Model Studies for FSHD Biomarkers

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Project 4: Model Studies for FSHD Biomarkers. Though genetic changes underlying facioscapulohumeral muscular dystrophy (FSHD) have been identified, there is a need to identify downstream pathogenetic mechanisms and to find additional disease biomarkers. Accordingly, the studies under Project 4 will focus on the use of potential mouse models and cultured human FSHD muscle cells to (i) discover or validate FSHD biomarkers, (ii) identify downstream pathogenetic mechanisms, and (iii) test possible therapies. Because affected FSHD muscles show only a small amount of regeneration and repair, it is possible that FSHD pathology could be ameliorated if regeneration and/or muscle hypertrophy were increased. One set of experiments, therefore, will determine if such treatments decrease biomarkers of disease in potential FSHD mouse models. Also, there is considerable indirect evidence to support the idea that apoptosis contributes to FSHD pathogenesis, e.g., activated caspase-3 is found in human FSHD muscle fibers and human FSHD myogenic cells appear to be more susceptible to cell death. No studies have yet directly assessed the contribution of apoptosis to FSHD pathogenesis, and the mechanisms of muscle cell apoptosis are not fully understood. The additional sets of studies are designed to provide a direct assessment of the role of apoptosis in FSHD, to investigate signs of apoptosis as disease biomarkers, and to elucidate apoptotic pathways in diseased muscle cells. The Specific Aims of Project 4 are to: (1) Determine in FSHD mouse models if apoptosis contributes to pathogenesis and if signs of apoptosis are valid disease biomarkers; (2) Determine if treatments that improve regeneration and/or induce hypertrophy will decrease disease biomarkers in FSHD models; and (3) Elucidate mechanisms underlying the increased susceptibility of human FSHD myoblasts and myotubes to cell death upon oxidative stress. Relevance to Public Health. The studies will increase our knowledge of biomarkers for disease progression and how genetic changes lead to disease in FSHD. The experiments could also identify possible new methods to ameliorate FSHD.