Cardiomyocyte Proliferation and Ventricular Morphogenesis

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DESCRIPTION (provided by applicant): This project addresses mechanisms that are responsible for formation of the ventricular chamber of the heart during mouse embryonic development. We have advanced a model in which signals secreted from the epicardium promote cell division and morphological organization of the underlying compact zone myocardium. In this application, we propose to pursue the following goals: Specific Aim 1: To define the role of IGF signaling in heart development. Several lines of evidence presented in this proposal indicate that IGF signaling is an important mediator of proliferation in the midgestation heart, although a functional role for IGF signaling in heart development has not been examined previously. In this Aim, we will primarily undertake a phenotypic assessment of mouse embryos in which IGF ligands and receptors are conventionally and conditionally mutated. Specific Aim 2: To define pathways that lead to morphogenic differentiation of the compact and trabecular myocardium under the influence of the epicardium and endocardium. Epicardial and endocardial factors converge on a common set of signaling intermediates to activate proliferation, yet diverge to achieve differential morphogenic outcomes. How the ventricular myocardium becomes partitioned into compact and trabecular compartments is a critical aspect of heart development, yet one that is not well- understood. In this Aim, we address the molecular pathways that result in the selective expression of genes in the compact zone or trabecular myocardium, with the consideration that these are surrogate markers for the larger biological processes of compact vs. trabecular morphogenesis. PUBLIC HEALTH RELEVANCE: This project considers how the muscle of the embryonic heart forms and becomes organized. An understanding of these processes may give insight into certain forms of congenital heart defects, and may be relevant to therapies to reverse or treat the pathology of adult heart failure.