L1CAM表观遗传沉默介导的自噬流受阻在糖尿病视网膜tau蛋白病变中的作用机制研究

申请人及团队新近在国际上首次证实：视网膜神经节细胞（RGCs）内tau蛋白异常过度磷酸化是导致糖尿病早期视网膜神经退行性病变的关键事件，但其是否与自噬流改变有关目前尚不清楚。我们前期发现糖尿病性RGCs发生自噬流受阻于自噬体-溶酶体融合，磷酸化tau蛋白无法呈递至溶酶体；进一步通过转录组学、蛋白质组学等方法发现：糖脂毒性下表观遗传沉默的L1CAM可能是一个全新的自噬流调控因子，可能与介导自噬体-溶酶体融合的关键分子Rab7和LAMP-1互作，其低表达导致RGCs自噬体-溶酶体融合障碍；推测：L1CAM表观遗传沉默介导的自噬体-溶酶体融合障碍可促进糖尿病视网膜tau蛋白病变。本项目拟在前期基础上查明L1CAM转录沉默介导的自噬体-溶酶体融合障碍在糖尿病视网膜tau蛋白变病中的作用及其调控自噬体-溶酶体融合的机制，并探索L1CAM转录沉默的表观遗传学机制，为DR治疗提供全新的分子标靶和思路。

We have recently demonstrated that abnormal hyperphosphorylation of tau in retinal ganglion cells (RGCs) is a key event leading to diabetic retinal neurodegeneration. However, whether abnormal hyperphosphorylation of tau in RGCs is associated with defect in autophagy at early phase of diabetes remains unknown thus far. We found that the autophagy flux in diabetic RGCs was blocked due to disruption of autophagosome-lysosome fusion, thereby inhibiting the delivery of phosphorylated tau to lysosome. Further transcriptomics and proteomics study revealed that the epigenetically silenced L1CAM may be a novel regulator of autophagic flux, which might interact with Rab7 and LAMP-1, the key molecule that mediate autophagosome-lysosome fusion. Moreover, knockdown of L1CAM led to disruption of autophagosome-lysosome fusion in RGCs. Thus, we speculate that disruption of autophagosome-lysosome fusion mediated by L1CAM epigenetic silencing can trigger diabetic retina tauopathy. This project is aimed to investigate the mechanism underlying the regulation of autophagosome-lysosomal fusion by L1CAM and the role of L1CAM transcription silencing in mediating the disruption of autophagosome-lysosomal fusion in diabetic retinal tauopathy. Furthermore, the epigenetic mechanism of L1CAM transcriptional silencing will be explored. The finding of this study is expected to provide new molecular targets for treatment of diabetic retinopathy.