# Identification and application of regulatory elements for heart regeneration

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $750,670

## Abstract

Myocardial infarction (MI) is a common injury that causes permanent loss of hundreds of millions of cardiac
muscle cells, increasing susceptibility to heart failure and sudden death. Major goals of regenerative medicine
are methodologies to enhance cardiomyocyte recovery after MI and to restore cardiac function to heart failure
patients. Heart regeneration is limited in adult mammals, but occurs naturally in adult zebrafish and neonatal
mice through the activation of cardiomyocyte division. Whereas the research community has identified several
factors important for heart regeneration over the past decade, we still know little of the regulatory mechanisms
needed to activate regeneration programs in injured cardiac tissue. In particular, questions of whether
regulatory enhancer elements are employed, and how specific they are to regeneration, are virtually
unexplored. This is a critical deficiency, as the identification and manipulation of such elements could both
expand our understanding of regeneration and have applications in regenerative medicine. In a recent
collaboration between our groups, we found evidence for tissue regeneration enhancer elements (TREEs) that
trigger gene expression in injury sites and can be engineered to modulate the regenerative potential of
vertebrate organs including the heart. Here, we propose a multi-PI project exploiting the strengths of the
zebrafish and mouse model systems to delineate regulatory sequences that control regeneration programs,
and to create TREE-based factor delivery constructs to optimize heart regeneration in higher and lower
vertebrates. 1) We will define the cis-regulatory motifs and binding factors necessary for activity of a TREE
that is linked to the zebrafish leptin b gene. 2) We will use this TREE to define effects of enhancer-delivered
pro-regenerative factors after cardiac injury in zebrafish and mice, focusing initially on provision of mitogenic
and angiogenic molecules. 3) We will use open chromatin profiling approaches to identify new TREEs that
activate expression in endothelial and/or endocardial cell types during zebrafish heart regeneration. We will
perform sequence comparisons in mice, and we will initiate a program to generate transgenic reporter and
TREE deletion animals to test the sufficiency and requirements for these sequences in directing regeneration
programs. With these approaches, we will test the hypothesis that cardiac injury activates regeneration
enhancer elements to facilitate heart regeneration.

## Key facts

- **NIH application ID:** 9838785
- **Project number:** 5R01HL136182-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Brian L Black
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $750,670
- **Award type:** 5
- **Project period:** 2016-12-15 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838785

## Citation

> US National Institutes of Health, RePORTER application 9838785, Identification and application of regulatory elements for heart regeneration (5R01HL136182-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9838785. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*