MOLECULAR MECHANISMS OF CONGENITAL HEART DISEASE

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The goal of this SCOR project is to further the understanding of the fundamental mechanism of congenital heart disease with the use of the state-of-the-art technology of molecular biology, developmental biology, human genetics, small animal cardiac physiology, and clinical pediatric cardiology. The Harvard SCOR in Pediatric Cardiology would bring together some of the finest basic science research faculty of the Harvard Medical School and its affiliated teaching hospitals. Each participant of this SCOR has a strong track record of making original and fundamental contributions to cardiovascular sciences as it relates to the aim of this RFA. The projects described in this SCOR application are designed to take the maximum advantage of studying the closely related scientific theme using the different model organisms and system to dissect the role of transcription factors and secreted factors in the cardiac morphogenesis and their mutations in human and in experimental animals, as well as their linkage into the population of pediatric patients with congenital heart disease. Accordingly, this Harvard SCOR application is entitled "Molecular Mechanisms of Congenital Heart Disease," and consists of five independent but highly interactive projects and three cores that provide highly specialized technological support as well as administrative support to facilitate the progress of each project. Specific projects include: Project I: Functional Analysis of the Cardiac Specific Homeobox Gene Csx/Nkx (P.I.-Seigo, Izumo). Project II: Genetic Analytic of Inherited Congenital Heart Diseases (P.I.-Christine E. Seidman; Co-P.I.-Jon Seidman). Project III. Identification of Signaling Molecules that Induce Heart Formation (P.I.-Andrew B. Lasser). Project IV: T-Box Gene in Congenital Heart and Limb Deformities (P.I.-Clifford J. Tabin). Project V: Genetic Determinants of Arrythmia Development Associated with Congenital Heart Malformation (P.I.-Charles I. Berul; Co-Investigators Mark E. Josephson and Edward Walsh). Small Animal Physiology Core (Director- James P. Morgan) will provide the state-of-the-art physiological analysis of the murine cardiovascular system using a multi-disciplinary approach. The Embryo Physiology and Imaging Laboratory will be a unique resource to the Harvard community. Morphology Core will be developed to facilitate morphological studies by each Project. The program is designed to have clear focus on the investigations of the molecular basis for cardiac development and their genetic alterations with particular emphasis on the studies of cardiac transcription factors and secreted factors that play critical roles in early cardiogenesis. All projects are extensively interconnected both in scientific theme and the technological aspects while taking advantage of both experimental and clinical methodologies. The program unites both basic science departments and clinical cardiology programs of Harvard Medical Campus. The SCOR Director has extensive experiences in organizing interactive multi-disciplinary programs that encompasses both clinical and academic disciplines. The SCOR has full institutional support to make the program successful. We believe that this SCOR will generate many new findings fundamental to our understanding of congenital heart disease and at the same time is designed to provide rich training opportunities for the next generation of cardiovascular scientists and clinicians.