严重的骨骼肌创伤，常可致机体的运动失能。研究表明，骨骼肌损伤后的修复与再生是肌卫星细胞的成肌分化过程，多种细胞因子单独或联合作用参与其中。但是，骨骼肌再生的确切机制远未弄清楚。2011年申请者报道了生长因子颗粒蛋白前体（Progranulin, PGRN）抑制小鼠成肌细胞分化的研究结果，揭示了PGRN在骨骼肌生长发育中的重要作用。然而，PGRN抑制骨骼肌成肌分化的具体分子机制尚不清楚。本项目作为上述研究的延伸，我们拟以小鼠成肌细胞和原代培养的肌卫星细胞体外诱导向肌管分化为主要方法，重点探讨骨骼肌发育中PGRN的上游调控分子；发现介导PGRN调控成肌分化作用的膜受体；明确PGRN调控成肌分化的下游信号传导通路。上述研究对解释骨骼肌的生长发育、骨骼肌的损伤后修复与再生都有着重要的理论价值，并为研发肌萎缩等难治性骨骼肌疾病的药物提供新的作用靶点。

Serious skeletal muscle trauma can lead to body motion disability. Repairment and regeneration of skeletal muscle after trauma is the course of myogenic differentiation. Multiple cytokines participate in this process, but the molecular mechanism of muscle repairment and regeneration is not clear. Progranulin (PGRN) is an autocrine growth factor with multiple functions. Recently we reported that PGRN suppresses myogenic differentiation by reducing the levels of transcription factors important for myogenesis. However, the molecular mechanism by which PGRN inhibits myogenesis remains largely unclear. This proposal is to determine 1) the upstream regulatory molecule of PGRN; 2) the receptor which PGRN inhibiting myogenic differentiation depends on; and 3) what is the signaling pathways responsible for PGRN inhibiting of myogenic differentiation. Proposed studies will not only provide insights into the molecular mechanism underlying the normal muscle development and the pathogenesis of muscle disease, but also may lead to novel therapeutic strategies for the treatment of muscle diseases.