The overall goal of this program is to elucidate factors that play major roles in cardiac organogenesis. A multidisciplinary approach has been developed with studies being carried out in areas of the earliest development of cardiac structures including extracellular matrix interactions, and atrioventricular canal mesenchyme formation, and cardiac contractile protein isoform switching during development in animal models. In addition, a study of the molecular genetic epidemiology of defects of the atrioventricular canal in human subjects is being carried out. There are nine investigators in five academic departments: Anatomy, Biochemistry, Biological Sciences, Pediatrics and Preventive Medicine. A clinical project, Molecular Genetic Epidemiology of Atrioventricular Canal and Perimembranous Interventricular Septal Defects is directed by R.M. Lauer and V. Sheffield. This project will identify genes involved in the pathogenesis of these defects by identifying polymorphisms within candidate genes for association studies as well as highly polymorphic short tandem repeat polymorphisms for a genome-wide linkage search in families with multiple affected members. There are four basic science projects related to cardiac embryogenesis and its molecular genetic control. All of the projects are related to the development of the endocardial cushions and their adjacent structures. These include: Regulation of Endothelial/Mesenchymal Transformation in Cardiac Development: The Stepwise Control of Endothelial Cell Transformation in Endocardial Cushion, directed by D. Weeks, R. Runyan; Extracellular Matrix Interactions in Cardiac Morphogenesis, directed by M. Solursh; Role of FGF's and an Int-2 Related Protein in Cushion Tissue Morphogenesis, directed by G. Kitten; Cytoskeleton and the Development of Endocardial-Cushions, directed by J. Lin. All projects will be supported by a Molecular Biology Core which will identify genes expressed during cardiac development and which are temporally and spatially regulated in the developing endocardial cushions and adjacent structures. The function of these genes and gene products will be studied in the animal basic science projects and these candidate genes will be utilized for examination of association and linkage in the human studies. All projects will also be supported by an Administration Core.
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