# Discovering cardiomyopathy modifiers and therapies via zebrafish genetics

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2022 · $513,512

## Abstract

Project Summary
 Cardiomyopathy is a disorder with high heterogeneity: >100 genes have been linked to different types
of cardiomyopathy, such as hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM); patients
with the same mutation can manifest highly variable disease onset and severity, presumably because of
different genetic and environmental factors. However, the identity of genetic modifiers remains largely
unknown. To address the need, our team has been leading the development of adult zebrafish as a vertebrate
model for cardiomyopathy. During the previous 2 funding cycles, we developed a novel forward genetic
screening strategy for discovering modifier genes for doxorubicin (DOX)–induced cardiomyopathy (DIC). Here,
we plan to extend this approach to inherited cardiomyopathies. We have generated substantial preliminary
data to prove the feasibility of the proposal, including the identification of 5 original DIC modifier genes and 4
additional candidate DIC modifier genes, the generation of a zebrafish model of BAG3 cardiomyopathy, the
identification of mtor as a therapeutic modifier gene, and the establishment of an embryonic fish-adult fish-
mouse drug assessment platform. Together, these data prompted us to test the central hypothesis of this
proposal, which predicts that modifier genes for an inherited cardiomyopathy model can be identified via a
forward genetic strategy in zebrafish, from which therapeutic target genes and related compounds can be
rapidly discovered by efficient zebrafish genetics. The proposal is organized into 2 specific aims. In Specific
Aim 1, we will test the hypothesis that a forward genetics-based approach is extendable to bag3
cardiomyopathy to identify therapeutic modifiers. We will determine phenotypic progression and variation in
zebrafish bag3 KO, assess modifying effects of 9 DIC modifiers on bag3 cardiomyopathies, and then identify
therapeutic modifiers for bag3 cardiomyopathy. We will elucidate underlying mechanism by transcriptome
analysis. In Specific Aim 2, we will elucidate underlying mechanisms of the therapeutic effects of mTOR
inhibition, prove autophagy-based therapy for bag3 cardiomyopathy, and repurpose FDA-approved autophagy-
activating drugs to treat bag3 cardiomyopathy. It is anticipated that the novel strategy developed by this
proposal will significantly advance prognostic test development, risk stratification, and personalized therapy for
cardiomyopathies.

## Key facts

- **NIH application ID:** 10397635
- **Project number:** 5R01HL107304-11
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Xiaolei Xu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $513,512
- **Award type:** 5
- **Project period:** 2011-04-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397635

## Citation

> US National Institutes of Health, RePORTER application 10397635, Discovering cardiomyopathy modifiers and therapies via zebrafish genetics (5R01HL107304-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10397635. Licensed CC0.

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