Mechanisms of TNFalpha-Induced Insulin Resistance in Retinal Cells

描述(申请人提供)：拟议的研究将测试新的假设，即在糖尿病视网膜，高血糖刺激肿瘤坏死因子a(TNFa)的产生，而肿瘤坏死因子a反过来减少胰岛素受体结合，导致信号转导减少。这一信号级联的总体效果将是造成胰岛素抵抗，加剧糖尿病患者胰岛素分泌有限造成的问题，从而促进1型和2型糖尿病视网膜病变的发展。虽然我们的初步数据和其他人之前的报告支持炎症介质如TNFa在糖尿病视网膜病变中的重要作用，但所涉及的途径基本上是未知的。我们建议的研究将集中在一个可能的候选基因，细胞因子信号转导抑制因子3(SOCS3)途径(图1)，该途径在视网膜中知之甚少，但在未来糖尿病视网膜病变的治疗中代表着一个有希望的治疗靶点。我们的总体目标是1)确定SOCS3通路在正常和糖尿病大鼠胰岛素信号转导(通过胰岛素受体底物-1；IRS-1)和细胞凋亡中的作用；2)评估上游药物靶点对SOCS3通路的影响以及它们对胰岛素信号转导和视网膜细胞凋亡的下游作用。

DESCRIPTION (provided by applicant): The proposed study will test the novel hypothesis that in the diabetic retina, hyperglycemia stimulates production of tumor necrosis factor a (TNFa), which in turn decreases insulin receptor binding leading to decreased signal transduction. The overall effect of this signaling cascade would be to create insulin resistance, exacerbate problems caused by limited insulin production in diabetes, and thus contribute to development of diabetic retinopathy seen in both type 1 and type 2 diabetes. While our preliminary data and previous reports by others support a major role for inflammatory mediators such as TNFa in diabetic retinopathy, the pathways involved are largely unknown. Our proposed studies will focus on one likely candidate, the suppressor of cytokine signaling 3 (SOCS3) pathway (Fig.1), which is poorly understood in retina and yet represents a promising therapeutic target in future treatments for diabetic retinopathy. Our overall goal is to 1) establish the role of the SOCS3 pathway in regulating insulin signaling (through insulin receptor substrate-1; IRS-1) and apoptosis in normal and diabetic rats and 2) evaluate effects of upstream drug targets on the SOCS3 pathway and their downstream effects on insulin signaling and retinal cell apoptosis.