# The Roles of Neural Crest Derived Cardiomyocytes in Adult-Onset Heart Failure and Regeneration

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $555,339

## Abstract

Project Summary
Adult-onset cardiomyopathies and heart failure are significant health and economic burdens throughout the
world, with prevalence projected to increase by 46% by 2030. However, there is a paucity of animal models in
which to test the etiologies and possible interventions in adult heart failure. This project has created two novel
models of adult-onset cardiomyopathy and heart failure in zebrafish. The first model utilizes intersectional
double transgenics to exclusively label Neural Crest derived Cardiomyocytes (NC-Cms), a small group of
cardiomyocytes that are stereotypically positioned in ventricles, are required for normal patterning of
trabeculae, and persist throughout adult life. Our double transgenics allow exclusive ablation of NC-Cm
lineages at any stage of life; ablation during embryogenesis results in adult-onset cardiomyopathy and heart
failure in exercise stress tests. The Notch pathway ligand jag2b is enriched in NC-Cms. Notch signaling is
activated in adjacent mesoderm-derived cardiomyocytes, not in NC-Cms. These important molecular
distinctions between cardiomyocyte lineages led to the second model, genetic mutants of jag2b, which have
both embryonic trabeculation patterning defects and adult-onset cardiomyopathy.
In contrast to zebrafish, adult mammals have evolutionarily lost the ability to regenerate hearts upon injury and
apparently lack NC-Cms, lost either evolutionarily or developmentally. Synergistic analysis of these
evolutionary distinctions between zebrafish and mammals will be informative. In response to ventricle
resection, adult zebrafish lacking NC-Cms fail to regenerate normal hearts, implicating NC-Cms and their
gene regulatory networks (GRNs) in adult heart regeneration. A multifaceted series of transgenic experiments
will test the regeneration requirements of embryonically-derived NC-Cm lineages and de novo activation of
NC-Cm GRNs in resected hearts. These results might lead to pathway interventions that can rescue the ability
to regenerate in adult mammalian hearts.
The proposed research uses two novel zebrafish models and a wide variety of tools, including lineage and
temporally regulated transgenics, mutants, cardiac physiological, cutting-edge imaging and molecular
approaches to understand the etiologies of adult-onset cardiomyopathy, heart failure and cardiac regeneration
in zebrafish. This research will discover developmental mechanisms and GRNs that make NC-Cms distinct
from their neighboring ventricle cardiomyocytes, and that are required to prevent adult-onset cardiomyopathy
and facilitate adult heart regeneration. Our goals are to position these zebrafish models to test pharmacological
and other interventions in order to contribute to our understanding and treatments of human heart diseases.

## Key facts

- **NIH application ID:** 9885996
- **Project number:** 1R01HL146854-01A1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** H. Joseph Yost
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $555,339
- **Award type:** 1
- **Project period:** 2020-02-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9885996

## Citation

> US National Institutes of Health, RePORTER application 9885996, The Roles of Neural Crest Derived Cardiomyocytes in Adult-Onset Heart Failure and Regeneration (1R01HL146854-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9885996. Licensed CC0.

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