This P01 proposes to study the development of congenital heart disease beginning from the embryo through childhood. This hypothesis-driven, cell-to-bench-to-bedside theme starts with the """"""""final common pathway"""""""" hypothesis of cardiac disease which suggests that every cardiac phenotype is dependent on a specific molecular target (the """"""""common pathway""""""""), which may be modified by interactive cascade pathways. This hypothesis has proven correct for disorders such as hypertrophic cardiomyopathy (target: sarcomere), ventricular arrhythmias (target: ion channels), and dilated abnormalities of transcription factors. As the specific transcription factor pathways under study interact, this P01 is highly embryology cores: Evaluation of early heart development begins with the role of TGF-beta family members bone morphogenic proteins (BMPs), Smad-6 and Tbx-2 in cardiac morphogenesis (Subproject 1; Robert Schwartz, P.I.). The regulatory roles of Smads will be evaluated along with the role of Tbx-2 in cardiac septation and valve formation. In Subproject 2, Dr. John Belmont further expands upon this cardiac developmental program by his study for the zinc finger differentiation and plays a key role in body pattern formation, specifically in left-right axis formation. ZIC3 null mice will be mesoderm-specific and developmental stage-specific gene expression, and the mechanism of body patterning targeted chromosomal deletion (Df1) eliminates most of the murine homologs of the gens deleted in DGS. The goal of this subproject is the identification and characterization of genes involved in this genetic pathways and its role in aortic arch members of the Df1- related pathway. Subproject 4 will utilize the information from subprojects 1-3 to determine the pathway(s) involved in the development of CHD in children with the myocardial disorder left ventricular non- compaction. This P01 will culminate in the development of a greater understanding of the molecular pathways involved in CHD and lead to better care of families at-risk for these disorders.
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