Molecular Basis of Myocardin Function in the Heart

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DESCRIPTION (provided by applicant): Transcriptional co-activators expand information encoded within the genome required for adaptation to environmental perturbation and stress. Myocardin is a remarkably potent transcriptional expressed exclusively in the heart and smooth muscle cells (SMCs). We have used transgenic and gene targeting strategies in mice to elucidate the molecular mechanisms that regulate heart and vascular development. Preliminary studies reveal that: i) myocardin is expressed in a precise developmentally regulated pattern in cardiomyocytes and SMCs, ii) forced expression of myocardin in embryonic stem cells activates cardiac-restricted genes associated with the hypertrophic gene program, iii) myocardin and MRTF-A activate overlapping, but distinct, sets of genes and most importantly iv) mice harboring a cardiac-specific conditional ablation of the myocardin gene exhibit hypertrophic cardiomyopathy. Together these studies suggest the central hypothesis that will be examined in the proposed studies: myocardin functions as a central regulator of cardiomyocyte growth and adaptation to stress via both feed-forward mechanisms, including activation of genes associated with the fetal /hypertrophic gene program, and feedback mechanisms regulating cell proliferation. The overall goal of this proposal is to elucidate the role of myocardin in the heart with particular focus on defining its function in cardiac myocyte differentiation and adaptation of the heart. The specific aims are to characterize: 1) the SRF- and MEF2-dependent transcriptional and morphogenetic programs regulated by myocardin in the heart, 2) mechanisms that distinguish activity and specificity of myocardin, MRTF-A and MRTF-B in the heart, and 3) molecular mechanisms modulating myocardin-dependent transcriptional activation in the adult heart and response to hypertrophic stimuli. The experimental strategy deployed emphasizes the translation and validation of molecular and cellular data in genetically engineered mice. At a basic level these studies will provide new insights into the transcriptional programs regulating cardiac myocyte differentiation and morphogenetic development of the heart. These studies also provide insights into the molecular mechanisms regulating adaptation of the heart to stress and the pathogenesis of cardiomyopathy. PUBLIC HEALTH RELEVANCE: This application will investigate how the transcriptional coactivator, Myocardin, regulates the differentiated state of the heart and the capacity of the heart to respond to hemodynamic stress. We have generated genetically altered mice with cardiac-restricted ablation of the Myocardin gene. Analysis of these mice will permit us to determine if myocardin controls the early differentiation of cardiac myocytes, as well as their role in re-programming gene expression in the adult heart when it is subjected to stress. These studies will provide new understanding into cardiac development as well as the underlying causes of heart failure and cardiomyopathy.