mTOR Signaling in Skeletal Myogenesis

描述（由申请人提供）：骨骼肌分化是一个精心策划的过程，由自分泌、旁分泌和内分泌因子通过多种信号转导途径调节。 细菌大环内酯雷帕霉素抑制广泛的细胞功能，从增殖，生长，分化，它已作为一个强大的工具来探测相关的信号通路。 虽然雷帕霉素敏感途径正在细胞生长和增殖的背景下进行深入研究，但其在骨骼肌发育中的重要性才刚刚开始被认识到。 雷帕霉素的哺乳动物靶标-mTOR-是一种多功能蛋白质，其充当被雷帕霉素抑制的多个信号通路的中心组分。 该研究者实验室的初步研究揭示了mTOR在骨骼肌分化中的重要功能以及mTOR信号传导的新机制的存在。 拟议的研究旨在验证以下假设：与细胞生长和增殖不同的mTOR途径通过控制IGF-I和IGF-II的自分泌产生来调节骨骼肌卫星细胞分化。 本研究综合运用生物化学、分子生物学、细胞学和遗传学方法，在组织培养模型（C2C12）和小鼠原代卫星细胞系统中，研究（1）mTOR对IGF自分泌的调节，（2）磷脂酶D-磷脂酸-mTOR通路在肌发生中的作用，（3）mTOR对IGF自分泌的调节，（4）mTOR对IGF自分泌的调节，（5）mTOR对IGF自分泌的调节，（6）mTOR对IGF自分泌的调节，（7）mTOR对IGF自分泌的调节，（8）mTOR对IGF自分泌的调节，（9）mTOR对IGF自分泌的调节，（10）mTOR对IGF自分泌的调节，（10）mTOR对IGF自分泌的调节，（11）mTOR对IGF自分泌的调节，（12）mTOR对IGF自分泌的调节，（13）mTOR对IGF自分泌的调节，（14）mTOR对IGF自分泌的调节，（15）mTOR对IGF自分泌的调节，（16）（3）mTOR的结构-功能关系和新的分化信号分子。 在这些研究中获得的知识不仅将为多效性mTOR通路的信号传导机制提供宝贵的见解，而且还为骨骼肌发育的分子理解做出了重大贡献，骨骼肌发育与健康相关的问题密切相关，如肌营养不良，运动诱导的肥大和衰老相关的萎缩。

DESCRIPTION (provided by applicant): Skeletal muscle differentiation is a well-orchestrated process regulated by autocrine, paracrine, and endocrine factors via multiple signal transduction pathways. The bacterial macrolide rapamycin inhibits a wide spectrum of cellular functions, from proliferation, growth, to differentiation, and it has served as a powerful tool to probe relevant signaling pathways. While the rapamycin-sensitive pathway is under intensive investigation in the context of cell growth and proliferation, its importance in skeletal muscle development is only beginning to be recognized. The mammalian target of rapamycin - mTOR- is a multi-functional protein that serves as a central component of multiple signaling pathways that are inhibited by rapamycin. Preliminary studies from this investigator's laboratory have revealed an essential function of mTOR in skeletal muscle differentiation and the existence of novel mechanisms of mTOR signaling. The proposed studies are designed to test the hypothesis that an mTOR pathway distinct from that in cell growth and proliferation regulates skeletal muscle satellite cell differentiation by controlling the autocrine production of IGF-I and IGF-II. With a combination of biochemical, molecular, cellular and genetic approaches, and in the systems of a tissue culture model (C2C12) and mouse primary satellite cells, the specific aims of this proposal are to investigate (1) regulation of IGF autocrine production by mTOR; (2) involvement of a phospholipase D-phosphatidic acid-mTOR pathway in myogenesis; and (3) mTOR's structure-function relationship and novel signaling partners in differentiation. Knowledge gained in these studies will not only provide invaluable insights into the signaling mechanisms of the pleiotropic mTOR pathway, but also make significant contributions to the molecular understanding of skeletal muscle development, which is tightly coupled to health-related issues such as muscular dystrophy, exercise-induced hypertrophy, and aging-related atrophy.