RAC1信号通路在肌腱病的病理微环境下对干细胞自我更新和分化的作用和机制研究

The tendon calcification of tendinopathy is a very common phenomenon. However, there is no its effective clinical treatment as the pathogenesis is still unclear. There are more and more evidence supporting that the variation of micro-environment have a great impact on stem cells’ function and this may be an important cause of tendon calcification. The hypothesis of this project is to find out whether Rac1-related signaling pathways influence tendon calcification process by controlling tendon stem/progenitor cells’ self-renewal and differentiation function. According to our previous researches, we will conduct our research on following stages. Firstly, we will investigate inflammation related-pathological process of tendon calcification and supplement the pathological data of tendinopathy. Secondly, we focus on investigating the importance and mechanism of Rac key factors and related signaling pathways in tendon calcification. Thirldly, we try to investigate the tendon stem cells’ function changes in pathological condition and its relationship with Rac1. At last, we try to discover the effects of TSPCs and Rac1 on the repair of tendinopathy. In the previous study, we found that Rac1 was highly expressed in diseased tendon and analyzed the possible signaling pathway preliminarily. What’s more, the controlled release microspheres have been successfully constructed in the previous experiments, which may also can be used in slow-releasing Rac1 inhibitor. It is expected that this study will improve our understanding of the molecular biology mechanism of tendon calcification, providing a new therapeutic target for the prevention and treatment of chronic tendinopathy. This may provide a new strategy for clinical stem cell therapy.

肌腱钙化是一种常见的疾病，然而其发生机制仍不清楚，致使缺乏有效的治疗方式。最近研究发现微环境因素变化对于组织干细胞功能有重要的影响，这可能是引起肌腱钙化的重要因素。本课题的假说是Rac1相关信号通路通过影响肌腱干细胞的自我更新和分化功能调控肌腱病钙化的发生发展。首先研究肌腱钙化和炎症相关的病理过程，完善肌腱病理学数据；其次专注研究Rac关键因子在肌腱钙化中的作用机制，病理状态下肌腱干细胞（TSPCs）的功能变化及其与Rac1的关系研究，明确Rac1在肌腱病中的病理性改变及其对TSPCs功能的影响；最终联合运用TSPCs和Rac1干预手段治疗肌腱病的可行性和功效性研究。在前期研究中我们发现Rac1在肌腱病中高表达，初步分析了可能的作用通路，并初步制备了缓释材料。预期本研究将对肌腱钙化的分子生物学机制有着进一步的认识，为慢性肌腱病的预防和治疗提供新的靶点，为临床干细胞治疗提供新的策略。

肌腱病是一种以疼痛、肿胀和功能障碍为特征的常见疾病。在疾病晚期可能发生病理改变，如肌腱钙化。本课题发现肌腱干细胞在病变肌腱的炎症微环境中发生成骨分化，并证明了这一过程伴随着Rac1相关信号通路的激活。特异性抑制剂NSC23766显著下调了IL-1β处理的肌腱干细胞中基质降解和钙化相关基因的表达，挽救了肌腱相关基因的表达。为了进行体内评估，我们进一步开发了负载Rac1抑制剂NSC23766的药物递送系统。壳聚糖/β-甘油磷酸酯包封的NSC23766能有效抑制跟腱骨化，促进跟腱再生。. 重要结果：1.Rac1相关信号通路的激活促进了肌腱干细胞的成骨分化；2.负载Rac1抑制剂的壳聚糖/β-甘油磷酸酯有效干预了肌腱病的病理性钙化。. 该课题为肌腱病病理性钙化的分子生物学机制以及肌腱干细胞的自我更新和分化异常在肌腱病病理性钙化发生中的病理作用及其调控机理提供了新知识，提供了新的治疗策略。