Role of TGFB signaling in muscle regeneration and various myopathic states

描述(由申请人提供)：本提案旨在为首席研究员罗纳德·D·科恩提供必要的科学经验，以便成功过渡到作为一名内科科学家的独立职业。科恩博士概述了一个五年计划，以研究转化生长因子-β信号在肌肉再生中的作用，以及对抗转化生长因子-β信号的增加和激活作为各种肌病状态的治疗方式的可能性。这项工作将在哈里·C·迪茨、Victor McKusick主席兼儿科学、医学、分子生物学、神经外科教授、McKusick-Nathans遗传医学研究所和约翰·霍普金斯大学霍华德·休斯医学研究所研究员的指导下进行。在过去的18年里，迪茨博士一直是纤维蛋白病领域的领军人物，他是第一个发现导致马凡综合征的纤维蛋白-1基因突变的人。他长期成功地指导在K奖励机制下资助的研究生和年轻调查人员。科恩博士的培训将设在约翰·霍普金斯大学的公共卫生学院，一个由专业基础和临床科学家组成的咨询委员会将提供科学和职业建议，为独立的内科科学家的发展创造一个富有成效的环境。去年，科恩博士在他的导师迪茨博士的实验室里，研究了马凡综合征小鼠模型肌肉发育不良和肌病的发病机制。这项提案中概述的工作将集中在由于过度的转化生长因子-β信号导致的肌肉再生和卫星细胞性能受损的分子机制上。具体目标包括：1)阐明在肌肉再生过程中，失调的转化生长因子-β活性对卫星细胞性能的影响。2)纤维蛋白-1缺陷的再生骨骼肌和卫星细胞的基因表达谱。3)过度的转化生长因子-β信号在肌营养不良发病机制中的作用。拮抗增加的转化生长因子-β信号从而改善肌肉再生的潜力与马凡综合征患者中表现为肌肉质量低和虚弱的相当一部分患者以及不同形式的肌营养不良患者有关。此外，肌肉再生的改善可能对其他情况有潜在的好处，如疾病、废用或与年龄相关的肌肉质量下降。

DESCRIPTION (provided by applicant): 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.