ANALYSIS OF A NOVEL MUSCLE INTEGRIN-BINDING PROTEIN

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DESCRIPTION (Taken from the application): Proper cellular interactions with extracellular matrix are critical for development as well as normal function of muscles. Recent studies have revealed important functions of integrin cytoplasmic domains in control of myogenesis and therefore implied that the interactions between integrin and their intracellular ligands may play a pivotal role in myogenesis. The long term objective of the proposed research is to understand the molecular bases and the functions of integrin intracellular interactions in myogenesis and myopathies. The proposed research focuses on a novel muscle-specific intracellular integrin-binding protein (MIBP) that was recently identified and cloned by the applicant. MIBP interacts with p1 integrin in vivo as well as in vitro. More importantly, MIBP expression is dramatically down-regulated during myogenic differentiation and overexpression of MIBP in myoblasts suppresses myogenic differentiation. The proposed studies will test the hypothesis that the binding of MIBP to the p1 integrin modulates integrin function, myoblast proliferation and differentiation. Experiments with the following specific aims are proposed: (1) To define the structural basis underlying the MIBP-integrin interaction, (2) To determine whether the MIBP-integrin interaction modulates myoblast differentiation and proliferation, and (3) To assess the effect of the MIBP-integrin interaction on integrin activation and extracellular matrix deposition. Results from these experiments will provide a molecular basis for future comprehensive investigations including those at the tissue and animal level as well as in human patients. Studies on integrin intracellular interactions in muscle cells will likely lead to insights into the general mechanism by which integrin function in muscle development and pathogenesis of muscle diseases, and may potentially translate into novel therapeutic approaches to control muscle cell proliferation and differentiation, and consequently, the outcome of muscular dystrophies and other myopathies.