2: R-SPONDIN2: A NOVEL REGULATOR OF SKELETAL MUSCLE REGENERATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 骨骼肌具有显著的再生潜力，这在很大程度上归因于存在于成体肌肉中的卫星细胞和其他肌肉干细胞。因此，卫星细胞对于肌肉损伤和退行性疾病的治疗应用具有极大的兴趣。为了开发基于卫星细胞生物学的有效治疗方法，关键是要确定在肌肉修复和再生过程中调节其增殖和/或分化的关键信号传导因子，途径和机制。 R-spondin是一类新型的分泌蛋白，其激活Wnt/β-连环蛋白途径。PI的实验室已经发现R-spondin 2的表达在肌肉再生过程中显著且选择性地增加，与卫星细胞增殖和肌源性分化的时间密切重叠。这表明R-spondin 2可以通过Wnt信号通路选择性地促进骨骼肌卫星细胞的增殖和/或分化。使用体外原代细胞培养和体内小鼠模型，我们将1）确定R-spondin 2在促进卫星细胞增殖和/或肌源性分化中的作用，并确定关键的R-spondin 2信号通路; 2）确定R-spondin 2功能的获得或丧失如何影响体内骨骼肌再生。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Skeletal muscle possesses remarkable regeneration potential, which largely is attributable to satellite cells and other muscle stem cells that reside in adult muscle. Satellite cells, therefore, are of great interest for therapeutic applications for muscle injury and degenerative diseases. To develop effective therapeutics based on satellite cell biology, it is critical to identify key signaling factors, pathways, and mechanisms that regulate their proliferation and/or differentiation during muscle repair and regeneration. R-spondins are a novel class of secreted proteins that activate Wnt/beta-catenin pathways. The PI's laboratory has discovered R-spondin2 expression is markedly and selectively increased during muscle regeneration, with close overlapping timing with satellite cell proliferation and myogenic differentiation. This suggests that R-spondin2 may selectively promote proliferation and/or differentiation of skeletal muscle satellite cells via Wnt signaling pathways. Using in vitro primary cell culture and in vivo mouse models, we will 1) determine the roles of R-spondin2 in promoting proliferation and/or myogenic differentiation of satellite cells, and define key R-spondin2 signaling pathways; and 2) determine how gain or loss of R-spondin2 function affects skeletal muscle regeneration in vivo.