Cellular and molecular biology of plakin crosslinking proteins in myogenic cells

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Multicellular organisms are comprised of a variety of cell types with unique shapes that are dictated primarily by scaffolding molecules located inside the cells. The ability of cells to either maintain or change their conformation has profound and direct implications on their function within an organism. Understanding how scaffolding proteins influence cell shape and function is the primary objective of the present grant application. The proposed studies are particularly focused on understanding the functions of one family of scaffolding proteins known as plakins. Plakins are particularly enriched in tissues that undergo significant mechanical stress such as skin and muscle and are thought to preserve the organization of these tissues when they are stretched or compressed. In humans, genetic lesions associated with certain plakin family members result in skin blistering disorders and muscular dystrophies. The applicant is particularly interested in determining the importance of plakins in skeletal muscle. To achieve this objective, studies to assess the localization of bullous pemphigoid antigen 1 (Bpag1), one specific plakin family member, in muscle tissue and studies to identify Bpag1-interacting proteins are envisioned. Furthermore, studies to determine the relative contributions of different plakin family members during the proliferation and differentiation of muscle cells are proposed. Collectively, these studies are expected to provide new insights into the fundamental structure and function of muscle fibers and will enhance our understanding of myopathies that are related to disruptions of the muscle fiber architecture.