Mechanisms of TNFalpha-Induced Insulin Resistance in Retinal Cells

描述（由申请方提供）：拟定的研究将检验新的假设，即在糖尿病视网膜中，高血糖刺激肿瘤坏死因子a（TNFa）的产生，进而降低胰岛素受体结合，导致信号转导减少。这种信号级联的总体影响将是产生胰岛素抵抗，加剧糖尿病中胰岛素产生有限引起的问题，从而导致1型和2型糖尿病中出现的糖尿病视网膜病变的发展。虽然我们的初步数据和其他人以前的报告支持炎症介质如TNFa在糖尿病视网膜病变中的主要作用，但所涉及的途径在很大程度上是未知的。我们提出的研究将集中在一个可能的候选者，细胞因子信号传导抑制因子3（SOCS 3）通路（图1），这是在视网膜中了解甚少，但代表了一个有前途的治疗目标，在未来的治疗糖尿病视网膜病变。我们的总体目标是：1）确定SOCS 3通路在正常和糖尿病大鼠中调节胰岛素信号传导（通过胰岛素受体底物-1; IRS-1）和细胞凋亡的作用; 2）评估上游药物靶点对SOCS 3通路的影响及其对胰岛素信号传导和视网膜细胞凋亡的下游影响。

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.