mTOR-NPAT信号轴在肌腱分化及损伤修复中的作用及机制研究

目前对肌腱分化的机制并不清楚，导致肌腱损伤缺乏有效的治疗手段。本课题组最近发现并报道mTOR蛋白是调控肌腱分化的关键节点分子，在此基础上我们进一步探索相关的分子机理。本项目的预实验显示肌腱特异性敲除mTOR会抑制组蛋白基因转录，而且抑制mTOR会导致NPAT(组蛋白转录的关键调控分子)在细胞内的定位改变。为了研究NPAT在肌腱分化中的作用，我们构建了首株肌腱特异性NPAT敲除小鼠。该小鼠呈现肌腱发育不良和四肢抓力减弱的表型，其肌腱中的胶原纤维直径变细，且一型胶原蛋白的表达下调。我们计划在上述预实验研究的基础上，利用分子细胞生物学手段阐明肌腱分化过程中mTOR对NPAT的调控机制；利用组织工程手段，通过干预mTOR-NPAT信号轴来促进人工类肌腱组织的质量，并尝试对肌腱损伤模型小鼠进行修复再生。本项目将有助于阐明肌腱分化的分子机理，为肌腱炎和肌腱损伤的治疗提供分子靶点和实验依据。

Tendon repair is a clinical challenge because of the limited understanding on tenogenesis. We recently identified mTOR as a node molecule for regulating tendon differentiation. Here we showed that tendon specific-ablation of mTOR inhibited histone gene transcription. Further, inhibition of mTOR impaired the cellular localization of NPAT, the key modulator of histone transcription. Therefore, we prepared the first tendon-specific NPAT knockout mice. The mice displayed tendon defect, impaired limb grip strength, reduced diameters of tendon collagen fibrils, and reduction of Collagen I expression. We will further elucidate the underlying molecular mechanisms, enhance the quality of tendon organoid by interfering mTOR-NPAT axis, and try to promote the repair effect on tendon-injury mice model. Our study will elucidate the mechanism for tenogenesis and provide a novel therapeutic target for tendinopathy and tendon injury.