# Morphogenesis and growth of the ventricular wall in development and disease

> **NIH NIH P01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $2,741,575

## Abstract

ABSTRACT
Congenital heart defects (CHDs) are the most commonly encountered birth defect. Despite its prevalence, the
underlying molecular etiology of most CHDs is not yet known. The central theme of this Program Project Grant
application is to elucidate mechanisms that regulate growth and morphogenesis of the ventricle during
development. Our objectives are to better understand how epigenetic, transcriptional, and cell signaling
regulation within cardiac progenitor cells (CPCs) and embryonic cardiomyocytes impact cardiac specification,
differentiation, and ventricular morphogenesis. Four highly interactive and complementary Projects are
proposed. Project 1 will study the molecular mechanisms contributing to the genesis of CHDs in early CPCs.
These studies build on work from Dr. Stephanie Ware’s laboratory and will test the overall hypothesis that severe
CHDs encountered in patients with ZIC3 X-linked heterotaxy result from abnormalities in cardiac progenitor cell
fate. Such mechanisms would explain why the spectrum of CHDs encountered in these patients is more severe
than what would be anticipated as a result of altered sidedness. Project 2 will study the epigenetic mechanisms
regulating the bHLH transcription factor HAND1, which is critical for left ventricular, papillary muscle, and cardiac
conduction system (CCS) morphogenesis. These studies build on work from Dr. Anthony Firulli’s laboratory and
will test the overall hypothesis that epigenetic regulation of HAND1 transcription directs normal cardiomyocyte
patterning. Other studies will identify HAND1 DNA occupancy and interacting transcriptional partners, and thus
establish the gene regulatory networks regulating left ventricle, papillary muscle, and CCS morphogenesis.
Project 3 will study epigenetic mechanisms critical to mesendoderm specification and cardiogenic differentiation.
These studies build on work from Dr. Weinian Shou’s laboratory and will test the overall hypothesis that the
lysine methyltransferase SMYD4 regulates Histone modifications essential for establishing correct numbers of
CPCs. Project 4 will study the role of a novel planar cell polarity effector protein, SHROOM3, in the pathogenesis
of CHDs. These studies build on work from Dr. Matthew Durbin’s laboratory and will test the overall hypothesis
that SHROOM3 interacts at a number of key points within the PCP pathway, and that identified rare CHD patient-
specific SHROOM3 variants disrupt PCP within cardiomyocytes. The proposed work will be facilitated by the
participation of three cores (Core A – Administration; Core B - Embryonic stem cell growth and genetically
modified models; and Core C - Cardiac physiology and imaging). Ultimately, the studies proposed in this Program
Project Grant application will illustrate how epigenetic, transcriptional, and signaling mechanisms occurring within
both cardiac progenitors and embryonic cardiomyocytes establish the gene regulatory networks necessary for
cardiac morphogenesis. Import...

## Key facts

- **NIH application ID:** 10755273
- **Project number:** 5P01HL134599-07
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Anthony B. Firulli
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,741,575
- **Award type:** 5
- **Project period:** 2017-02-15 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10755273

## Citation

> US National Institutes of Health, RePORTER application 10755273, Morphogenesis and growth of the ventricular wall in development and disease (5P01HL134599-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10755273. Licensed CC0.

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