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: 10222701
• 负责人: Steven F Abcouwer
• 金额: $ 46.36万
• 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/10222701
• 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; reparative capacity; 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修复 摘要 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 显示靶向血管内皮生长因子（抗VEGF）治疗糖尿病性黄斑水肿（DME） 水肿和改善视力在大约一半的治疗患者。然而，需要替代治疗， 大量患者对抗VEGF治疗无反应。本申请提出了一种新颖的 了解疾病病理学的方法，并将临床前测试应用于DR的潜在治疗。 一个新的假设是，糖尿病损害视网膜的修复机制，这有助于 糖尿病视网膜中未修复损伤的累积。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血视网膜屏障（iBRB）的能力。这 类似于皮肤伤口愈合的缺陷，其导致不愈合的糖尿病足溃疡。虽然 最近的研究已经开始阐明眼睛发育过程中iBRB的形成，但对iBRB的形成知之甚少。 成人iBRB的维持和恢复机制。这代表了一个主要的 与DR预防和治疗高度相关的知识差距，因为恢复iBRB正是 我们在治疗DME方面的努力。变革性的方法是使用视网膜损伤， 就像皮肤裂伤被用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，促进视网膜修复。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缺血再灌注损伤的影响。 iBRB的恢复机制。IR损伤模仿DR病理学的几个特征， 包括：内视网膜神经元丢失、小胶质细胞活化、白细胞停滞、屏障紧密连接紊乱，以及 血管通透性我们认为IR是研究糖尿病对视网膜损伤的最佳选择 因为IR是唯一一种包括自消退炎症的视网膜损伤模型， 和延长的血管渗透性，随后恢复iBRB。初步数据显示， IR损伤后iBRB的恢复通常发生在2-3周内，但在糖尿病小鼠中是有缺陷的，这 与先天免疫反应的增强相吻合。为了确定糖尿病如何阻碍炎症 分辨率和视网膜血管恢复，我们将完成三个具体目标：1：了解过程 血管屏障的修复2.确定糖尿病阻碍恢复的机制， iBRB。3.靶向非典型PKC介导的炎症，以促进屏障恢复。研究工作 代表了Abcouwer和Antonetti实验室在视网膜炎症方面的专家之间的密切合作 和血视网膜屏障。这项研究有望为机制提供新的见解 iBRB恢复的可能性，并提供额外的治疗选择，以促进患者的这一过程。