# GENETIC AND DEVELOPMENTAL MECHANISMS OF CONGENITAL DIAPHRAGMATIC HERNIA

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $395,607

## Abstract

PROJECT SUMMARY
Normal development of the lungs and pulmonary vasculature, and their physiological adaptation to birth, is
essential for the survival of all newborn infants. One group of patients who suffer from abnormal lung and
pulmonary vascular development are infants born with congenital diaphragmatic hernia (CDH). CDH is among
the most common and severe of all congenital malformations with a frequency of 1 in 3500 live births and a
mortality rate of 20-50%. Patients with CDH have a hole in the diaphragm allowing the abdominal organs to
herniate into the chest during fetal development. As a result, the lungs and pulmonary vasculature in these
patients are often underdeveloped due to a lack of sufficient space in the fetal thorax. In addition to this lack of
space, our recent data demonstrate that the genetic defects responsible for abnormal diaphragm development
in patients also cause abnormal development of the lungs and pulmonary vasculature. These lung-intrinsic
defects result in lung hypoplasia and pulmonary hypertension that are the major cause of mortality and long-
term morbidity in patients with CDH. The genetic and developmental mechanisms responsible for lung
hypoplasia and pulmonary hypertension in patients with CDH are not yet understood. Furthermore, current
therapies for CDH are non-specific and do not take the underlying genetic and developmental defects unique to
each patient into account. Our overall hypothesis is that genetic defects in patients with CDH play a central role
in the mechanisms responsible for lung hypoplasia and pulmonary hypertension. We believe that by identifying
the lung-intrinsic mechanisms of abnormal development and physiological function associated with CDH, we will
uncover new and more specific approaches for treatment. Our proposed experiments will address this hypothesis
by determining the roles played by two key transcriptional regulators found to be mutated in patients with CDH,
PBX1 and SIN3A. The Aims of our proposal address each of the underlying mechanisms responsible for lung
hypoplasia and pulmonary hypertension including: abnormal embryonic development of the lungs and pulmonary
vasculature, failure of pulmonary vascular physiological adaptation to birth, and failure of postnatal lung and
pulmonary vascular development. In Aim 1 we focus on the role played by Pbx1 in postnatal lung development
and pulmonary vascular physiological adaptation to birth. In Aim 2 we focus on the role played by Sin3a in
embryonic lung and pulmonary vascular development by controlling lung, vascular, and vascular smooth muscle
cell proliferation and differentiation. In both Aims we will identify the downstream genetic and molecular defects
caused by loss-of-function of Pbx1 or Sin3a and determine how these genetic defects cause impaired
physiological function of the lungs and pulmonary vasculature. The results of our experiments will lay the
groundwork for future therapeutic interventions for patients with CDH t...

## Key facts

- **NIH application ID:** 10600029
- **Project number:** 5R01HL146859-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** David J McCulley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $395,607
- **Award type:** 5
- **Project period:** 2021-04-17 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10600029

## Citation

> US National Institutes of Health, RePORTER application 10600029, GENETIC AND DEVELOPMENTAL MECHANISMS OF CONGENITAL DIAPHRAGMATIC HERNIA (5R01HL146859-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10600029. Licensed CC0.

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