This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Congenital Diaphragmatic Hernia (CDH) is a frequent and often fatal developmental condition that appears to be caused by diverse factors. This project will use a molecular genetic strategy that combines clinical, molecular biological, developmental, and genetic expertise to identify genetic causes of this anomaly. The long-term goal of this project, after identifying genetic causes of CDH, is to elucidate functional biochemical pathways to serve as targets for pharmacologic intervention. Ongoing projects as Massachusetts General Hospital are working to identify novel genes in insect, avian, and rodent models of lung development, which could be associated with the human condition of CDH. Additional screens are ongoing at MGH using discarded tissue speciments from aborted human fetuses. With the portion of the project dtailed in this application, specifically we plan to: I. Assemble a carefully phenotyped cohort of patients with Congenital Diaphragmatic Hernia (CDH) and create a structurally sound database for categorization. II. Collect and store biological materials corresponding with patients phenotyped and entered into the created CDH database. III. Test the hypothesis that mutations in one or more meritorious candidate genes, currently being generated in ongoing screens in Drisophila, chicks, rodents and aborted human fetuses are a molecular cause of CDH in humans. IV. Test the alternative hypothesis that CDH is caused by defects in gene pathways not revealed in current animal models, using collected CDH patient/family biological samples to identify novel genes associated with this anomaly.
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