Molecular Genetics of Congenital Diaphragmatic Hernia

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DESCRIPTION (provided by applicant): The applkicant is a senior clinical genetics fellow who has completed his clinical training. His long-term objective is to become an independent physician scientist focused on studying genetic disorders that impact the health of children. This application will provide the candidate with training in developmental biology, new technologies in human genetics, and mouse genetics. The overall scientific goal is to identify and characterize genes responsible for congenital diaphragmatic hernia (CDH). CDH is a developmental abnormality in which regions of the diaphragm fail to form, allowing the contents of the abdominal cavity to invade the space normally reserved for the developing lung. CDH affects approximately 1 in 2,500 newborns. Mortality ranges from 30 to 60%, and infants who survive often have significant morbidity from pulmonary hypoplasia and pulmonary hypertension. Specific aims for this study include: 1) establishing a collaborative DNA repository for the study of CDH, 2) screening candidate genes for CDH-causing mutations, 3) identifying and mapping chromosomal regions involved in CDH using novel comparative genomic hybridization (CGH) technology, and 4) characterizing a mouse model of CDH. Candidate genes, selected based on chromosome position and putative function, will be screened for CDH-causing mutation by direct sequencing. DNA from individuals with CHD will be screened for abnormalities by G-banded chromosome analysis and CGH using a genome-wide microarray of over 20,000 overlapping clones with a approximately 300 kb resolution. A CDH mouse model that mimics the most common form of CDH in human has been developed by selective ablation of COUP-TFII, a gene for transcription factor regulated by the retinoic acid pathway. The candidate will characterize these mice by determining the effect of COUP-TFII ablation on diaphragm musculature, innervation, cellular proliferation, as well as apoptosis. Identifying and characterizing the genes that cause CDH may lead to the development of new preventative and therapeutic strategies, and will provide insight into the molecular basis of diaphragm development.