EHTs) and relevant
mouse models of spontaneous AF and AF progression. Our focus on identifying repurposable drugs wil...

## Key facts

- **NIH application ID:** 10896387
- **Project number:** 5P01HL158502-03
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Mina Kay Chung
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $608,924
- **Award type:** 5
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896387

## Citation

> US National Institutes of Health, RePORTER application 10896387, Project 3 Genes to Omics-Informed Drugs: Drug Repositioning and Testing to Prevent AF Progressions (5P01HL158502-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10896387. Licensed CC0.

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