# Reactivating regulatory programs for regeneration

> **NIH NIH DP2** · UNIVERSITY OF CALIFORNIA BERKELEY · 2023 · $1,344,373

## Abstract

PROJECT SUMMARY/ABSTRACT
Human cardiac injury, such as a heart attack, leads to irreparable damage and life-long heart complications.
Developing translational strategies for inducing heart repair has been limited to laboratory accessible models
such as the zebrafish and mouse. Using the zebrafish, which can regenerate their heart after substantial injury,
we have previously shown that neural crest-derived cardiomyocytes promote injury-induced proliferation of
surrounding cardiomyocytes by re-activating developmental gene networks after injury. Importantly, genetic
ablation of neural crest-derived cardiomyocytes leads to a failure of regeneration and a large scar. Now knowing
the importance of neural crest-derived cardiomyocytes and re-activating developmental networks, many
questions remained unanswered on how these networks are re-deployed after injury and if these networks
remain silenced in human hearts after injury. Our current hypothesis is that human neural crest-derived
cardiomyocytes are unable to redeploy developmental gene networks after injury and are therefore unable to
induce repair mechanisms. Until recently, assessing gene regulatory dynamics in human-derived cardiac tissues
was not possible. Now, self-assembling cardiac organoids derived from human pluripotent stem cells have
presented a new avenue for exploring cardiac repair in human-derived tissues; however, these cardioid models
do not contain cardiomyocytes derived from neural crest. Here, we propose to (i) assess the dynamic chromatin
landscapes of the regenerating zebrafish heart using single cell ATAC-seq to unravel critical components
necessary for re-activating developmental programs that control cardiac regeneration in the zebrafish, (ii)
interrogate the reactivation of developmental programs in a human-derived cardioid model after injury using a
multiomics approach, and finally, (iii) use next-generation CRISPR-based functional genomics screens to identify
gene circuits responsible for “repair impairment” of human neural crest-derived cardiomyocytes. Ultimately, our
goal is to combine gene regulatory network information from zebrafish repair circuits and our human-derived
screen to identify optimal targets for potential intervention using any relevant therapeutic modality for driving
cardiac repair in vivo post-injury.

## Key facts

- **NIH application ID:** 10687448
- **Project number:** 1DP2HL173858-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Megan Lee Martik
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,344,373
- **Award type:** 1
- **Project period:** 2023-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10687448

## Citation

> US National Institutes of Health, RePORTER application 10687448, Reactivating regulatory programs for regeneration (1DP2HL173858-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10687448. Licensed CC0.

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