Facioscapulohumeral muscular dystrophy (FSHD) is a complex genetic disorder resulting in the progressiveand selective degeneration of the FSH muscles in adults. Many histopathological features of FSHD mirrormuscle aging and loss of regenerative capacity, as evidenced by reduced populations of myogenicprogenitors in affected muscles and their defective growth and survival behavior in cell culture. The diseaseis linked to the contraction of D4Z4 repeats in the subtelomeric region of Chromosome 4, leading to the ideathat deletion of these repeats results in the overexpression of adjacently located genes or to TelomerePosition effects that lead to telomere shortening and cellular aging. The central hypothesis to be tested inProject 3 is that FSHD is a regenerative disease caused by genetic regulatory disruptions that reduce theviability and/or telomere function in myogenic progenitors, resulting in premature cell aging and consequentloss of muscle regenerative capacity. Immunohistological, cell culture and biomarker approaches will beused to systematically investigate myogenesis in affected and unaffected muscles recovered by surgicalbiopsy of a large cohort of FSHD patients and first-degree relatives. The goals of these studies are: 1) toidentify biomarkers expressed in FSHD muscle and muscle progenitors for monitoring the efficacy of FSHDclinical trials; 2) to identify disease-specific biomarkers that have functional roles in FSHD muscle pathologyas 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 ofFSHD. Biomarker and telomere studies will enable investigations of the underlying molecular pathology ofFSHD to test D4Z4 locus control and telomere position effect (TPE) disease mechanisms. Project 3 benefitsfrom the distinct multidisciplinary expertise of Center investigators and collaborators working in an interactiveresearch environment and from the exceptional resources and technical support of the Cell Core with itsunique collection of FSHD muscle biopsies and muscle cell cultures. The proposed studies will elucidate thedisease role of myogenesis and muscle regeneration in FSHD and provide validated cell models forinvestigations of FSHD disease mechanisms and the development of drug and cell-based therapeutics forthe treatment of FSHD, a currently untreatable disease.
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