Facioscapulohumeral muscular dystrophy (FSHD) is a complex genetic disorder resulting in the progressive and selective degeneration of the FSH muscles in adults. Many histopathological features of FSHD mirror muscle aging and loss of regenerative capacity, as evidenced by reduced populations of myogenic progenitors in affected muscles and their defective growth and survival behavior in cell culture. The disease is linked to the contraction of D4Z4 repeats in the subtelomeric region of Chromosome 4, leading to the idea that deletion of these repeats results in the overexpression of adjacently located genes or to Telomere Position effects that lead to telomere shortening and cellular aging. The central hypothesis to be tested in Project 3 is that FSHD is a regenerative disease caused by genetic regulatory disruptions that reduce the viability and/or telomere function in myogenic progenitors, resulting in premature cell aging and consequent loss of muscle regenerative capacity. Immunohistological, cell culture and biomarker approaches will be used to systematically investigate myogenesis in affected and unaffected muscles recovered by surgical biopsy of a large cohort of FSHD patients and first-degree relatives. The goals of these studies are: 1) to identify biomarkers expressed in FSHD muscle and muscle progenitors for monitoring the efficacy of FSHD clinical trials;2) to identify disease-specific biomarkers that have functional roles in FSHD muscle pathology as targets for development of drugs, RNAi, and cell-based therapeutics that promote satellite cell survival, myogenesis and improved muscle regeneration;and 3) to establish validated cell and mouse models of FSHD. Biomarker and telomere studies will enable investigations of the underlying molecular pathology of FSHD to test D4Z4 locus control and telomere position effect (TPE) disease mechanisms. Project 3 benefits from the distinct multidisciplinary expertise of Center investigators and collaborators working in an interactive research environment and from the exceptional resources and technical support of the Cell Core with its unique collection of FSHD muscle biopsies and muscle cell cultures. The proposed studies will elucidate the disease role of myogenesis and muscle regeneration in FSHD and provide validated cell models for investigations of FSHD disease mechanisms and the development of drug and cell-based therapeutics for the treatment of FSHD, a currently untreatable disease.
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