Conotruncal cardiac defects account for approximately 17 percent of congenital heart defects and, while impressive progress has been made in identifying genes that regulate myocardial differentiation and looping of the heart, mechanisms regulating outflow tract ontogeny remain obscure. The investigators have focused on the role of genes within the deleted region of chromosome 22q11 as an approach to understanding outflow tract pathology. It is now evident that this is not the sole cause nor always sufficient to cause an abnormality. This strongly suggests the existence of genetic modifiers. Capitalizing on a now well established consortium of collaborators, the goal of the five projects and three cores proposed in this renewal of the SCOR in Pediatric Cardiovascular Diseases at the Children's Hospital of Philadelphia is to continue to evaluate genes within 22q11 and expand the focus to identify and characterize new molecular pathways which might play a role in normal outflow tract morphogenesis Project 1, the clinical project, will pursue a strategy to identify factors which act as modifiers of the cardiac phenotype in 22q11 deleted patients as well as identify genes that cause outflow tract defects in non-deleted patients. Project 2 will pursue a candidate gene approach in defining the role of mutations in Jagged1 and other Notch signaling ligands as causative agents in conotruncal defects. Project 3 will continue to characterize the mouse homologues of human 22q11 genes as well as to independently identify genes uniquely expressed in the conotruncal region of the heart. Project 4 will delineate the role of NFATc, a novel endothelial specific transcription factor, in the ontogeny of semilunar valve defects, and Project 5 will explore the role of Pax3 regulatory elements in control of the morphogenetic behavior of the cardiac neural crest. The Clinical Core will continue to be the focal point of the SCOR. This Core has collected samples from over 400 patients with conotruncal cardiac defects, it will expand this data base to include family members and patients with related cardiovascular defects. The Molecular and Cytogenetics Core will be providing additional services in the chromosomal mapping of genes and the Gene Expression Core will characterize their developmental expression. Through this combined effort of pediatric cardiologists, molecular biologists, developmental biologists, and geneticists, utilizing the resources of one of the world's largest pediatric cardiology centers, the investigators will be able to determine the function of critical genes involved in conotruncal development and thus begin to comprehend the molecular etiology of a set of the most common congenital heart defects affecting children throughout the world.
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