Glycemic Control and Progression of Diabetic Retinopathy

描述(申请人提供)：视网膜病变，糖尿病最衰弱的并发症之一，是年轻人后天失明的主要原因。临床研究表明，视网膜病变在良好的控制开始后抵抗停止，先前的血糖暴露对后期微血管并发症的遗留效应通常被称为代谢记忆。拟议的研究集中于了解导致这种早期视网膜病变停止的机制。该假说认为，视网膜病变的抗阻部分是由于线粒体功能障碍，氧化修饰的蛋白质和DNA在视网膜微血管系统中积聚，导致视网膜毛细血管细胞不可逆转的丧失。在支持方面，我们已经表明，在大鼠重新建立良好的血糖控制后，视网膜蛋白质的氧化应激和亚硝化仍在继续，糖尿病患者的视网膜经历了线粒体功能障碍，并且MnSOD的过表达保护视网膜免受DNA损伤。目的1在建立良好的血糖控制后，将确定线粒体功能障碍在视网膜中的作用。利用代谢记忆的大鼠模型，我们将检验这样的假设：“超氧化物继续积累，导致线粒体功能障碍，并在血管系统中形成氧化修饰的DNA，这在良好的控制建立后很难逆转。”目的2将探讨超氧化物对代谢记忆的贡献机制，并将检验这样的假设：由于超氧化物歧化作用的增加，GAPDH的活性被抑制，导致AGEs的积累；而AGEs的增加导致视网膜微血管系统不可逆转的变化。目的3将确定在高血糖逆转后抑制超氧阴离子蓄积对视网膜病变持续进展的影响。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，从而将抑制视网膜病变的进展的假设将在大鼠身上进行验证，方法是通过治疗抑制超氧化物歧化酶的积累，并在过量表达MnSOD的小鼠身上进行验证。对导致糖尿病视网膜病变抵抗停止的异常的表征有望揭示防止其进展的治疗新靶点，并为患者提供一个机会，以辅助治疗补充他们可能最好的血糖控制。

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.