# Molecular control of cardiac regenerative potential

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $403,750

## Abstract

Project Summary/Abstract
Most adult mammalian tissues and organs have very limited regenerative potential. In patients with a heart
attack, the death and loss of heart muscle cells is irreversible and often results in permanent scarring and
potentially life-threatening arrhythmias. In contrast, neonatal mice and adult zebrafish are able to rapidly
regenerate their hearts. Genetic lineage-tracing experiments have revealed proliferation of pre-existing
cardiomyocytes as the dominant mechanism to generate new muscle cells. However shortly after birth, the
majority of cardiomyocytes in most mammalian species undergoes a last round of DNA replication without
cytokinesis, become binucleated, and withdraw from the cell cycle. What physiological signals trigger
mammalian cardiomyocyte perinatal binucleation and cell cycle arrest, and how these stimuli are differentially
regulated in animals with distinct cardiac regenerative potentials are among the most long-standing questions in
cardiomyocyte biology. Our preliminary observations from comparative analyses of cardiomyocytes across
phylogeny, in vivo chemical screens of candidate pathways, together with functional studies in both mice and
zebrafish suggest a critical role of the perinatal changes of endocrine systems in driving cardiomyocyte
proliferative and regenerative potential loss in the mammalian heart. In this proposal, we plan to combine a
novel cardiomyocyte quantification assay with state-of-art genetic tools to investigate the functions of nuclear
hormone receptor activation in regulating cardiomyocyte proliferation during postnatal growth (Aim 1) and heart
regeneration following myocardial injury (Aim 2). In addition, we will examine the underpinning cellular and
molecular basis, and determine the function of novel downstream target genes in cardiomyocyte cell cycle
control through gain- and loss-of-function approaches (Aim 3). Successful completion of the proposed work will
thus reveal mechanisms underlying the loss of cardiomyocyte regenerative potential in ontogeny and
phylogeny.

## Key facts

- **NIH application ID:** 10073348
- **Project number:** 5R01HL138456-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Guo Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $403,750
- **Award type:** 5
- **Project period:** 2017-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073348

## Citation

> US National Institutes of Health, RePORTER application 10073348, Molecular control of cardiac regenerative potential (5R01HL138456-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10073348. Licensed CC0.

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