TBK1调控c-Cbl/TrkB介导青光眼视网膜神经节细胞凋亡的作用机制研究

视网膜神经节细胞（RGCs）凋亡是青光眼视功能损害的根本原因，而TrkB降解是营养因子BDNF摄取障碍导致RGCs凋亡的关键因素。国内外研究发现，c-Cbl是目前已知的能够介导TrkB降解的E3泛素酶。根据生物信息学预测和申请人前期研究基础，TBK1具有潜在磷酸化c-Cbl诱导RGCs凋亡的作用。结合预实验：TBK1抑制剂能够抑制c-CblS669位点磷酸化和TrkB降解。基于此，我们提出假说：青光眼损伤刺激下，TBK1磷酸化激活c-Cbl介导TrkB泛素降解，进而引起BDNF摄取障碍导致的RGCs凋亡。课题组拟首先明确TrkB泛素降解在介导RGCs凋亡中的重要作用；随后，探讨TBK1磷酸化激活c-CblS669位点介导TrkB泛素降解的分子机制；最终在整体水平验证，shRNA靶向干扰TBK1可以抑制TrkB降解和RGCs凋亡；有望为青光眼视神经保护治疗提供新的靶点和理论依据。

Retinal ganglion cells apoptosis is the primary cause of glaucoma visual deterioration, while TrkB degradation is a key factor in RGCs apoptosis induced by dysfunction of BDNF uptake. Latest domestic and foreign studies found that c-Cbl was currently identified as an E3 Ub-ligase for TrkB. Combined with Bioinformatics prediction and our previous research results, TBK1 has potential phosphorylation c-Cbl to induce RGCs apoptosis. Our preliminary experiments showed that the TBK1 inhibitor can suppress the phosphorylation of c-Cbl S669 and reverse TrkB degradation. Accordingly, we speculated that TBK1 phosphorylated c-Cbl mediated TrkB degradation, which leads to RGCs apoptosis caused by dysfunction of BDNF uptake. We first elucidate TrkB degradation in RGCs apoptosis were derived from ubiquitination. And then, to explore the mechanism of TrkB ubiquitination by TBK1 phosphorylated c-Cbl S669 at the molecular level. Finally, to verify the intervention effect of TBK1 shRNA on RGCs apoptosis via regulation of c-Cbl/TrkB in vivo. Our research will provide a novel target and basis for neuroprotective therapy in glaucoma.