Targeting Interleukin-6 Trans-signaling in Diabetic Retinopathy

靶向白细胞介素 6 反式信号转导治疗糖尿病视网膜病变

基本信息

批准号：
9157948
负责人：
Shruti Sharma
金额：
$ 38万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9157948
关键词：
Adhesions Affinity American Anti-Inflammatory Agents Anti-inflammatory Apoptosis Attenuated Autoimmune Diseases Binding Blindness Blood Vessels Blood capillaries Body Fluids Cell Nucleus Cell surface Cells Characteristics Chimera organism Clinical Data Clinical Trials Complex Data Diabetes Mellitus Diabetic Retinopathy Diabetic mouse Dimerization Disease Disease Progression Endothelial Cells Endothelium Glycoproteins Hepatocyte Human IL6 Signaling Pathway IL6 gene In Vitro Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Insulin-Dependent Diabetes Mellitus Interleukin 6 Receptor Interleukin-6 Intervention Lead Lymphocyte Maintenance Malignant Neoplasms Mediating Membrane Microvascular Dysfunction Molecular Morphogenesis Pathogenesis Pathology Pathway interactions Patients Pericytes Pharmaceutical Preparations Pharmacotherapy Phosphorylation Physiological Play Process Production Publishing Reporting Retina Retinal Rheumatoid Arthritis Role STAT3 gene Serum Signal Pathway Signal Transduction Site Staging Streptozocin System Testing Therapeutic Tight Junctions Vision Visual Work aged angiogenesis capillary cytokine diabetic patient disability extracellular glycoprotein 130 in vivo macrophage migration neutrophil novel novel therapeutic intervention novel therapeutics prevent receptor receptor binding regenerative repaired success therapeutic target vascular inflammation

项目摘要

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.

项目概要糖尿病视网膜病变（DR）是一种威胁视力的神经血管病变，是导致糖尿病视网膜病变的主要原因工作年龄的美国人失明。预防视网膜损伤和增强视网膜功能的新疗法维修是一项未满足的关键需求。该提案的主要重点是测试一种新型药理学化合物sgp130Fc用于治疗DR。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的发病机制中发挥着重要作用。有趣的是，尽管视网膜内皮细胞缺乏膜结合 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-6R复合物可以与糖蛋白130结合 (gp130) 在不表达 IL-6 受体的细胞中启动下游信号传导该过程称为 IL-6 信号转导。目前阻断 IL-6 信号传导的方法同时抑制这两种信号经典和跨信号传导途径。最近的研究表明 IL-6 反式信号传导对于调节疾病或感染部位的局部过程尤其重要，并且与炎症性疾病密切相关。我们假设仅抑制转信号 IL-6 途径将优于完全 IL-6 阻断，因为重要的生理学 IL-6的功能将保持完整。这种新颖的干预策略代表了首次尝试研究选择性 IL-6 反式信号传导阻断在 DR 治疗中的效果。我们有令人兴奋的初步数据表明，IL-6 反式信号传导的抑制显着降低人视网膜内皮细胞和糖尿病小鼠视网膜的炎症反应。在本提案中，我们将测试 sgp130-Fc 将减缓疾病进展的假设，以及减轻糖尿病视网膜病变的病理性眼部炎症（在之前给药时）到 DR 发作或在临床上明显的疾病阶段之后。在 Aim-1 中，我们将使用体外确定 IL-6 反式信号传导对内皮-周细胞相互作用影响的方法，内皮系统中粘附和紧密连接分子的表达，维持屏障功能、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 (T1D) 小鼠模型以确定 sgp130Fc 药物治疗对糖尿病引起的视网膜的影响通过对糖尿病小鼠进行分子、结构和功能研究来研究血管病理学视网膜。该项目有可能为治疗视网膜疾病提供一种新的治疗方法与糖尿病相关的血管病理学。