HIF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

Chronic, painful tendon conditions, known as tendinopathy, affect millions people in both athletic and elderly settings. However, in spite of intensive research on tendinopathy in recent years, scientific data about its critical pathogenesis process are still lacking, and traditional treatment had limited success in treating chronic painful conditions. There are accumulating evidence supporting that hypoxia exerts profound effects on tenocyte apoptosis and inflammation reaction. Thus the central hypothesis of this project is that alterations of TSPC self-renew and differentiation contribute to tendinopathy pathogenesis process, which is mediated by hypoxia-inducible factor (HIF) signal pathway. Building upon our previous research on applying TSPC for tendon regeneration, we will conduct our research on following stages. Using interdisciplinary and integrative approaches, we will investigate the developmental mechanisms of tendinopathy by characterizing changes in the phenotypic expression of tendon fibroblasts as well as signal pathways related to them, such as inflammation and hypoxia. In addition, we will determine the effect of interfering HIF signal pathway on TSPC self-renew and differentiation. Finally, we will estimate the safety and efficacy of TSPC combined HIF inhibitor treatment on tendinopathy. The scientific findings of this project will improve our understanding of the precise pathogenic processes of tendinopathy. They will also aid in devising new protocols for the clinical management of tendinopathy and provide some preclinical data for TSPC combined HIF inhibitor treatment for tendinopathy.

肌腱病是最常见的软组织疾病之一，然而其关键的发病机理尚不明确且临床缺乏长期有效的治疗方法。最新研究表明低氧信号对于肌腱细胞凋亡及炎症反应有重要影响，可能是导致肌腱发病的早期因素。而体内肌腱干细胞对于维持组织正常功能至关重要，其更新与分化调控的异常往往是组织器官发病的根源。因此，本课题的假说为低氧信号通路影响肌腱干细胞的自我更新和分化，调控了肌腱病的发生发展。我们立足于本研究组在运用肌腱干细胞治疗肌腱损伤的研究成果（Biomaterials2010），探索低氧应激信号通路和关键因子在肌腱病中的调控作用及其机理；阐明低氧应激信号通路关键基因HIF与肌腱干细胞自我更新和分化异常的关系；最后通过动物实验评估肌腱干细胞联合HIF干预手段治疗肌腱病的有效性和可行性。该课题将为肌腱病的分子生物学发病机制以及肌腱干细胞的自我更新和分化异常在肌腱病发生中的病理作用及其调控机理提供新知识，创新肌腱病治疗手段。

肌腱病是最常见的软组织疾病之一，然而其关键的发病机理尚不明确且临床缺乏长期有效的治疗方法。最新研究表明低氧信号对于肌腱细胞凋亡及炎症反应有重要影响，可能是导致肌腱发病的早期因素。而体内肌腱干细胞对于维持组织正常功能至关重要，其更新与分化调控的异常往往是组织器官发病的根源。本课题探索低氧应激信号通路和关键因子在肌腱病中的调控作用及其机理；阐明低氧应激信号通路关键基因HIF 与肌腱干细胞自我更新和分化异常的关系；最后通过动物实验评估肌腱干细胞联合HIF 干预手段治疗肌腱病的有效性和可行性。.重要结果：1. 地高辛体外抑制HIF-2α调控TSPCs分化；2，地高辛体内抑制HIF-2α调控肌腱修复。.该课题将为肌腱病的分子生物学发病机制以及肌腱干细胞的自我更新和分化异常在肌腱病发生中的病理作用及其调控机理提供新知识，创新肌腱病治疗手段。.