Regulation of mTOR by Mechanically-Induced Signal Events

描述（由申请人提供）：众所周知，机械刺激在肌肉质量的调节中起核心作用，并且肌肉质量的维持有助于疾病预防和生活质量;然而，将机械信号转化为控制该过程的分子事件的机制尚未得到充分理解。例如，最近的工作已经确定，雷帕霉素敏感机制（可能是mTOR信号传导）是机械诱导生长所必需的;然而，该途径的分子组分尚未明确定义。此外，促进雷帕霉素敏感途径活化的机械诱导的信号传导事件尚不清楚。为了更好地理解机械诱导的雷帕霉素敏感途径，我们提出使用离体机械刺激剂结合各种药理学和分子工具来解决以下目标：1）确定参与机械诱导的雷帕霉素敏感途径活化的上游分子，2）评估mTOR在机械诱导的雷帕霉素敏感性途径中的作用和3）阐明机械诱导的mTOR信号传导机制。这项工作将有助于确定机械刺激如何激活雷帕霉素敏感通路，并为未来的研究提供基础信息，旨在了解机械信息如何转化为调节肌肉质量的生化事件。

DESCRIPTION (provided by applicant): It is well established that mechanical stimuli play a central role in the regulation of muscle mass and that maintenance of muscle mass contributes to disease prevention and quality of life; however, the mechanisms involved in converting mechanical signals into the molecular events that control this process are not well understood. For example, recent work has established that a rapamycin-sensitive mechanism (presumably mTOR signaling) is necessary for mechanically-induced growth; yet, the molecular components of this pathway have not been clearly defined. Furthermore, the mechanically-induced signaling events that promote the activation of the rapamycin-sensitive pathway are not known. In an effort to better understand the mechanically-induced rapamycin-sensitive pathway, we propose to use an ex-vivo mechanical stimulator in conjunction with various pharmocological and molecular tools to address the following aims 1) determine the upstream molecules involved in the activation of mechanically-induced rapamycin-sensitive pathway, 2) assess the role of mTOR in the mechanically-induced rapamycin-sensitive pathway and 3) elucidate the mechanically-induced mTOR signaling mechanism(s). This work will help define how mechanical stimuli activate the rapamycin-sensitive pathway and will provide fundamental information for future studies aimed at understanding how mechanical information is converted into the biochemical events that regulate muscle mass.