Glycemic Control and Progression of Diabetic Retinopathy

描述（由申请人提供）：视网膜病变是糖尿病最严重的并发症之一，是年轻人获得性失明的主要原因。临床研究表明，视网膜病变在良好的控制开始后抵抗停滞，并且先前血糖暴露对微血管并发症后期过程的遗留效应通常被称为“代谢记忆”。拟议的研究重点是了解导致这种早期视网膜病变停止趋势的机制。总体假设预测，“视网膜病变对停滞的抵抗部分是由于视网膜微血管中持续的线粒体功能障碍和氧化修饰蛋白质和DNA的积累，导致视网膜毛细血管细胞的不可逆损失”。作为支持，我们已经表明，在大鼠中重新建立良好的血糖控制后，视网膜蛋白的氧化应激和亚硝基化仍在继续，视网膜在糖尿病中经历线粒体功能障碍，MnSOD的过表达保护视网膜免受DNA损伤。目的1将确定良好的血糖控制后视网膜线粒体功能障碍的作用。使用大鼠模型的代谢记忆，我们将测试的假设，即“超氧化物继续积累，导致线粒体功能障碍和形成氧化修饰的DNA在血管系统中，这是很难逆转后，良好的控制是建立”。目的2将研究超氧化物对代谢记忆的作用机制，并将检验“由于超氧化物的增加，GAPDH的活性受到抑制，导致AGEs的积累; AGEs的增加导致视网膜微血管的不可逆变化”的假设。目的3将确定抑制超氧化物积累对高血糖逆转后视网膜病变继续进展的影响。“抑制超氧化物将能够直接抑制氧化应激、GAPDH和受这些过程影响的生化异常，从而抑制视网膜病变的进展”的假设将在大鼠中通过治疗性抑制超氧化物积累和在过表达MnSOD的小鼠中进行测试。对导致糖尿病视网膜病变对停止抵抗的异常的表征有望揭示预防其进展的治疗的新靶点，并为患者提供用辅助治疗补充其最佳血糖控制的机会。

DESCRIPTION (provided by applicant): Retinopathy, one of the most debilitating complications of diabetes, is the leading cause of acquired blindness among young adults. The clinical studies have shown that retinopathy resists arrest after good control is initiated, and the carry-over effect of prior glycemic exposure on the later course of microvascular complications is commonly termed as 'metabolic memory'. The proposed studies are focused to understand the mechanism responsible for this tendency of incipient retinopathy to halt. The overall hypothesis predicts that 'the resistance of retinopathy to arrest is, in part, due to the continued mitochondrial dysfunction and accumulation of oxidatively modified proteins and DNA in the retinal microvasculature, resulting in irreversible loss of retinal capillary cells'. In support, we have shown that oxidative stress and nitrosylation of retinal proteins continue after re-institution of good glycemic control in rats, the retina experiences mitochondrial dysfunction in diabetes, and overexpression of MnSOD protects the retina from DNA damage. Aim 1 will determine the role of mitochondrial dysfunction in the retina after good glycemic control is instituted. Using the rat model of metabolic memory we will test the hypothesis that 'superoxide continues to accumulate resulting in mitochondrial dysfunction and formation of oxidatively modified DNA in the vasculature that is difficult to reverse after good control is instituted'. Aim 2 will investigate the mechanism by which superoxide contributes to the metabolic memory, and will test the hypothesis that 'due to increased superoxide the activity of GAPDH is inhibited resulting in accumulation of AGEs; and increased AGEs result in irreversible changes in retinal microvasculature'. Aim 3 will determine the effect of inhibiting superoxide accumulation on continued progression of retinopathy after hyperglycemia is reversed. The hypothesis that 'inhibition of superoxide will be capable of directly inhibiting oxidative stress, GAPDH and the biochemical abnormalities influenced by these processes, and thus will inhibit the progression of retinopathy' will be tested in rats by therapeutically inhibiting superoxide accumulation, and in mice overexpressing MnSOD. Characterization of the abnormalities responsible for the resistance of diabetic retinopathy to halt is expected to reveal novel targets for therapies to prevent its progression, and offer patients an opportunity to supplement their best possible glycemic control with adjunct therapies.