Insulin-like Growth Factors and Muscle Differentiation

胰岛素样生长因子和肌肉分化

• 批准号: 7993219
• 负责人: Peter S Rotwein
• 金额: $ 10万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7993219
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adult; Aging; Autocrine Communication; Automobile Driving; Binding; Binding Proteins; Biochemical; Cell Maturation; Cells; Complex; Disease; Event; Fetus; Gene Expression; Genes; Genetic Transcription; Goals; Growth Factor; H19 gene; Hormones; Injury; Insulin-Like Growth Factor II; Insulin-Like-Growth Factor I Receptor; Maintenance; Mediating; Mediator of activation protein; Muscle; Muscle Cells; Muscle Development; Muscle Fibers; Myoblasts; Play; Production; Regulation; Response Elements; Role; Secondary to; Signal Pathway; Signal Transduction; Skeletal Muscle; Somatomedins; System; Testing; Tissues; Whole Organism; base; muscle form; muscle regeneration; nerve supply; programs; promoter; public health relevance; receptor binding; repaired; research study; transcription factor

DESCRIPTION (provided by applicant): The differentiation, maturation, and maintenance of a complex tissue such as skeletal muscle requires ongoing cooperation between signaling pathways activated by hormones and growth factors, and intrinsic regulatory programs controlled by myogenic transcription factors. Insulin-like growth factors (IGFs) play key roles in normal muscle development in the fetus, are important for coordinating muscle regeneration following injury in the adult, and are critical for maintaining muscle mass during aging and in disease. The focus of this application will be on the IGF system in muscle development and repair, and represents part of a long-term effort to understand the mechanisms by which actions of the IGFs, their receptors, and binding proteins are integrated within the cell and in the whole organism. Based on current observations, we have postulated the existence of a robust autocrine signaling network in muscle cells that is critical for differentiation. The first key step in activating this network is production and secretion of IGF-II by differentiating myoblasts, which is secondary to induction of IGF-II gene transcription. Secreted IGF-II binds to and activates the IGF-I receptor, which leads to sustained stimulation of the PI3-kinase - Akt signaling pathway. Akt activity, principally Akt1, then plays a central role in driving early differentiation, in part by enhancing muscle gene expression through stabilization of active transcriptional complexes on muscle promoters. As differentiation proceeds, signal amplification occurs as more Akt2 is produced, and both Akts then participate in muscle cell maturation and in myocyte fusion to form multinucleated myotubes. I propose the following three Specific Aims to test this IGF-mediated signaling network hypothesis: 1. To determine the mechanisms of action of Akt1 in muscle differentiation. Proposed studies will test the idea that Akt1 is an obligate mediator of myoblast differentiation, and that its major functions are to enhance the actions of myogenic transcription factors on muscle gene promoters by stimulating key co-activators and inhibiting critical co-repressors. 2. To define the actions of Akt2 in muscle differentiation. Proposed experiments will examine the hypothesis that Akt2 acts to control late events in myoblast maturation and myotube formation. 3. To elucidate mechanisms of regulation of IGF-II gene transcription during muscle differentiation. Proposed experiments will test the hypothesis that a critical control region for differentiation-dependent activation of IGF-II gene transcription resides downstream of the H19 gene. Major goals will be to define the mechanisms of action of this chromosomal response element. PUBLIC HEALTH RELEVANCE: Insulin-like growth factors (IGFs) play key roles in normal muscle development in the fetus, are important for coordinating muscle regeneration following injury in the adult, and are critical for maintaining muscle mass during aging and in disease. The focus of this application will be on the IGF system in muscle development and repair, and represents part of a long-term effort to understand the mechanisms by which actions of the IGFs, their receptors, and binding proteins are integrated within the cell and in the whole organism.

描述（由申请人提供）：复杂组织（如骨骼肌）的分化、成熟和维持需要激素和生长因子激活的信号通路与生肌转录因子控制的内在调控程序之间的持续合作。胰岛素样生长因子（IGFs）在胎儿的正常肌肉发育中起关键作用，对于协调成人损伤后的肌肉再生很重要，并且对于在衰老和疾病期间维持肌肉质量至关重要。该应用程序的重点将是肌肉发育和修复中的IGF系统，并代表长期努力的一部分，以了解IGF，其受体和结合蛋白的作用在细胞内和整个生物体中整合的机制。基于目前的观察，我们假设存在一个强大的自分泌信号网络的肌肉细胞，是分化的关键。激活该网络的第一个关键步骤是通过分化成肌细胞产生和分泌IGF-II，这是继发于IGF-II基因转录的诱导。分泌的IGF-II结合并激活IGF-I受体，这导致持续刺激PI3-激酶-Akt信号通路。Akt活性，主要是Akt1，然后在驱动早期分化中发挥核心作用，部分通过稳定肌肉启动子上的活性转录复合物来增强肌肉基因表达。随着分化的进行，随着产生更多的Akt 2而发生信号放大，然后两种Akt都参与肌细胞成熟和肌细胞融合以形成多核肌管。我提出了以下三个具体目标来测试这个IGF介导的信号网络假说：1。确定Akt1在肌肉分化中的作用机制。拟议的研究将测试的想法，即Akt1是成肌细胞分化的专性介质，其主要功能是通过刺激关键的共激活因子和抑制关键的共抑制因子，以增强肌源性转录因子对肌肉基因启动子的作用。2.明确Akt2在肌肉分化中的作用。提出的实验将检验Akt2作用于控制成肌细胞成熟和肌管形成中的晚期事件的假设。3.阐明肌肉分化过程中IGF-Ⅱ基因转录的调控机制。拟议的实验将测试的假设，一个关键的控制区域的分化依赖性激活IGF-II基因转录驻留下游的H19基因。主要目标将是确定这种染色体反应元件的作用机制。公共卫生关系：胰岛素样生长因子（IGFs）在胎儿的正常肌肉发育中起关键作用，对于协调成人损伤后的肌肉再生很重要，并且对于在衰老和疾病期间维持肌肉质量至关重要。该应用程序的重点将是肌肉发育和修复中的IGF系统，并代表长期努力的一部分，以了解IGF，其受体和结合蛋白的作用在细胞内和整个生物体中整合的机制。