The proper association of muscle fibers with their extracellular matrix is essential to the normal functioning of skeletal muscle. Defective association of muscle fibers with their surrounding basal lamina underlies the pathologies associated with Duchenne and M-laminin congenital muscular dystrophies. The associations between myofibers and their surrounding matrix are maintained by two mechanisms. Dystrophin and the dystrophin associated transmembrane glycoprotein complex link laminin in the extracellular matrix with the cell cytoskeleton. The a7b1 integrin, a transmembrane laminin receptor, also links muscle fibers with their basal laminin. The applicant's long term objective is to understand the role of this integrin in muscle development, function and disease. The applicant recently discovered that the a7b1 integrin is overexpressed in patients with Duchenne muscular dystrophy and in the mdx mouse. He suggests that the increased expression of the a7b1 integrin in these patients and mice compensates for the absence of dystrophin by stabilizing the association of myofibers with the extracellular matrix.
His aim i s to explore this hypothesis. The expression and localization of the different a7b1 integrin isoforms will be studied throughout the course of degeneration and regeneration in the mdx mouse using immunocytochemistry, immunoblots northernblot analysis and RT-PCR. Mice deficient in both the dystrophin and a7b1 linkage systems will be created by breeding mdx mice with a7-/- animals that have been generated by homologous recombination. The double mutant mice will be used to determine whether the absence of the integrin enhances the development of muscle pathology and altered function in the absence of dystrophin. Morphologic, biochemical, and physiologic analyses of these animals will be done. Finally, synthesis of either dystrophin and/or the a7 chain will be restored in the muscles of the double mutant mdx/a7-/-mice using myoblast transfer and/or infection with replication defective recombinant adenovirus vectors. The extent of structural and functional restoration that accompanies the renewed synthesis of each transmembrane linkage system will be determined. Determining whether overexpression and inhibition of expression of the a7b1 integrin can alter the course of muscle pathogenesis in the mdx mouse will reveal whether attempts to increase a7 expression in muscle might be clinically relevant and worth pursuing in the future.
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