高糖环境诱导ROS及内质网应激与糖尿病相关干眼的关系

糖尿病人群的干眼发病率高，严重者甚至失明。其发病机制不清楚。高糖环境诱导活性氧(ROS)的累积，引起氧化应激和内质网应激(ERS)，可导致细胞损伤，甚至凋亡。基于我们前期实验，①糖尿病患者泪液中氧化应激反应和凋亡路径相关蛋白表达上调②角膜上皮细胞在高渗透压干预下，产生大量ROS，诱导磷酸化JNK表达(活化)③糖尿病患者未发生干眼时，已出现角膜上皮细胞的损伤，我们推测糖尿病患者泪液的高糖微环境诱导结膜/角膜上皮细胞产生大量ROS，引起氧化应激和ERS，介导结膜/角膜上皮细胞的双重损伤，从而发生干眼。本项目拟在体外观察高糖环境诱导的ROS对结膜/角膜上皮细胞损伤的调控作用及引起细胞凋亡的作用机制；然后建立糖尿病相关干眼的动物模型，探索结膜/角膜上皮细胞损伤之间的关系，并观察ROS抑制剂对结膜/角膜上皮细胞的保护作用。通过上述研究，进一步阐明糖尿病相关干眼的发病机制，为其个体化治疗提供重要依据。

Dry Eye often occurred in diabetes mellitus (DM) patients, even induced the loss of vision, while its pathogenesis was unclear. High concentration of sugar could induce the accumulation of reactive oxygen species (ROS), then oxidative stress and endoplasmic reticulum stress (ERS) happened, which led cells to be damaged, even apoptosis. Here also showed our study results as followed: ① the analysis of tear proteomics hinted that oxidative stress and apoptosis related proteins were up-expressed; ② in the condition of high osmotic pressure, ROS was accumulated in corneal epithelial cells (ECs) and induced the expression of active p-JNK; ③ the corneal ECs has been damaged in the patients with DM when dry eye did not take place. Then we suggest that because of DM patients’ tears with high concentration of glucose, much ROS are accumulated in conjunctival ECs and corneal ECs; and the ROS induce the damage, even apoptosis of conjunctival and corneal ECs through oxidative stress/ERS; which finally cause dry eye. In this project, we will observe that how high concentration of sugar-induced ROS regulate the damage of the conjunctival and corneal ECs and how ROS contribute to ERS, leading to the apoptosis of ECs; then an animal model of DM related dry eye will be set up; in which we will investigate the relationship of conjunctival and corneal ECs when damages occur, in addition, if ROS-blocked agent can protect the ECs or not. The results of this project can further clarify the pathogenesis of DM related dry eye and support the important academic evidence for its individualized treatment.