mTOR Signaling in Skeletal Myogenesis

骨骼肌生成中的 mTOR 信号转导

基本信息

批准号：
8037770
负责人：
Jie Chen
金额：
$ 31.9万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-06-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8037770
关键词：
Address Aging Amino Acids Animal Model Biochemical Biology Breeding Cell Line Data Differentiation and Growth Disease Endocrine Exercise Follistatin Genetic Goals Grant Growth Health Hypertrophy In Vitro Insulin-Like Growth Factor II Knowledge Laboratories Mediating Molecular Mus Muscle Muscle Cells Muscle Development Muscle Fibers Muscular Atrophy Muscular Dystrophies Myoblasts Natural regeneration Nutrient Pathway interactions Phosphotransferases Physiological Positioning Attribute Process Production RNA Interference Regulation Resistance Role Signal Transduction Signal Transduction Pathway Sirolimus Skeletal Muscle Staging System Testing Transgenic Mice Validation Work autocrine cell growth chemokine cytokine genome-wide in vivo inhibitor/antagonist mTOR protein muscle hypertrophy muscle regeneration mutant myogenesis novel paracrine repaired response skeletal skeletal muscle differentiation skeletal muscle growth

项目摘要

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. PUBLIC HEALTH RELEVANCE: Skeletal muscle differentiation is a well-orchestrated process regulated by autocrine, paracrine, and endocrine factors via multiple signal transduction pathways. Our proposed studies aim to dissect the molecular mechanisms underlying the regulation of skeletal muscle differentiation and regeneration, with a focus on the mammalian target of rapamycin signaling network. Knowledge gained in these studies will contribute to the molecular understanding of skeletal muscle biology, which may have significant impact on health-related issues such as muscular dystrophy, aging or disease-induced muscle atrophy, muscle regeneration, and exercise- induced muscle hypertrophy.

描述（由申请人提供）：骨骼肌分化是通过信号转导途径的调节网络进行自分泌，旁分泌和内分泌因子调节的良好处理过程。近年来，雷帕霉素的哺乳动物靶标（MTOR）开始被认为是骨骼肌分化，生长和肥大的关键调节剂。我们实验室的工作有助于当前对MTOR调节成肌细胞分化的理解，并导致了MTOR通过组装不同的不同途径来调节肌发生的多个阶段的启示，其中一些途径是意外的，尚未完全划定。通过生化，分子，细胞和遗传方法的结合，并利用体外和体内系统，我们旨在填补当前对骨骼肌发生调节的分子途径的知识，通过解决这三个主要问题：（1）与之相关的成长过程：这可以调节响应氨基酸的可用性信号的肌细胞分化？（2）专门调节第二阶段心肌融合的MTOR途径是什么对Myotube/Myotiber生长和成熟至关重要的，哪些分泌的因素调节了这一过程？（3）MTOR在肌肉再生中的作用是什么？我们在信号转导机制的生化表征，强大的初步数据以及我们创建的独特动物模型方面的专业知识使我们处于解决这些问题的理想位置。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。公共卫生相关性：骨骼肌分化是通过多种信号转导途径通过自分泌，旁分泌和内分泌因子调节的良好策划过程。我们提出的研究旨在剖析调节骨骼肌分化和再生的分子机制，重点是雷帕霉素信号网络的哺乳动物靶标。这些研究中获得的知识将有助于对骨骼肌生物学的分子理解，这可能会对与健康相关的问题产生重大影响，例如肌肉营养不良，衰老或疾病诱发的肌肉萎缩，肌肉再生，运动诱导的肌肉肥大。