COMMITMENT & DIFFERENTIATION OF CARDIAC CELL PHENOTYPES

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A Program Project consisting of 5 projects and 2 cores is proposed. The theme is one of an exploration of commitment and differentiation by two cell types in the embryonic heart, endothelia and myocytes. This exploration will be carried out by a combination of experimental embryology and molecular biology common to the five projects. One event of interest in the epithelial-mesenchymal cell transformation of endothelial cells in the atrioventricular canal that produces the earliest progenitors of the vales and membranous septa. Studies focused on these cells will explore the regulation of cell transformation at three levels. Project 1 will explore the transcription factors Slug and Mox-1 as mediators of cell transformation at three levels. Project 1 will explore the transcription factors Slug and Mox-1as mediators of cell transformation in response to TGFbeta and other signal transduction pathways. Project 2 will explore the role of cadherins and beta-catenin in the down-regulation of cell, cell adhesion that accompanies cell transformation. Project 3 is focused on the role of Hyaluronan Synthase 2 (Has2) in the formation of the cardiac cushions and the apparent requirement for hyaluronan for cell transformation and migration. Also of interest to this group of investigators is the development of cardiac myocytes. Project 4 is an examination of the role of Nkx (thinman) genes in commitment to the cardiac phenotype by myocyte precursors. Project 5 focuses on the differentiation of cardiac myocytes by examining the formation of the sarcomere. Exploration of the 3rd and 4th filament systems is proposed in order to understand the regulation of the assembly of the contractile apparatus. The five projects are supported by administrative and research cores. The research core will provide common capabilities in antisense oligonucleotides, viral vectors and whole mount in situ hybridization. The administrative core will provide support to all projects and utilize both an external review committee and regularly scheduled consultants to provide review and feedback. This program is designed to enhance communication between the member laboratories and promote the synergistic exploration of heart development. Information obtained by this Program Project will contribute significantly to our understanding of congenital heart disease.