Malformations of the cardiovascular system are the most frequent occurring form of birth defect and account for the majority of premature deaths caused by congenital anomalies. In turn, the majority of congenital heart defects result from maldevelopment of the primordia for valves and septa. Termed cushions or ridges, valvuloseptal primordia are mesenchymal outgrowths that form segmentally in the atrioventricular (AV) canal and outflow tract. The formation, fusion and differentiation of these mesenchymal cushions/ridges are critical events in cardiogenesis as they serve to subdivide the primitive heart tube with a single, continuous lumen into a four chambered heart. The central theme of the Program Project is the cell and molecular processes that regulate the formation of cushion cells and their conversion to valves and septa. In each of the five projects, specific and mechanistic hypotheses are proposed. for example, we propose that (i) the cushion progenitor cells are derived from bipotential precardiac mesoderm and are induced by endoderm to enter a special endothelial lineage; (ii) the latter are subsequently induced by novel, myocardial paracrine factors to transform to cushion mesenchyme; (iii) changes in the expression of splice variants for neural cell adhesion molecule and cytotactin mediate the transformation of endothelium to mesenchyme; (iv) the 3-dimensional distribution of endothelial progenitor cells and/or myocardial paracrine signals determine the position and placement of valvuloseptal primordia; (v) microfibrillar proteins (fibrillin and fibulin) promote the remodeling of mesenchyme into valve tissue and (vi) abnormal changes in either cell transformation or remodelling of the collagenous matrix underlie abnormal cushion size, shape, plasticity and failure of fusion. To accomplish these experimental goals, we will use site-directed microinjection techniques to study effects of molecular perturbations at the organ specific level employing confocal microscopy and image analysis, genetics, recombinant DNA technology, in situ-relevant biological assays models, a new differentiation-inducible, cardiac stem cell line (QCE-6), and animal models of valvuloseptal dysmorphogenesis including transgenics and trisomy 16 mice in which 100% have AV septal defects similar to human Down's syndrome. In summary, the proposed projects establish a clinically relevant conceptual framework to molecularly examine valvuloseptal morphogenesis.
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