This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Congenital heart disease affects 0.5% of newborns each year, and approximately 20% of these defects are outflow tract (OFT) defects affecting proper formation of the great arteries of the heart, the aorta and the pulmonary artery. There are several models in mouse of congenital heart disease. However, these models provide an incomplete understanding of pathological events because few molecular markers sufficiently detail OFT anatomy during development and bifurcation into distinct vessels. In our studies of Nkx2.5 promoter regulation we have characterized a transgene that has asymmetric expression in the outflow tract during critical periods of outflow tract formation, expansion and septation. We plan to use these regulatory regions to analyze the relationship of early heart field and splanchnic mesoderm populations through development to formation of the mature great arteries during development. We plan to use this transgenic marker to examine OFT patterning and rotation events in several mouse models of OFT dysgenesis affecting myocardial, endocardial and cardiac neural crest populations. Also, through an analysis of the enhancer regions regulating asymmetric OFT and selective pulmonary artery versus aortic expression, we wish to understand the transcriptional factors and related signaling controlling great artery differentiation and underlying this important form of congenital heart disease.
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