# Genetic and Environmental Regulation of Diaphragm Development and Congenital Diaphragmatic Hernias

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $471,238

## Abstract

The diaphragm is an essential mammalian skeletal muscle, as it is vital for respiration and serves as a barrier
between the thoracic and abdominal cavities. Defects in diaphragm development are the cause of congenital
diaphragmatic hernias (CDHs), a common birth defect (1:3000 births) that results in severe morbidity and 50%
mortality. Given the diaphragm's functional importance and the frequency and severity of CDH, an
understanding of diaphragm development normally and during herniation is critical. Using mouse genetics, we
definitively established that the pleuroperitoneal folds, transient embryonic structures, and the muscle
connective tissue fibroblasts derived from them critically regulate development of the diaphragm muscle
(Merrell et al. 2015). Furthermore, we showed that mutations in Gata4 in these fibroblasts cause CDH.
Although conditional Gata4 mouse mutants have been critical for dissecting the role of PPFs and Gata4 in
CDH, they are not representative of the genetic and phenotypic characteristics of CDH. We have identified and
created new hypomorphic alleles of Gata4 that faithfully recapitulate both the genotypic and phenotypic
characteristics of human CDH. Based on preliminary data with these new Gata4 alleles, we will test the
hypothesis that Gata4 regulates in a dose-dependent manner development of development of the diaphragm
and CDH. Genetic and environmental disruptions in retinoic acid (RA) signaling have also been proposed to be
an important source of CDH. Using a series of mouse genetic alleles and protocols for modulating maternal
vitamin A, we will explicitly test a role for RA and as well as RA and Gata4 interactions in diaphragm
development and CDH. Our research will provide insights into the multifaceted genetic, molecular, cellular, and
environmental mechanisms underlying the etiology of CDH and its phenotypic and clinical variability.

## Key facts

- **NIH application ID:** 10811627
- **Project number:** 5R01HD104317-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Gabrielle Kardon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $471,238
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10811627

## Citation

> US National Institutes of Health, RePORTER application 10811627, Genetic and Environmental Regulation of Diaphragm Development and Congenital Diaphragmatic Hernias (5R01HD104317-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10811627. Licensed CC0.

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