Regulation of muscle growth by SHP-2

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确定调节这一过程的细胞信号传导机制。SHP-2是肌生成所需的细胞质蛋白酪氨酸磷酸酶。我们的初步数据表明，SHP-2需要通过Ca 2+钙调神经磷酸酶和RhoA信号通路激活NFAT，NFAT是肌肉生长的关键调节剂。我们将使用原代成肌细胞来确定SHP-2激活Ca 2+钙调神经磷酸酶和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将用于鉴定SHP-2调节NFAT的底物。具有SHP-2的骨骼肌特异性缺失的小鼠将用于肌肉损伤模型中以研究SHP-2在调节肌肉生长和再生中的体内作用。更好地理解SHP-2在调节肌肉生长和再生中的作用将增强我们对细胞信号传导这一知之甚少的方面的理解，并可能为治疗肌病开辟新的途径。

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.