Role of ADAMs in Heart Myocyte Development

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DESCRIPTION (provided by applicant): Development of the vertebrate heart is dependent on a number of cellular processes including migration, proliferation, differentiation and apoptosis. Imperative to these processes are interactions between adjacent cells and between cells and the surrounding extracellular matrix. The A Disintegrin And Metalloproteases (ADAMs) are a recently identified family of cell surface proteins that are thought to mediate cell-cell interactions and to play significant roles in the proteolytic cleavage of extracellular matrix components and other cell surface molecules. There are at least 30 ADAMs identified to date which are all characterized by a multidomain structure including metalloprotease, disintegrin, cysteine-rich, epidermal growth factor-like, transmembrane and cytoplasmic domains. We have recently determined that several ADAMs are expressed by heart myocytes; however, their roles in myocyte development have not been determined. Based on the published literature in other systems and the preliminary data presented here, we hypothesize that ADAMs, through their multidomain structure, play essential roles in cardiomyocyte development and organization. Furthermore, we hypothesize that localized metalloprotease activity by the ADAMs and ADAM-mediated cell-cell interactions are imperative to normal myocyte development. The experimental aims designed to test these hypotheses include: 1) to determine whether alterations in expression of specific ADAMs affects the differentiation, organization or function of heart myocytes; 2) to determine the functional roles of ADAM metalloprotease activity in myocyte organization and maturation; and 3) to determine the roles of ADAM-mediated cell-cell interactions in modulating myocyte development and organization. These studies will elucidate the roles of members of this novel protein family in cardiomyocyte differentiation and organization in the developing heart.