The overarching goal of this SCCOR is to improve the prevention, detection, treatment, and outcomes of tetralogy of Fallot (TOF). The component projects, three clinical (Projects 1, 2, and 3) and three basic (Projects 4, 5, and 6), represent diverse but intersecting approaches toward this central objective. In critical respects, the studies in certain projects will leverage the findings of others, and all will benefit from key core resources. Their interactions relate to three principal sub-themes: the etiology of TOF, long- term right ventricular (RV) function, and neurocognitive outcome. Project 1 will examine the developmental, behavioral, and neurologic outcome in TOF, establishing the nature and basis of neurodevelopmental sequelae. Project 2 will be a Phase II prospective randomized trial of pulmonary valve replacement with or without surgical remodeling of the RV. Project 3 will identify sequence variants in known and novel TOF disease genes and correlate them with important cardiac and neurocognitive sub-phenotypes. Project 4 will explore the hypothesis that surgical ischemia-reperfusion in the hypertrophied infant RV causes mitochondrial dysfunction, activation of cell death pathways, and significant myocyte loss that can be prevented by mechanistically targeted interventions. Project 5 will elucidate the molecular pathways involving NKX2.5 in the etiology of TOF and in the response of the ventricle to hemodynamic load in relevant mouse models. Project 6 will define the molecular and cellular mechanisms of myocardial regeneration in the zebrafish model, with the long-term goal of identifying potential novel strategies for reversing RV failure in TOF. In critical respects, the studies in certain projects will leverage the findings of others, and all will benefit from key core units. Core A will provide data management, biostatistical analysis, and administrative support. Core B will perform microarray transcription profiling experiments, including bioinformatics analysis. Core C will create a centralized repository of clinical and genetic data, DNA, and cardiac tissues from TOF patients. In addition, Core D, a skills development core, will train physicians for academic careers in congenital heart disease by providing an interdisciplinary educational experience that emphasizes the importance of anatomy, pathology, and physiology understanding mechanisms in congenital heart disease.
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