Oxidative stress & development of diabetic retinopathy

我们假设氧化应激可能在视网膜病变的发展中起重要作用，并收集了(1)糖尿病大鼠视网膜中的代谢证据，这与氧化应激增加（硫代巴比妥酸活性物质和谷胱甘肽[GSH]异常）一致，(2)组织学证据表明，补充抗氧化剂抑制视网膜病变的发展。由于“抗氧化剂”也可以作为与氧化应激无关的机制，并且由于一些研究人员最近质疑糖尿病是否会导致氧化应激，我们将进一步探讨氧化应激与糖尿病视网膜病变的关系，具体目标有三个：首先，我们将评估正常和糖尿病人和动物的视网膜，确定已知氧化应激标志物的特定化学修饰的数量和分布。通过这种方式，我们可以对糖尿病视网膜暴露于氧化的性质和程度提供观点。其次，我们将研究氧化应激与糖尿病视网膜细胞加速死亡之间的关系，使用3种不同但相关的动物模型(1)喂食添加抗氧化剂的实验性糖尿病大鼠，(2)过度表达抗氧化酶MnSOD的糖尿病小鼠，(3)糖尿病小鼠缺乏caspase-1(一种与氧化应激相关的酶，我们的数据表明它可能是促caspase-1缺失的小鼠（一种与氧化应激相关的酶，我们的数据表明它可能是促糖尿病细胞凋亡的酶）。第三，我们将研究最近报道的神经生长因子（NGF）对糖尿病大鼠视网膜病变发展的有益作用的可能性，这种作用主要是通过神经营养因子对糖尿病诱导的视网膜氧化应激的作用来介导的。其他研究人员未能在血管内皮细胞上发现NGF受体，这表明了一个非常有趣的结论，如果实质性地表明NGF作用于血管内皮细胞，这表明了一个非常有趣的结论，如果得到证实，这表明NGF对视网膜病变的有益作用如预期的那样直接作用于脉管系统，而不是通过其他附近的细胞类型，如视网膜神经元或神经胶质细胞。这三个特定的目标都集中在氧化应激在糖尿病视网膜病变中的作用，并有望为视网膜病变的发病机制和治疗提供新的见解。

We have postulated that oxidative stress may be important in the development of retinopathy, and have collected (1) metabolic evidence in the retina of diabetic rats that is consistent with increased oxidative stress (supranormal thiobarbituric acid reactive substances and subnormal glutathione [GSH], and (2) histologic evidence that antioxidant supplementation inhibits the development of lesions of the retinopathy. Since "antioxidants" can act also be mechanisms not related to oxidative stress, and since some investigators recently have questioned whether diabetes results in an oxidative stress at all, we will further explore the relationship of oxidative stress to diabetic retinopathy in 3 specific aims: Firs, we will evaluate retinas from normal and diabetic humans and animals, determining the amount and distribution of specific chemical modifications that are known markers of oxidative stress. In this way, we can provide perspective on the nature and degree of oxidative that the retina is exposed to in diabetes. Second, we will investigate the relationship between oxidative stress and accelerated death of retinal cells in diabetes, using 3 different but pertinent animal models (1) experimentally diabetic rats fed supplemental antioxidants, (2) diabetic mice over-expressing the anti-oxidant enzyme, MnSOD, and (3) diabetic mice deficient in caspase-1 (an enzyme which is related to oxidative stress and which our data suggests may be pro-mice deficient in caspase-1 (an enzyme which is related to oxidative stress and which our data suggests may be pro-apoptotic in diabetes). Third, we will investigate the possibility that a recently reported beneficial effect of nerve growth factor (NGF) on the development of retinopathy in diabetic rats is mediated largely via effects on the neurotrophin on diabetes-induced oxidative stress in the retina. Other investigators have failed to find receptors for NGF on vascular endothelial cells, suggesting the very interested conclusions which, if substantia, suggests that NGF on vascular endothelial cells, suggesting the very interesting conclusion which, if substantiated, suggests that the beneficial effect of NGF on retinopathy is mediated directly on the vasculature as expected, but instead via some other nearby cell type such as retinal neurons or glial cells. Each of the three specific aims proposed focus on the role of oxidative stress in diabetic retinopathy, and are expected to provide new insight into the pathogenesis and treatment of the retinopathy.