mTOR Signaling in Skeletal Myogenesis

描述（由申请人提供）：骨骼肌分化是一个精心安排的过程，由自分泌、旁分泌和内分泌因素通过信号转导通路的调节网络调节。近年来，哺乳动物雷帕霉素靶点（mTOR）开始被认为是骨骼肌分化、生长和肥大的关键调节因子。我们实验室的工作促进了目前对mTOR调控成肌细胞分化的理解，并揭示了mTOR通过组装不同的途径调节肌形成的多个阶段，其中一些是意想不到的，尚未得到充分描述。结合生物化学，分子，细胞和遗传方法，并利用体外和体内系统，我们的目标是通过解决以下三个主要问题，填补目前骨骼肌发生调控的分子途径知识的相当大的空白：(1)已知的生长调节mTOR通路的组分是如何参与肌发生的？根据氨基酸可用性信号调节成肌细胞分化起始的mTOR通路是什么？(2)对肌管/肌纤维生长和成熟至关重要的第二阶段肌细胞融合的mTOR通路是什么？哪些分泌因子调节这一过程？(3) mTOR在肌肉再生中的作用和机制是什么？我们在信号转导机制的生化表征方面的专业知识，我们强大的初步数据，以及我们创造的独特的动物模型，使我们处于解决这些问题的理想位置。在这些研究中获得的知识将有助于对骨骼肌发育、修复、再生和肥大的分子理解。

DESCRIPTION (provided by applicant): Skeletal muscle differentiation is a well-orchestrated process regulated by autocrine, paracrine, and endocrine factors via a regulatory network of signal transduction pathways. In recent years the mammalian target of rapamycin (mTOR) has begun to be recognized as a critical regulator of skeletal muscle differentiation, growth and hypertrophy. Work from our laboratory has contributed to the current understanding of mTOR regulation of myoblast differentiation, and has led to the revelation that mTOR regulates multiple stages of myogenesis by assembling distinct pathways, some of which unexpected and yet to be fully delineated. With a combination of biochemical, molecular, cellular and genetic approaches, and utilizing both in vitro and in vivo systems, we aim to fill a sizable gap in the current knowledge of molecular pathways underlying the regulation of skeletal myogenesis by addressing these three major questions: (1) How are the known components of growth-regulating mTOR pathway involved in myogenesis, and what is the mTOR pathway(s) that regulates the initiation of myoblast differentiation in response to amino acids availability signals? (2) What is the mTOR pathway that specifically regulates the second-stage myocyte fusion critical for myotube/myofiber growth and maturation, and which secreted factors regulate this process? (3) What is mTOR's role in muscle regeneration and what are the mechanisms? Our expertise in biochemical characterization of signal transduction mechanisms, our strong preliminary data, and the unique animal models we have created, put us in an ideal position to tackle those questions. Knowledge gained in these studies will contribute to the molecular understanding of skeletal muscle development, repair, regeneration and hypertrophy.