# The molecular basis of cardiac differentiation control

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2022 · $574,504

## Abstract

Congenital Heart Disease (CHD) is the most common class of life-threatening birth defect.
Whereas hundreds of genes have been implicated in CHD, the mechanistic basis of abnormal
cardiac morphogenesis causing CHD is unknown in almost all cases. Our work on Hedgehog
signaling and CHD over the last decade has culminated in the novel hypothesis that loss of
Hedgehog signaling causes a failure of stereotypical control of cardiac progenitor differentiation
timing as an underlying cause of CHD. This work may highlight molecular control of differentiation
timing as a cornerstone of cardiac development with defects in differentiation timing as a
candidate mechanism underlying CHD etiology.
 This proposal is formed from a decade of study of the molecular mechanisms underlying
Atrioventricular septal defects (AVSDs). AVSDs are a serious form of CHD in humans, comprising
5-10% of all CHD and a greater proportion of cases with significant morbidity and mortality1. We
have previously contributed to a paradigm shift in the understanding of AV septation,
demonstrating that cilia-based Hedgehog (Hh) signaling is required in second heart field (SHF)
cardiac progenitors, rather than in the heart itself, for AV septation. Our laboratory has implicated
cilia, Hedgehog signaling, and cardiogenic transcription factors in the SHF for AV septation. In
preliminary results, our recent work demonstrates that Hh signaling controls SHF progenitor
differentiation delay and that removal of Hh signaling causes precocious cardiac differentiation.
 In this proposal we harness this novel paradigm for cardiac differentiation control to address
the genetic and molecular mechanisms underlying cardiac morphogenesis. In Specific Aim 1, we
directly interrogate the relationship between cardiac differentiation and cardiac morphogenesis to
determine the relationship between Hh signaling, cardiac progenitor differentiation control, and
cardiac morphogenesis. In Specific Aim 2, we will investigate the Forkhead box transcription
factor gene Foxf1 as a Hh-target gene and candidate mediator of SHF differentiation delay; and
in Specific Aim 3, we will identify the diversity of developmental lineages in the SHF and in which
lineages Hh signaling acts as a differentiation control switch. If successful, these aims will
contribute to a mechanistic understanding of AVSDs and support a novel paradigm for Hh
signaling control of differentiation timing.
!

## Key facts

- **NIH application ID:** 10460174
- **Project number:** 5R01HL147571-04
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Ivan Paul Moskowitz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $574,504
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10460174

## Citation

> US National Institutes of Health, RePORTER application 10460174, The molecular basis of cardiac differentiation control (5R01HL147571-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10460174. Licensed CC0.

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