This proposal is designed to provide the principal investigator, Ronald D. Cohn, with the necessary scientific experience to allow for a successful transition to an independent career as a physician-scientist. Dr. Cohn outlines a five-year plan to study the role of TGF-beta signaling in muscle regeneration and the potential for antagonizing increased signaling by and activation of TGF-beta as a therapeutic modality for various myopathic states. This work will be performed under the mentorship of Harry C. Dietz, Victor McKusick Chair and Professor of Pediatrics, Medicine, Molecular Biology, Neurosurgery, the McKusick-Nathans Institute of Genetic Medicine and investigator of the Howard Hughes Medical Institute at Johns Hopkins University. Dr. Dietz has been the leading researcher in the field of fibrillinopathies for the past 18 years, and he was the first to identify mutations in fibrillin-1 gene that cause Marfan syndrome. He has a long record of successful mentorship to graduate students and young investigators funded under the K award mechanism. Dr. Cohn's training will be based in the School of Public Health at Johns Hopkins and an advisory committee of expert basic and clinical scientists will provide both scientific and career advise to create a fruitful environment for the development of an independent physician-scientist. Within the last year Dr. Cohn spent his time in the laboratory of his mentor, Dr. Dietz, investigating the pathogenetic mechanisms of muscle hypoplasia and myopathy in mouse models of Marfan syndrome. The work outlined in this proposal will focus on the molecular mechanisms involved in impaired muscle regeneration and satellite cell performance due to excessive TGF-beta signaling. Specific Aims include: 1) Elucidation of the contribution of dysregulated TGF-beta activity on satellite cell performance during muscle regeneration. 2) Gene expression profiling of fibrillin-1 deficient regenerating skeletal muscle and satellite cells. 3) Impact of excess TGF-beta signaling on the pathogenesis of muscular dystrophy. The potential of antagonizing increased TGF-beta signaling and thereby improvement of muscle regeneration is relevant for a significant subset of patients with Marfan syndrome who exhibit low muscle mass and weakness as well as for patients with different forms of muscular dystrophy. Moreover, improvement of muscle regeneration may have potential benefit for other conditions such as disease, disuse or age related decrease in muscle mass.