Congenital diaphragmatic hernia (CDH), a life-threatening birth defect, is a major cause of pediatric mortality and mobility. The pathological anomalies are characterized by the inappropriate protrusion of the abdominal contents, possibly including the stomach, liver, intestines and spleen, through an improperly formed diaphragm into the thoracic cavity which impairs lung growth and development. In addition to the secondary defect resulting from protrusion of abdominal contents, lung development itself may be also effected and contribute to CDH phenotypes in these patients. Although the disease was described more than 350 years ago, the etiology of CDH is poorly understood. Using a conditional null mutant in which COUP-TFII is deleted in the mesentery, we showed that tissue specific null mutants of COUP-TFII exhibit Bochdalek CDH, the most common form of CDH. COUP-TFII, a member of orphan nuclear receptors, is expressed in regions critical for the formation of the diaphragm and lung during embryonic development. Ablation of COUP-TFII in the foregut mesenchyme, including the post-hepatic mesenchymal plate (PHMP), results in the malformation of the diaphragm and the failure of appropriate attachment of the PHMP to the body wall. Recently a critical region within 15q26.1-26.2 has been mapped by array CGH and Fish analysis to be deleted in CDH patients. COUP-TFII is one of the four known genes resided within this critical region. Together with results of our COUP-TFII conditional mutants, the genetic analysis implicates COUP-TFII as most likely candidate gene for the most common type of Bochdalek CDH. To delineate how COUP-TFII regulates diaphragm and lung development and how perturbation of proper diaphragm formation might result in CDH, three specific aims are proposed: 1). Analysis of the defects exhibited by the conditional null mice during diaphragm development;2). Analyze the role of COUP-TFII in lung development and its relationship to CDH;3). Screen and characterize COUP-TFII mutations in CDH patients. With the proposed study, we hope to provide important insights on morphogenesis of the diaphragm and lung and how malformation of these organs leads to such devastating congenital defects. And eventually, by screening CDH patients for the mutations in COUP-TFII, it will certainly improve the translational prospect in setting up a diagnostic kit and devise an intervention for some CDH patients.
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