# Mouse Models Will Elucidate Genetics of CDH and Associated Pulmonary Defects and Identify Clinically Relevant Targets

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $372,486

## Abstract

PROJECT II: CHARACTERIZATION OF MOUSE MODELS TO VALIDATE NOVEL CDH GENES AND
IDENTIFY CLINICALLY RELEVANT TARGETS FOR TREATMENT OF PULMONARY DEFECTS OF CDH
PATIENTS.
ABSTRACT:
This proposal reflects an ongoing collaboration by a multidisciplinary team of scientists from The Jackson
Laboratory (JAX) and the Massachusetts General Hospital (MGH) to make discoveries that could address the
medical needs of Congenital Diaphragmatic Hernia (CDH) patients. As a team, we bring together expertise in
genomics, bioinformatics, mouse models, and clinical experience in the care of these patients with this lethal
human condition in which a small increase in respiratory function could lead to survival and normal life
expectancy. To address the current gaps in knowledge about the underlying genetic etiology of CDH, we have
sequenced human exomes of CDH patients, prioritized the variants as candidate genes through computational
integration of human genetic data with developmental expression data from mouse lung and diaphragm tissue,
and then linked those prioritized candidates into molecular pathways using protein-protein interaction data.
Candidate genes emanating from these integrative analyses will be evaluated in in vitro assays of
alveologenesis and for subsequent functional validation in mouse models. If these prioritization steps are
favorable and if current models are unavailable, new models will be generated by gene editing in the
CRISPR/Cas9 pipeline at the JAX. We will also leverage ongoing unbiased phenotype screens underway at
JAX as part of the second phase of the Knockout Mouse Project (KOMP2) to identify novel genes associated
with diaphragm and lung defects, one of which (SVEP1) is already under evaluation (see Fig. 4 ). Mutant mice
will be phenotyped directly by microCT imaging of E15.5 or E18.5 embryos and postnatal pups at the JAX, and
with histological analyses, lung morphometrics, and expression of cell lineage specific markers at the MGH.
Our top priority will be on phenotypic evaluation of genes manifesting as pulmonary hypoplasia with alveolar
simplification or failure of septation, with the hypothesis that such gene defects can be improved
therapeutically after birth. Bioinformatics will be used to incorporate candidate gene variants prioritized by
expression in lung and diaphragm transcriptomes, into molecular pathways from which to impute therapeutic
targets. The most appropriate cell based, organ culture, and postnatal mouse models that respond to
therapeutics selected from small molecule screens in Project III and inferred from drug discovery algorithms,
will be carefully studied to demonstrate rescue of function in in vitro, ex vivo and, eventually, in vivo knockout
mouse models generated from this Project.

## Key facts

- **NIH application ID:** 10159742
- **Project number:** 5P01HD068250-10
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** PATRICIA K DONAHOE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $372,486
- **Award type:** 5
- **Project period:** 2011-08-29 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159742

## Citation

> US National Institutes of Health, RePORTER application 10159742, Mouse Models Will Elucidate Genetics of CDH and Associated Pulmonary Defects and Identify Clinically Relevant Targets (5P01HD068250-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10159742. Licensed CC0.

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