# Gene Mutation and Rescue in Human Diaphragmatic Hernia

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $1,724,849

## Abstract

OVERALL PROGRAM
ABSTRACT
Our research strategy for the Program project “Gene Mutation and Rescue in Human Diaphragmatic Hernia” is
to 1) identify gene variants in patients with Congenital Diaphragmatic Hernia from genomic analyses, 2) test
high priority candidates for validation and function in vitro and ex vivo, and in animal models, 3) determine
molecular pathways defined by integrating already known and new candidate genes, and 4) select molecular
targets from which to conceive postnatal treatment strategies for CDH. CDH is a birth defect which occurs in
1/3000 live births, and has a high mortality and morbidity, with survivors requiring high technology-driven
interventional perinatal care in tertiary or quarternary neonatal intensive care units. 40% of CDH patients have
multiple anomalies in addition to CDH, but as many as 60% are isolated with the potential for increased
survival if we can improve the associated lung hypoplasia responsible for its high morbidity. The societal and
individual burden of CDH can hopefully be lessened by reducing the patient and family stresses caused by the
considerable morbidity and mortality, as well as the cost of care, coincident with this birth defect. If substantial
pulmonary differentiation can be induced to occur in the lung postnatally, the use of Extra Corporeal Membrane
Oxygenation (ECMO) and aggressive ventilatory management may be reduced, thus protecting fragile lungs
from secondary barotrauma and bronchopulmonary dysplasia.
 To affect a salutary change, we plan to continue to employ genomic methods such as Whole Exome
Sequencing (WES), array Comparative Genomic Hybridization (aCGH), and Whole Genomic Sequencing
(WGS), and to integrate variant findings with data from expression analyses of developing diaphragm and lung
tissues in mouse models, and with diaphragm biopsies from human CDH patients. WES, WGS, and aCGH
data will be continually ascertained and analyzed on a clinically well characterized cohort of singletons and
parent/child trios, as well as rare extended families. It is the goal of this P01 to use this growing cohort and our
analytic approach to generate candidate genes that will yield important clues as to the molecular pathogenesis
of CDH, particularly after integrating the highest priority candidates into molecular pathways.
PROJECT I: Genomic and gene expression analyses to discover human CHD genes and pathways.
PROJECT II: Mouse models will elucidate genetics of CDH and associated pulmonary defects and identify
clinically relevant targets.
PROJECT III: Functional evaluation of CDH patient gene variants in vitro and in select animal models.

## Key facts

- **NIH application ID:** 9929435
- **Project number:** 5P01HD068250-09
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** CAROL J BULT
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,724,849
- **Award type:** 5
- **Project period:** 2011-08-29 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929435

## Citation

> US National Institutes of Health, RePORTER application 9929435, Gene Mutation and Rescue in Human Diaphragmatic Hernia (5P01HD068250-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9929435. Licensed CC0.

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