TRANSCRIPTIONAL REGULATION OF CARDIOMYOCYTE DEVELOPMENT

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DESCRIPTION (the applicant's description verbatim): The normal development of the cardiovascular system is regulated by a complex set of molecular pathways that interpret environmental and developmental signals into changes in cardiovascular gene expression. Perturbations of these signaling pathways have been implicated in a number of prevalent human cardiovascular diseases including congenital cardiac malformations, pathologic cardiac hypertrophy, and dilated cardiomyopathy. During the last ten years we have studied the nuclear transcription factors that regulate the development and function of the mammalian cardiovascular system. In an initial series of experiments we identified a cardiac-specific transcriptional promoter/enhancer in the 5' flanking region of the cardiac troponin C (cTnC) gene. We used this promoter to identify a set of nuclear transcription factors that appear to play important roles in regulating early cardiomyocyte development and cardiac morphogenesis. Among these was the GATA4 zinc finger protein that binds to and trans-activates a wide variety of cardiac specific transcriptional regulatory elements. Using a gene targeting approach we showed that GATA4 is necessary for the formation of the primitive ventral heart tube during early murine embryogenesis. More recently, we identified a second zinc finger protein called cardiac friend of GATA (CFOG) that is expressed in the developing heart and that binds specifically to the N-terminal zinc finger of GATA4. Similarly, Olson and coworkers recently demonstrated that GATA4 also interacts with the rel-related protein NFAT3 and that these two proteins appear to be important regulators of cardiac myocyte hypertrophy. The long term goal of the studies described in this continuing RO1 proposal is to understand the molecular mechanisms by which GATA proteins, in conjunction with other transcriptionfactors and coactivator/ repressor proteins regulate cardiogenesis and cardiac hypertrophy. Specifically we will (1) map the regions of GATA4 that are required for its central role in the heart tube formation. (2) genetically and biochemically characterize the interaction between GATA4 and CFOG and understand the effects of this interaction on the transcriptional activity of GATA4, (3) Use gene targeting to determine the roles of NFAT3 and CFOG in cardiac development and function in the mouse. Together, the results of these studies should provide novel basic insights into the molecular pathways that regulate normal cardiac development and function. They should also be relevant to understanding the molecular pathophysiology of a number of clinically important inherited and acquired cardiovascular diseases.