O-糖基化修饰参与糖尿病性视网膜病变神经损伤机制研究

As the prevalence of diabetes has continued to rise, diabetic retinopathy ( DR) has become one of the main blinding disease. The key of DR prevention and control is that for early diagnosis of disease and early intervention treatment. The early pathological changes of DR including retinal capillary anomalies and neural injury, the nerve damage often happen earlier more than the capillary pathological changes. The best time for DR treatment is before the appearance of visual function damage, namely the corresponding intervention should be taken before the damage of retina nerve tissue occurred. This study was to take the enzymatic modification of glycosylated change as the breakthrough point, which caused by the glucose metabolic disorder due to hyperglycemia, discusses the mechanism of neural injury related to O-GlcNAc modification which is one of products of the enzyme glycosylation. To know the function of O-GlcNAc modified in the role of cell apoptosis through the research: 1. O-GlcNAc modified directly influence, 2. O-GlcNAc modified influenced the protein related to cell apoptosis and 3. O-GlcNAc modified influence the protein control the cell apoptosis. Offer the research foundation to the related intervention measure for the treatment of DR.

糖尿病性视网膜病变（diabetic retinopathy DR）神经损伤早于微血管病变。早期干预的最佳时机在视网膜神经组织发生损伤前进行。糖代谢紊乱所引起的酶促糖基化改变是早期主要的病理生理改变，是启动下游通路的关键因素。本课题在前期研究糖基转移酶、N-糖基化修饰的基础上，进一步探讨酶促糖基化的重要产物O-糖基化修饰中的O-GlcNAc修饰形式参与DR 视网膜神经损害的相关机制，以此作为研究酶促糖基化修饰与DR相关性的切入点。相关研究尚属空白，希望通过研究： O-GlcNAc修饰与视网膜神经节细胞（RGC）凋亡关系；其诱导RGC凋亡的相关调控机制，了解高糖引起的酶促糖基化改变在DR发病中的重要作用；通过蛋白组学研究翻译后修饰过表达蛋白寻找相关研究靶点，为相关干预机制的采用提供实验室基础。

糖尿病性视网膜病变(diabetic retinopathy DR)已成为我国主要致盲眼病之一。DR 防治的关键在于对疾病进行早期的诊断与干预治疗。DR早期病理改变包括视网膜微血管异常和神经损伤，其中神经损伤往往较微血管病变发生得更早。DR早期干预治疗的最佳时机在于视功能出现损害之前，即在视网膜神经组织发生损伤前进行相应干预。本研究拟从高血糖引起的糖代谢紊乱所导致的酶促糖基化修饰的改变为切入点，探讨酶促糖基化的重要产物O-糖基化修饰中的O-糖基化修饰形式参与DR视网膜神经损害的相关机制。本课题通过研究O-糖基化修饰及N-糖基化修饰对糖尿病性视网膜病变炎症机制的作用，糖基化修饰与视网膜神经细胞凋亡的关系以及RUNX1的O-糖基化修饰参与糖尿病性视网膜病发病机制，发现高糖状态下血管内皮细胞ICAM-1的表达上调受转录因子Sp1的O-糖基化修饰的调控，BRCE膜表面ICAM-1分子表达上调与N-糖基化修饰相关，因此糖基化修饰可能成为治疗DR的新靶点。过表达EMCN从而减少DR导致的视网膜组织神经元细胞的凋亡可能通过活化AKT通路，抑制caspase-3的激活而实现。不论在高糖还是正常糖条件下，RUNX1都能被O-糖基化修饰, 但高糖条件下RUNX1 O-糖基化修饰增强；RUNX1的O-糖基化修饰能促进HRMECs增殖，促进人视网膜微血管内皮细胞迁移。本研究证明了高糖引起的酶促糖基化改变在 DR 发病中的重要作用，为相关干预机制的采用提供实验室基础。

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