Inflammatory Resolution and Vascular Restoration in Diabetic Retinopathy

标题：糖尿病视网膜病变的炎症消退和血管重建 摘要 糖尿病视网膜病变(DR)在美国仍然是导致失明的主要原因。最近的临床试验 靶向血管内皮生长因子(抗血管内皮生长因子)减轻糖尿病黄斑水肿(DME) 大约一半的接受治疗的患者出现浮肿和视力改善。然而，需要替代治疗的是 大量对抗血管内皮生长因子治疗无效的患者。本申请提出了一种新颖的 了解疾病病理并将临床前试验应用于我们博士潜在治疗的方法 新的假设是，糖尿病损害了视网膜的修复机制，这有助于 糖尿病视网膜中未修复的损伤堆积。在这项提案中，我们将探讨糖尿病是如何损害 视网膜在损伤后消除炎症和恢复内部血-视网膜屏障(IBRB)的能力。这 类似于皮肤伤口愈合不足，导致无法愈合的糖尿病足部溃疡。虽然 最近的研究已经开始阐明眼睛发育过程中iBRB的形成，但对此知之甚少 成人iBRB的维持和恢复机制。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恰恰是 我们在治疗DME方面努力实现的目标。变革性的方法是使用视网膜损伤，在许多情况下 用同样的方法来研究糖尿病对伤口愈合的影响，目的是 克服糖尿病导致的修复抑制，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)损伤模型研究糖尿病对大鼠视网膜缺血再灌注损伤的影响 管理iBRB恢复的机制。IR损伤模仿DR病理的几个特征， 包括：视网膜内神经元丢失，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。我们认为IR是研究糖尿病影响的视网膜损伤的最佳选择 关于修复机制，因为IR是唯一包括自我消退炎症的视网膜损伤模型 血管通透性增加，iBRB修复。初步数据显示， IR损伤后iBRB的恢复通常发生在2-3周后，但糖尿病小鼠有缺陷，这 与先天免疫反应的放大相吻合。确定糖尿病是如何阻碍炎症的 在解决视网膜血管修复问题时，我们将完成三个具体目标：1：了解过程 血管屏障的修复。2.找出糖尿病阻碍心脏功能恢复的机制 IBRB。3.靶向非典型PKC介导的炎症反应，促进屏障修复。研究工作的努力 代表了阿布库沃和安东内蒂实验室在视网膜炎症方面的密切合作 和血视网膜屏障。这项研究有望为机理提供新的见解 并提供更多的治疗选择，以促进患者的这一过程。

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.