Regulation of muscle growth by SHP-2

说明(申请人提供)：肌肉的生长和修复是一个复杂的过程，涉及成肌细胞的增殖和分化，成肌细胞与现有的肌肉纤维融合。这项研究提案的广泛目标是定义调节这一过程的细胞信号机制。SHP-2是一种细胞质蛋白酪氨酸磷酸酶，是肌肉发生所必需的。我们的初步数据表明，SHP-2需要通过钙调神经磷酸酶和RhoA信号通路激活NFAT，NFAT是肌肉生长的关键调节因子。我们将使用原代成肌细胞来确定SHP-2激活钙调神经磷酸酶和RhoA信号来调节NFAT和肌肉发生的机制。SHP-2底物捕获突变体和质谱学将被用来鉴定SHP-2调节NFAT的底物。骨骼肌特异性缺失SHP-2的小鼠将被用于肌肉损伤模型，以研究SHP-2在体内调节肌肉生长和再生的作用。更多地了解SHP-2在调节肌肉生长和再生中所起的作用将增强我们对细胞信号这一鲜为人知的方面的理解，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.