Targeting Interleukin-6 Trans-signaling in Diabetic Retinopathy

项目摘要 糖尿病视网膜病变(DR)是一种威胁视力的神经血管病变，是糖尿病的主要原因 工作年龄的美国人中的失明。预防视网膜损伤的新疗法 维修是一种严重的未得到满足的需求。这项提议的主要焦点是测试一种新的药理作用 复方sgp130Fc治疗糖尿病视网膜病变 白介素6(IL-6)是炎症的主要介质，越来越多的证据表明 有趣的是，IL-6途径在博士的发病机制中扮演着重要角色，即使 视网膜内皮细胞缺乏膜结合的IL-6受体，观察到IL-6介导的信号转导 在这些牢房里。研究表明，IL-6/可溶性IL-6R复合体可与糖蛋白130结合 (Gp130)在不表达IL-6受体的细胞中启动下行信号，这 这个过程被称为IL-6反式信号转导。目前阻断IL-6信号的方法抑制了这两种信号 经典和转导信号通路。最近的研究表明，IL-6转导信号是 在调节局部的疾病或感染部位的过程中尤为重要 与炎症性疾病密切相关。我们假设只抑制转导信号 IL-6途径将优于完全阻断IL-6，因为重要的生理 IL-6的功能将保持不变。这一新颖的干预策略是对 探讨选择性阻断IL-6转导信号在糖尿病视网膜病变治疗中的作用。 我们有令人兴奋的初步数据表明，对IL-6转导信号的抑制显著 降低人视网膜内皮细胞和糖尿病小鼠视网膜的炎症反应。 在这项提案中，我们将测试sgp130-Fc将减缓疾病进展和 减轻糖尿病视网膜病变患者的病理性眼部炎症 到DR的发病或以后临床明显的疾病阶段。在AIM-1中，我们将在体外使用 确定IL-6反式信号转导对内皮细胞-周细胞相互作用影响的方法 内皮系统中黏附和紧密连接分子的表达，维持 屏障功能、周细胞迁移、ROS的产生、内皮细胞的凋亡和增殖 细胞和周细胞。在AIM-2中，我们将使用链脲佐菌素(STZ)诱导的1型糖尿病(T1D) 用sgp130Fc药物治疗糖尿病视网膜的小鼠模型 糖尿病小鼠血管病理的分子、结构和功能研究 视网膜。该项目有可能提供一种治疗视网膜的新方法。 与糖尿病相关的血管病理学。

Project Summary Diabetic retinopathy (DR) is a sight-threatening neurovasculopathy, which is the leading cause of blindness in working-aged Americans. The new therapies to prevent retinal injury and enhance repair is a critical unmet need. The main focus of this proposal is to test a novel pharmacological compound sgp130Fc for the treatment of DR. Interleukin-6 (IL-6) is the major mediator of inflammation and increasing evidence suggests that the IL-6 pathway plays a prominent role in the pathogenesis of DR. Interestingly, even though the retinal endothelial cells lack membrane bound IL-6 receptor, IL-6 mediated signaling is observed in these cells. Studies have shown that IL-6/soluble IL-6R complex can bind to glycoprotein 130 (gp130) to initiate downstream signaling in cells that do not express the IL-6 receptor and this process is known as IL-6 trans-signaling. Current approaches to block IL-6 signaling inhibit both classical and trans-signaling pathways. Recent studies suggest that IL-6 trans-signaling is particularly important in regulating processes localized to the site of disease or infection and is crucially involved in inflammatory diseases. We hypothesize that inhibiting only the trans-signaling pathway of IL-6 will be superior to complete IL-6 blockade, because important physiologic functions of IL-6 will remain intact. This novel intervention strategy represents the first attempt to investigate the effects of selective IL-6 trans-signaling blockade in DR treatment. We have exciting preliminary data showing that inhibition of IL-6 trans-signaling significantly decreases the inflammatory response in human retinal endothelial cells and diabetic mice retina. In this proposal we will test the hypothesis that sgp130-Fc will slow disease progression and attenuate pathological ocular inflammation in diabetic retinopathy, when administered either prior to onset of DR or later at a clinically evident disease stage. In Aim-1, we will use in vitro approaches to determine the effects of IL-6 trans-signaling on endothelial-pericyte interaction, expression of adhesion and tight junctions molecules in the endothelial system, maintenance of barrier function, pericyte migration, ROS production, apoptosis and proliferation of endothelial cells and pericytes. In Aim-2, we will use the streptozotocin (STZ)-induced type-1 diabetes (T1D) mouse model to determine the effect of sgp130Fc drug treatment on the diabetes-induced retinal vascular pathology by conducting molecular, structural and functional studies in diabetic mice retinas. This project has the potential to provide a new therapeutic approach to treat retinal vascular pathology associated with diabetes.