For more than 10 years, abnormalities of dystrophin have been known to be the major cause of muscle cell degeneration. Dystrophin is part of a larger complex of proteins, some of which are also involved in distinct forms of limb girdle muscular dystrophy (LGMD). This complex of proteins links the internal cytoskeleton to the extracellular matrix, and alteration in this linkage causes membrane instability, and ultimately, muscle cell degeneration. In LGMD, caused by abnormalities in the sarcoglycans, this linkage is preserved, yet muscles still degenerate. The recent identification of FLNC as a sarcoglycan-interacting protein raises the possibility that there is a signaling role to the sarcoglycans, and it is this signaling that is necessary to maintain the muscle cell integrity. To better understand the normal function of the sarcoglycans and FLNC in muscle fiber stability and the potential for therapy, we propose 5 specific aims: 1) To look at FLNC in normal and diseased muscle to determine the role it might play in muscle myofiber stability; 2) To look for novel proteins associated with FLNC and the sarcoglycans via yeast two-hybrid and chemical cross-linking; 3) To use gene chip and gene array technologies to characterize the mRNA expression patterns in dystrophin, sarcoglycan, calpain-3 and FLNC deficient human muscle and compare it to normal; 4) To validate the expression results and develop new hypotheses about the pathogenesis of these diseases and begin the confirmation of these findings by more conventional approaches such as co-IP and co-localization; 5) To determine the existence of stem cells in the muscle of animal models of these diseases and determine whether normal muscle stem cells are corrective for these dystrophies. The latter knowledge is essential if these stem cells are ever to be used in human therapy.
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