Abnormal development of the heart occurs in one percent of all human births. Still, the basic cellular and molecular controls which govern cardiac myogenesis are unknown. The long term goals of the projected research are to understand the cellular and molecular mechanisms which direct the determination of cardiac myoblasts and their later diversification into atrial, ventricular and conduction system myocytes. Specifically, our aims are: 1) to identify the cellular and molecular bases of cardiogenic determination: 20 to determine the cellular and molecular bases of cardiac myocyte diversification; 30 to identify genes which direct cardiogenic commitment. Newly developed microculture systems which permit the clonal analysis of cardiogenic differentiation in vitro will be employed to determine the cell types which promote the determination and diversification of cardiac myoblasts. 5-azacytidine treatment and DNA transfection will be used to """"""""rescue"""""""" differentiation blocked cardiac myoblasts in an effort to identify and isolate the genes which direct cardiogenic determination. Monoclonal antibodies and cDNAs for the myosin heavy chain will be used to monitor the cellular and molecular mechanisms by which heterogeneous cardiac myocyte populations are generated. Taken together, it is hoped that these studies will aid in our basic understanding of the initial determination and later diversification of cardiac myocytes in the formation of a functional myocardium. Data from the proposed research will provide basic information concerning the cellular and molecular mechanisms by which heterogeneous populations of myocytes and lay the groundwork for analysis of abnormal heart development.
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