The isolation of human embryonic stem (ES) cells has fostered development of a potent area of investigation which will impact our understanding of disease mechanisms and has potential to yield effective therapies. These pathogenetic insights and possible treatments may be applied to the various types of muscular dystrophy. This proposal has as its goal the establishment of a Core Facility which will serve as a resource for investigators seeking the causes and cures for these diseases. Two primary services will be offered by this Core: 1) targeting or inactivating genes in human ES cells which cause various forms of muscular dystrophy and 2) in vitro differentiation of these gene targeted cell lines along the skeleteal muscle lineage pathway. Cardiac muscle could also be differentiated. Proof-of-principle experiments will initially target the genes which cause limb-girdle muscular dystrophy 2I (LGMD2I) and fascioscapulohumeral muscular dystrophy (FSHD). Protocols to differentiate skeletal muscle and its precursors will be developed coincident with the gene targeting studies. These latter studies will take advantage of embryoid bodies, derived from cultured human ES cells, which form tissues from all three germ layers. Revealing studies will become possible when gene targeting of muscular dystrophy genes is combined with in vitro differentiation of these cell lines. The ultimate goal of this approach is the provision of cell-based models of disease for development of therapies directed against the diverse forms of muscular dystrophy. The Core Facility proposed herein is envisioned to be a resource which may be utilized by investigators across the country.
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