Regulation of muscle growth by SHP-2

SHP-2 对肌肉生长的调节

• 批准号: 7112039
• 负责人: PETER M BURCH
• 金额: $ 4.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7112039
• 关键词: RNA interference; biological signal transduction; calcineurin; calcium flux; cell differentiation; cell proliferation; disease /disorder model; enzyme mechanism; enzyme substrate; genetic transcription; genetically modified animals; guanine nucleotide binding protein; immunoprecipitation; laboratory mouse; mass spectrometry; musculoskeletal injury; musculoskeletal regeneration; myoblasts; myogenesis; phosphorylation; polymerase chain reaction; postdoctoral investigator; protein tyrosine phosphatase; site directed mutagenesis; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Muscle growth and repair is a complex process that involves the proliferation and differentiation of myoblasts which fuse with existing muscle fibers. The broad objective of this research proposal is to define the cell signaling mechanisms that regulate this process. SHP-2 is a cytoplasmic protein tyrosine phosphatase that is required for myogenesis. Our preliminary data suggests that SHP-2 is required to activate NFAT, a critical regulator of muscle growth, through the Ca2+ calcineurin and RhoA signaling pathways. We will use primary myoblasts to determine the mechanism by which SHP-2 activates Ca2+ calcineurin and RhoA signaling to regulate NFAT and myogenesis. Substrate-trapping mutants of SHP-2 and mass spectrometry will be used to identify the substrates through which SHP-2 regulates NFAT. Mice with a skeletal muscle specific deletion of SHP-2 will be used in a muscle injury model to investigate the in vivo role of SHP-2 in regulating muscle growth and regeneration. A greater appreciation for the role SHP-2 serves in regulating muscle growth and regeneration will enhance our understanding of this poorly understood facet of cell signaling and may open new avenues for therapies to treat myopathies.

描述（由申请人提供）：肌肉生长和修复是一个复杂的过程，涉及与现有肌纤维融合的成肌细胞的增殖和分化。这项研究计划的主要目标是定义调节这一过程的细胞信号传导机制。 SHP-2 是一种细胞质蛋白酪氨酸磷酸酶，是肌生成所需的。我们的初步数据表明，SHP-2 是通过 Ca2+ 钙调磷酸酶和 RhoA 信号通路激活 NFAT（肌肉生长的关键调节因子）所必需的。我们将使用原代成肌细胞来确定 SHP-2 激活 Ca2+ 钙调磷酸酶和 RhoA 信号传导以调节 NFAT 和肌生成的机制。 SHP-2 的底物捕获突变体和质谱分析将用于鉴定 SHP-2 调节 NFAT 的底物。骨骼肌特异性删除 SHP-2 的小鼠将用于肌肉损伤模型，以研究 SHP-2 在调节肌肉生长和再生中的体内作用。对 SHP-2 在调节肌肉生长和再生中的作用的更多认识将增强我们对细胞信号传导这一鲜为人知的方面的理解，并可能为治疗肌病的疗法开辟新途径。