Thursday, May 22, 2025
5/22/2025
Pathogenesis of Muscular Dystrophies - DESCRIPTION (provided by applicant): The goals of our studies are to (i) determine pathogenetic mechanisms and (ii) identify new therapeutic strategies for a group of severe muscular dystrophies. We have found that aberrant activation of cell death - mediated by the pro-death protein Bax and its cytosolic binding partner Ku70 - appears to be a pathogenetic mechanism in at least three human muscular dystrophies: Congenital Muscular Dystrophy Type 1A (MDC1A, mutations of laminin- alpha2); Limb-girdle Muscular Dystrophy Type 2D (LGMD2D, mutations of alpha-sarcoglycan); and LGMD2C (mutations of gamma-sarcoglycan). For each of these muscular dystrophies, a key step in pathogenesis appears to be aberrantly increased acetylation of Ku70, which in turn leads to induction of Bax-mediated cell death. We now propose to identify the mechanisms that underlie this disease-induced dysregulation of the Ku70/Bax pathway. One set of experiments will identify the deacetylase and acetyltransferase mechanisms that regulate Ku70 function. Our early studies suggest that SIRT1 and SIRT3 are two deacetylases that interact with Ku70 or the Ku70/Bax complex in muscle. A second set of experiments will determine if restoring normal Ku70 acetylation will ameliorate pathology in disease models. The studies will analyze both mouse disease models and cells from our extensive library of myogenic cells from human patients. The patient cells provide a particularly favorable system to study mechanisms of pathogenesis, because we find that myotubes formed in culture from human MDC1A, LGMD2C, and LGM2D patient myoblasts, but not normal myoblasts, spontaneously undergo cell death. Under Specific Aim 1, we will identify Ku70 deacetylase and acetyltransferase mechanisms in normal and diseased muscle cells. These studies will test our hypothesis that aberrant function of Ku70 deacetylases and/or acetyltransferases causes muscle pathology. Under Specific Aim 2, we will determine if restoring normal Ku70 acetylation ameliorates pathology. These studies will test our hypothesis that restoring a healthy low level of Ku70 acetylation will inhibit cell death and lessen pathology in disease models. Our studies are designed to identify pathogenetic mechanisms that are common to multiple muscular dystrophies. From our results, we expect to identify potential therapeutic strategies that could be effective for multiple diseases.
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