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，是糖尿病视网膜病变的主要原因。 美国工作年龄段的失明。预防视网膜损伤的新疗法， 维修是一个关键的未满足的需求。该提案的主要重点是测试一种新的药理学 用于治疗DR的化合物sgp 130 Fc。 白细胞介素-6（IL-6）是炎症的主要介质，越来越多的证据表明， IL-6通路在DR的发病机制中起着重要作用。有趣的是，尽管IL-6通路在DR的发病机制中起着重要作用， 视网膜内皮细胞缺乏膜结合的IL-6受体，观察到IL-6介导的信号传导 在这些细胞中。研究表明，IL-6/可溶性IL-6 R复合物可与糖蛋白130结合 （gp 130）在不表达IL-6受体的细胞中启动下游信号传导， 这个过程被称为IL-6 trans-signaling。目前阻断IL-6信号传导的方法抑制了 经典和反式信号通路。最近的研究表明，IL-6反式信号转导是 在调节疾病或感染部位的过程中特别重要， 与炎症性疾病密切相关。我们假设仅仅抑制反式信号传导 IL-6通路将上级完全的IL-6阻断，因为重要的生理学 IL-6的功能将保持完整。这种新的干预策略代表了第一次尝试， 研究选择性IL-6反式信号传导阻断在DR治疗中的作用。 我们有令人兴奋的初步数据表明，抑制IL-6的反式信号显着 降低人视网膜内皮细胞和糖尿病小鼠视网膜中的炎症反应。 在本提案中，我们将检验sgp 130-Fc将减缓疾病进展的假设， 减轻糖尿病视网膜病变中的病理性眼部炎症， 至DR发作或之后的临床明显疾病阶段。在Aim-1中，我们将使用体外 确定IL-6反式信号传导对内皮细胞-周细胞相互作用的影响的方法， 内皮系统中粘附和紧密连接分子的表达， 屏障功能、周细胞迁移、ROS产生、内皮细胞凋亡和增殖 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（T1 D） 小鼠模型以确定sgp 130 Fc药物治疗对糖尿病诱导的视网膜病变的影响 通过在糖尿病小鼠中进行分子、结构和功能研究， 视网膜该项目有可能提供一种新的治疗方法来治疗视网膜病变。 与糖尿病相关的血管病变。

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.