Regulation of retinopathies

描述（由申请人提供）：糖尿病视网膜病变是美国失明的主要原因。黏附分子、趋化因子、一氧化氮合酶（NOS2）、诱导环氧合酶（COX-2）和血管内皮生长因子（VEGF）的上调被认为是这种疾病的重要促炎反应。人们越来越认识到，这些反应有助于视网膜损伤和神经血管变性。了解这些反应的调控是很重要的，因为神经元死亡在很大程度上导致了糖尿病视网膜病变的视力丧失，目前可用的治疗方案还不能预防神经元丧失。本应用的目的是进一步了解糖尿病视网膜病变中促炎反应和神经血管变性的调节。本研究的中心假设是，在糖尿病视网膜病变中存在一种先前未被识别的上游分子，该分子可触发上述促炎反应并介导神经血管变性。发现单个分子控制与该疾病发病机制有关的各种细胞反应将具有重要意义，因为它表明靶向单个分子会损害多种促视网膜病变因子。在第一个具体目标中，我们将描述视网膜小胶质细胞，Muller细胞和内皮细胞中促炎反应的调节。这将通过免疫分析和阻断特定信号蛋白的基因转移方法来完成。此外，我们将测试一种新的方法来传递细胞内分子是否可以用来阻断控制视网膜细胞中促炎反应的信号。使用类似的方法，在第二个特定目标中，我们将描述由这些视网膜病变前反应引起的神经元和内皮细胞死亡的调节。利用野生型和基因敲除小鼠的糖尿病视网膜病变动物模型，我们将评估炎症调节对糖尿病视网膜病变发展的体内影响。这项工作可能会导致治疗糖尿病视网膜病变的新策略。

DESCRIPTION (provided by applicant): Diabetic retinopathy is a major cause of blindness in the United States. Upregulation of adhesion molecules, chemokines, nitric oxide synthase (NOS2), inducible cyclooxygenase (COX-2) and vascular endothelial growth factor (VEGF) are pro- inflammatory responses believed to be important in this disease. It is increasingly recognized that these responses contribute to retinal injury and neuro-vascular degeneration. Understanding the regulation of these responses is important because neuronal death largely contributes to visual loss in diabetic retinopathy and currently available treatment regimens have not been able to prevent neuronal loss. The objective of this application is to further our understanding of the regulation of pro-inflammatory responses and neuro-vascular degeneration in diabetic retinopathy. The central hypothesis for the proposed research is that there is a previously unrecognized upstream molecule that triggers the pro-inflammatory responses mentioned above and mediates neuro-vascular degeneration in diabetic retinopathy. Finding that a single molecule controls various cellular responses involved in the pathogenesis of this disease would be significant because it would suggest that targeting a single molecule would impair multiple pro-retinopathy factors. In the first specific aim we will characterize the regulation of pro-inflammatory responses in retinal microglia, Muller cells and endothelial cells. This will be accomplished using immunological assays and gene transfer approaches that block specific signaling proteins. In addition, we will test whether a novel approach to deliver molecules intra-cellularly can be used to block signaling that controls pro-inflammatory responses in retinal cells. Using similar methodologies, in the second specific aim we will characterize the regulation of neuronal and endothelial cell death caused by these pro-retinopathy responses. Using an animal model of diabetic retinopathy in wild-type and knock-out mice we will evaluate the in vivo effects of regulation of inflammation on the development of diabetic retinopathy. The proposed work may lead to new strategies to treat diabetic retinopathy.