TRAF6在失神经肌萎缩过程中的作用及机制研究

探讨失神经肌萎缩的分子机制，对于周围神经损伤修复后功能重建至关重要。本课题组前期研究发现，TRAF6在失神经肌萎缩过程中表达显著上调；抑制其表达，不仅可减轻肌萎缩，降低E3泛素连接酶的表达，还可减少失神经引起的自噬，提示TRAF6在失神肌萎缩过程中发挥重要作用。为进一步探讨其作用机制，本项目拟系统研究TRAF6在失神经肌萎缩过程中对泛素化蛋酶体水解、自噬-溶酶体水解、Akt/mTOR介导的蛋白合成以及Notch通路介导的肌纤维再生等途径的影响，揭示其通过对蛋白降解、合成以及肌纤维再生等方面调控失神经肌萎缩的机制。在此基础上通过体内实验进一步探讨靶向抑制TRAF6对失神经肌萎缩的保护作用及机理。通过研究，将可为失神经肌萎缩的分子调控机制增加新内容，为将TRAF6作为失神经肌萎缩防治的新靶点提供实验依据。

The understanding of molecular mechanisms responsible for denervation-induced muscle atrophy is of utmost importance for functional reconstruction after peripheral nerve injury repair. Our previous studies have found that the expression of TRAF6 is significantly up-regulated during the process of denervation-induced muscle atrophy, and inhibition of TRAF6 attenuates muscle atrophy, suppresses the expression of the E3 ubiquitin ligase, and reduces denervation-induced autophagy. These findings suggest that TRAF6 may play a critical role in denervation-induced muscle atrophy. To have a further insight into the action mechanisms of TRAF6, this project intends to investigate how TRAF6 affects ubiquitin-proteasome system, autophagy-lysosomal system, Akt/mTOR-mediated protein synthesis and Notch pathway-mediated muscle fiber regeneration, and then to reveal how TRAF6 modulates denervation-induced muscle atrophy through regulating protein degradation, protein synthesis and muscle fiber regeneration. Furthermore, we plan to conduct the in vivo tests to explore the protective effect and mechanism of target inhibition of TRAF6 against muscle atrophy. We believe that this project will contribute to the knowledge of the molecular regulation of denervation-induced muscle atrophy, and the development of TRAF6 as a therapeutic target for the prevention and treatment of denervation-induced muscle atrophy.