The main goal of the research proposed in this application continues to be the elucidation of basic molecular mechanisms involved in the production of the normal and abnormal phenotype of the cardiac muscle, both during development and in response to diverse physiological and pathological stimuli. To this end, three main specific aims will be pursued: I) To identify and characterize cardiac lineage-determining genes using a combination of newly developed molecular approaches and cell lines that have many of the characteristics of cardiac cells. Once isolated, the gene(s) involved will be used to dissect the pathway leading from an undifferentiated mesodermal cell to a cardiocyte. II) To identify and characterize the gene(s) responsible for the terminally differentiated phenotype of cardiac cells and their apparent irreversible withdrawal from the cell cycle. We will make use of a variety of cell lines that have lost the ability to commit to the terminally differentiated state as well as the ability of certain oncogenes to reverse the terminally differentiated state. III) To identify and characterize muscle specific transcription factor(s) that are involved in the expression of the cardiac alpha- and beta-MHC genes. These two genes contain a muscle specific enhancer that is not regulated by the MyoD gene family. The enhancer on the beta-MGC gene is also negatively regulated by the thyroid hormone receptor. These enhancers provide a unique opportunity to identify cardiac-specific transcriptional factors that are involved in the production of phenotypic changes during development and in response to pathologic stimuli. The experiments proposed address some of the most fundamental questions of cardiac biology, namely, the origin of the cardiac myocyte and the production, as well as the maintenance, of the differentiated phenotype. The answer to these questions has significant practical import in the modulation of cardiac contractility and the potential to affect regeneration of the myocardium.
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