Congenital and acquired myopathies are common and deadly diseases. Clinical trials utilizing the transfer of myoblasts have yielded disappointing results. Failure of these therapies reflects an inadequate knowledge of the fundamental regulatory mechanisms of myogenic progenitor cells (including satellite cells). We have defined a novel marker, Foxkl (formerly termed MNF), for the myogenic progenitor cell (MPC) population. Using a gene disruption strategy, we have observed that mice that lack Foxkl have impaired muscle regeneration, dysregulation of the cyclin dependent kinase inhibitor, p21, and perturbed cell cycle progression of the MPC population. Using molecular biological and biochemical techniques, we have verified that p21 is a downstream target for Foxkl, we have identified an upstream fragment of the Foxkl gene that directs expression to the MPC, we have identified Sox15 as an upstream regulator of Foxkl gene expression and we have shown that mice lacking both dystrophin and Foxkl are lethal during the postnatal period. Recent studies undertaken in our laboratory have identified additional nuclear factors that regulate Foxkl and the myogenic progenitor cell population. Moreover, new preliminary data are provided to further support the rationale and feasibility of the experimental strategy that will be pursued. The overall hypothesis of this revised proposal is that discrete transcriptional regulators interact and modulate the myogenic progenitor cell population to promote skeletal muscle regeneration. To address this hypothesis we will pursue the following three specific aims: 1) To define the transcriptional regulation of Foxkl gene expression by Sox15 and Fhl3. 2) To mechanistically define the functional role of Fhl2 as a regulator of Foxkl and the myogenic progenitor cell population. 3) To define the functional interaction of Foxkl and mSinSA in the myogenic progenitor cells. These studies will enhance our understanding of the transcriptional regulation of myogenic progenitor cells that are resident in adult muscle and regeneration. In addition, the results of these studies will serve, in part, as a platform for therapeutic strategies directed towards the treatment congenital and acquired myopathic diseases. ? ? ? ?
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