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Ronald D. Cohn提供必要的科学经验，使其能够成功过渡到独立的医学科学家职业。Cohn博士概述了一项五年计划，研究tgf - β信号在肌肉再生中的作用，以及通过tgf - β的激活来对抗信号增加的潜力，并将其作为各种肌病状态的治疗方式。这项工作将在Harry C. Dietz的指导下进行，他是Victor McKusick- nathan遗传医学研究所的儿科、医学、分子生物学、神经外科教授和McKusick- nathan遗传医学研究所的研究员，也是约翰霍普金斯大学霍华德休斯医学研究所的研究员。Dietz博士在过去的18年里一直是纤原蛋白病变领域的主要研究人员，他是第一个发现导致马凡氏综合征的纤原蛋白-1基因突变的人。长期以来，他在K奖机制资助下成功指导研究生和年轻研究人员。科恩博士的培训将在约翰霍普金斯大学公共卫生学院进行，一个由基础和临床科学家专家组成的咨询委员会将提供科学和职业建议，为独立的医生科学家的发展创造一个富有成效的环境。去年，Cohn博士在他的导师Dietz博士的实验室里研究马凡综合征小鼠模型中肌肉发育不全和肌病的发病机制。本提案中概述的工作将集中在过度tgf - 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。具体目的包括：1)阐明在肌肉再生过程中tgf - β活性失调对卫星细胞性能的影响。2)纤维蛋白1缺陷再生骨骼肌和卫星细胞的基因表达谱。3)过量tgf - β信号在肌营养不良发病机制中的影响。拮抗增加的tgf - β信号，从而改善肌肉再生的潜力，与马凡综合征中表现出低肌肉质量和虚弱的重要亚群患者以及不同形式的肌肉萎缩症患者相关。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、不使用或与年龄相关的肌肉量减少。

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.