Inflammatory Resolution and Vascular Restoration in Diabetic Retinopathy

糖尿病视网膜病变的炎症消退和血管恢复

• 批准号: 9979905
• 负责人: Steven F Abcouwer
• 金额: $ 47.79万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979905
• 关键词: Adult; Age; Anti-Inflammatory Agents; Blindness; Blood Vessels; Blood-Retinal Barrier; Cataract; Cells; Characteristics; Clinical Trials; Collaborations; Complex; Data; Diabetes Mellitus; Diabetic Foot Ulcer; Diabetic Retinopathy; Diabetic mouse; Disease; Dominant-Negative Mutation; Edema; Endothelial Cells; Endothelium; Equilibrium; Extravasation; Eye Development; Genetic Transcription; Glaucoma; Glucocorticoids; Goals; Growth; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Ischemia; Knowledge; Laboratories; Laceration; Leukostasis; Light; Light Coagulation; Maintenance; Mediating; Microglia; Microscopy; Modeling; Mus; Pathology; Patients; Peripheral; Pharmacology; Preclinical Testing; Prevention; Process; Production; Property; Proteins; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Research Proposals; Resolution; Retina; RiboTag; Risk; Skin; Skin wound healing; Stress; Swelling; System; Technology; Testing; Therapeutic; Tight Junctions; United States; Vascular Endothelial Growth Factors; Vascular Endothelium; Vascular Permeabilities; Vesicle; Vision; Western Blotting; alternative treatment; cytokine; diabetic; diabetic ulcer; diabetic wound healing; healing; improved; inhibitor/antagonist; insight; intravitreal injection; laser photocoagulation; macular edema; neovascularization; neuron loss; novel; novel drug class; novel strategies; novel therapeutics; prevent; protein transport; repaired; restoration; retinal ischemia; retinal neuron; skin wound; transcriptome; wound healing

Title: Inflammatory Resolution and Vascular Restoration in Diabetic Retinopathy ABSTRACT Diabetic retinopathy (DR) remains a leading cause of blindness in the United States. Recent clinical trials reveal targeting vascular endothelial growth factor (anti-VEGF) for diabetic macular edema (DME) reduces edema and improves vision in about half of treated patients. However, alternative treatment is needed for the large number of patients who do not respond to anti-VEGF therapies. The current application presents a novel approach to understand disease pathology and apply preclinical testing to a potential treatment for DR. Our novel hypothesis is that diabetes impairs the retina's reparative mechanisms, and that this contributes to the accumulation of unrepaired damage in the diabetic retina. In this proposal we will explore how diabetes impairs the retina's ability to resolve inflammation and to restore the inner blood-retinal barrier (iBRB) after injury. This is analogous to the deficiency in skin wound healing that results in non-healing diabetic foot ulcers. Although recent studies have begun to shed light on formation of the iBRB during eye development, little is known about the mechanisms governing maintenance and restoration of the iBRB in the adult. This represents a major knowledge gap that is highly relevant to DR prevention and treatment since restoring the iBRB is precisely what we strive to achieve for treatment of DME. The transformative approach is to use a retinal injury, in much the same way that skin laceration is used to study the effects of diabetes on wound healing, with the goal of overcoming diabetes induced inhibition of repair and promoting retinal restoration. These studies therefore utilize the mouse retinal ischemia-reperfusion (IR) injury model to examine the effects of diabetes on mechanisms governing restoration of the iBRB. IR injury mimics several characteristics of DR pathology, including: inner retina neuron loss, microglial activation, leukostasis, barrier tight junction disorganization, and vascular permeability. We believe that IR is the optimal choice of retinal injury to study the effects of diabetes on reparative mechanisms because IR is the only retinal injury model that includes self-resolving inflammation and extended vascular permeability followed by restoration of the iBRB. Preliminary data shows that restoration of the iBRB after IR injury normally occurs over 2-3 weeks but is defective in diabetic mice, and this coincides with amplification of innate immune responses. To determine how diabetes impedes inflammatory resolution and retinal vascular restoration, we will complete three Specific Aims: 1: Understand the process of vascular barrier restoration. 2. Identify the mechanism by which diabetes impedes restoration of the iBRB. 3. Target atypical PKC-mediated inflammation to promote barrier restoration. The research efforts represent a close collaboration between the Abcouwer and Antonetti laboratories expert in retinal inflammation and the blood retinal barrier, respectively. The research is expected to provide novel insight into mechanisms of iBRB restoration and provide additional therapeutic options to promote this process in patients.

标题：糖尿病视网膜病变的炎症消退和血管恢复 抽象的 糖尿病视网膜病变（DR）仍然是美国失明的主要原因。最近的临床试验 揭示靶向血管内皮生长因子（抗 VEGF）治疗糖尿病性黄斑水肿（DME）可减少 大约一半的接受治疗的患者可以减轻水肿并改善视力。然而，需要替代治疗 大量患者对抗 VEGF 疗法没有反应。当前的应用提出了一种新颖的 了解疾病病理学并将临床前测试应用于 DR 的潜在治疗方法。我们的 新的假设是糖尿病会损害视网膜的修复机制，这有助于 糖尿病视网膜中未修复的损伤不断累积。在本提案中，我们将探讨糖尿病如何损害 视网膜在受伤后解决炎症和恢复内部血视网膜屏障（iBRB）的能力。这 类似于皮肤伤口愈合不足，导致糖尿病足溃疡无法愈合。虽然 最近的研究已经开始揭示眼睛发育过程中 iBRB 的形成，但人们对此知之甚少。 成人 iBRB 维持和恢复的调节机制。这代表着一个重大的 与 DR 预防和治疗高度相关的知识差距，因为恢复 iBRB 正是 我们在 DME 治疗方面努力实现的目标。变革性的方法是利用视网膜损伤，在很多方面 就像使用皮肤撕裂来研究糖尿病对伤口愈合的影响一样，目的是 克服糖尿病引起的修复抑制并促进视网膜恢复。因此这些研究 利用小鼠视网膜缺血再灌注（IR）损伤模型来检查糖尿病对视网膜的影响 iBRB 恢复的管理机制。 IR 损伤模仿 DR 病理学的几个特征， 包括：视网膜内神经元损失、小胶质细胞激活、白细胞停滞、屏障紧密连接破坏，以及 血管通透性。我们相信 IR 是研究糖尿病影响的视网膜损伤的最佳选择 修复机制，因为 IR 是唯一包含自消性炎症的视网膜损伤模型 并延长血管通透性，然后恢复 iBRB。初步数据表明 IR 损伤后 iBRB 的恢复通常需要 2-3 周的时间，但在糖尿病小鼠中存在缺陷，这 与先天免疫反应的放大同时发生。确定糖尿病如何阻止炎症 分辨率和视网膜血管修复，我们将完成三个具体目标： 1：了解过程 血管屏障修复。 2. 确定糖尿病阻碍功能恢复的机制 iBRB。 3. 针对非典型 PKC 介导的炎症，促进屏障修复。研究工作 代表了 Abcouwer 和 Antonetti 实验室视网膜炎症专家之间的密切合作 和血视网膜屏障。该研究有望为机制提供新的见解 iBRB 恢复并提供额外的治疗选择来促进患者的这一过程。