视网膜血管线粒体DNA氧化损伤启动糖尿病视网膜病变“代谢记忆”机制研究

Known as the key problem of diabetic retinopathy(DR), metabolic memory is closely related to the oxidative damage, which means DR worsening continuously after blood glucose controlled. It has been reported by us that the presence of retinal vascular mitochondrial DNA (mtDNA) oxidative damage is confirmed, which is involved in the onset of DR by resulting the vicious cycle of reactive oxygen species(ROS) overproduction. Being activated, the vicious cycle continue to produce a large number of ROS, but no depending hyperglycemia. So, retinal vascular mtDNA oxidative damage will be investigated to prove the relationship with metabolic memory of DR in vivo, and the possibility of it triggering metabolic memory by the vicious cycle in vitro. In addition, mtDNA oxidative damage in retinal vascular endothelium will be targeted repaired to clear the best time to break the vicious cycle and the protection on "residual" oxidative stress. Combined, an new opinion will be provide for exploring the "window period" and the target to protect metabolic memory in DR by managing mtDNA oxidative damage.

"代谢记忆"是糖尿病视网膜病变(Diabetic Retinopathy, DR)防治的关键难题，是指血糖控制后DR进程难于静止的现象，氧化损伤与其密切相关。本课题组已发表文章证实DR早期存在视网膜血管线粒体DNA(Mitochondrial DNA ,mtDNA)氧化损伤，且由之引发的"活性氧(Reactive Oxygen Species, ROS)过量产生恶性循环"参与DR早期发病。该恶性循环激活后可不依赖高血糖环境是否存在，持续产生大量ROS。本研究拟体内试验证实视网膜血管mtDNA氧化损伤与DR代谢记忆发生密切相关；体外模拟代谢记忆条件，了解mtDNA氧化损伤通过恶性循环启动代谢记忆的可能性；靶向修复高糖作用后的视网膜血管内皮细胞mtDNA氧化损伤，明确打断恶性循环的最佳时间点，及其对 "残余"氧化应激的保护作用，从mtDNA氧化损伤角度探讨DR代谢记忆防护的"窗口期"及靶点。

“代谢记忆”是糖尿病视网膜病变(Diabetic Retinopathy, DR)防治的关键难题，是指血糖控制后DR进程难于静止的现象，氧化损伤与其密切相关。本课题组已发表文章证实DR早期存在视网膜血管线粒体DNA(Mitochondrial DNA ,mtDNA)氧化损伤，且由之引发的“活性氧(Reactive Oxygen Species, ROS)过量产生恶性循环”参与DR早期发病。该恶性循环激活后可不依赖高血糖环境是否存在，持续产生大量ROS。本研究拟体内试验证实视网膜血管mtDNA氧化损伤与DR代谢记忆发生密切相关；研究发现糖尿病视网膜病存在代谢记忆现象，mtDNA 氧化损伤确实参与DR代谢记忆，可能通过参与代谢记忆导致 DR 发病；通过线粒体靶向DNA修复酶hOGG1修复线粒体DNA 氧化损伤可以升高线粒体膜电位和NADPH-1和CO1水平，降低Cytochrome C和ROS水平，从而可能阻止DR病程。