# Development of the Diaphragm and Congenital Diaphragmatic Hernias (CDH)

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $314,363

## 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. Development of the diaphragm requires the integration of
multiple tissues that derive from several embryonic sources. 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. Recently, 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 these fibroblasts cause CDH. However,
the molecular signals from the fibroblasts that regulate muscle development normally and are defective in CDH
are not yet known. Based on preliminary studies, we hypothesize that connective tissue fibroblasts are an
important source of secreted signals that recruit muscle progenitors into the developing diaphragm; regulate
muscle morphogenesis; and are mis-regulated in CDH. In addition, our mouse studies (Merrell et al. 2015)
suggest the novel hypothesis that somatic mosaic mutations in connective tissue fibroblasts are critical for the
etiology of CDH – a hypothesis that may explain the genetic complexity and phenotypic variability of CDH. We
propose to use mouse genetic studies and CDH patient samples to test these hypotheses. Our research will
elucidate the genetic, molecular, and cellular mechanisms regulating the development of the diaphragm and
CDH and provide important insights into potential therapeutic targets to treat CDH.

## Key facts

- **NIH application ID:** 9923458
- **Project number:** 5R01HD087360-05
- **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:** 2020
- **Award amount:** $314,363
- **Award type:** 5
- **Project period:** 2016-08-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923458

## Citation

> US National Institutes of Health, RePORTER application 9923458, Development of the Diaphragm and Congenital Diaphragmatic Hernias (CDH) (5R01HD087360-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9923458. Licensed CC0.

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