糖尿病血管并发症是DM患者致死致盲的首要原因，降糖并控制血管并发症已成为DM管理的攻关重点。我们前期工作首次发现抑癌蛋白FBXW7具有抗氧化应激的新功能，能降低高糖下大血管、微血管内皮细胞的高ROS水平，抑制PARP过度激活，纠正了“统一机制学说”的两个上游关键致病环节。在此基础上，本项目将进一步研究和证实FBXW7对高糖下血管内皮线粒体功能障碍的影响，抵抗DR氧化应激损伤的效率与力度；探讨其分子机制，是否与FBXW7通过激活ATM介导的HR和经典NHEJ通路，促进DSBs修复以抑制PARP的过度激活及其负性作用有关。这些研究将阐明高糖下DNA损伤修复的重要作用与地位，揭示微血管和大血管内皮的异同，为深刻理解“统一机制学说”做了有利补充；作为防治新靶点，FBXW7蛋白或其激动剂修复了传统药物PARP抑制剂所遗留的DSBs威胁，较之有明显优势，为糖尿病并发症现有的治疗手段开发了一种新的思路。

Vascular complications are the leading cause of death and blindness in diabetic patients. Reducing blood glucose and controlling vascular complications have become the key points of diabetes mellitus (DM) management. For the first time in our previous work, we found that the tumor suppressor FBXW7 has new functions of antioxidant stress, which can reduce the high reactive oxygen species (ROS) level of macrovascular and microvascular endothelial cells, inhibit poly-ADP-ribose polymerase (PARP) excessive activation, the two upstream key pathogenic moleculars of the "unified mechanism theory" under high glucose medium. On this basis, this project will further study the effect of FBXW7 on the mitochondrial dysfunction of vascular endothelium under hyperglycemia, confirm the efficiency of its protective effect on diabetic retinal tissues against oxidative stress damage, and explore the molecular mechanism whether FBXW7 protein enhances ATM-mediated homology recombination (HR) and classical non homologous end joining (NHEJ) pathways to promote DNA double strand breaks (DSBs) repair to inhibit PARP activity and its negative effects. These studies will clarify the important role of DNA repairing against oxidant stress injury, and reveal the differences between micro vessels and large vascular endothelium, which are favorable supplements to understanding the pathogenesis of DM complications. It’s also illustrated that FBXW7 protein or its agonist, owing to repairing the DSBs threat left by the traditional drug PARP inhibitors, is a preferred alternative over the traditional treatment drug PARP inhibitors, offers a new approach to the medicines of DM complications.