Morphogenesis and growth of the ventricular wall in development and disease

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ABSTRACT Congenital heart defects (CHDs) are the most commonly encountered birth defect. Despite its prevalence, the underlying molecular etiology of most CHDs is not yet known. The central theme of this Program Project Grant application is to elucidate mechanisms that regulate growth and morphogenesis of the ventricle during development. Our objectives are to better understand how epigenetic, transcriptional, and cell signaling regulation within cardiac progenitor cells (CPCs) and embryonic cardiomyocytes impact cardiac specification, differentiation, and ventricular morphogenesis. Four highly interactive and complementary Projects are proposed. Project 1 will study the molecular mechanisms contributing to the genesis of CHDs in early CPCs. These studies build on work from Dr. Stephanie Ware’s laboratory and will test the overall hypothesis that severe CHDs encountered in patients with ZIC3 X-linked heterotaxy result from abnormalities in cardiac progenitor cell fate. Such mechanisms would explain why the spectrum of CHDs encountered in these patients is more severe than what would be anticipated as a result of altered sidedness. Project 2 will study the epigenetic mechanisms regulating the bHLH transcription factor HAND1, which is critical for left ventricular, papillary muscle, and cardiac conduction system (CCS) morphogenesis. These studies build on work from Dr. Anthony Firulli’s laboratory and will test the overall hypothesis that epigenetic regulation of HAND1 transcription directs normal cardiomyocyte patterning. Other studies will identify HAND1 DNA occupancy and interacting transcriptional partners, and thus establish the gene regulatory networks regulating left ventricle, papillary muscle, and CCS morphogenesis. Project 3 will study epigenetic mechanisms critical to mesendoderm specification and cardiogenic differentiation. These studies build on work from Dr. Weinian Shou’s laboratory and will test the overall hypothesis that the lysine methyltransferase SMYD4 regulates Histone modifications essential for establishing correct numbers of CPCs. Project 4 will study the role of a novel planar cell polarity effector protein, SHROOM3, in the pathogenesis of CHDs. These studies build on work from Dr. Matthew Durbin’s laboratory and will test the overall hypothesis that SHROOM3 interacts at a number of key points within the PCP pathway, and that identified rare CHD patient- specific SHROOM3 variants disrupt PCP within cardiomyocytes. The proposed work will be facilitated by the participation of three cores (Core A – Administration; Core B - Embryonic stem cell growth and genetically modified models; and Core C - Cardiac physiology and imaging). Ultimately, the studies proposed in this Program Project Grant application will illustrate how epigenetic, transcriptional, and signaling mechanisms occurring within both cardiac progenitors and embryonic cardiomyocytes establish the gene regulatory networks necessary for cardiac morphogenesis. Importantly, defining the molecular mechanisms of these events will inform interventions aiming to mitigate deleterious impacts of CHD.