COMP-Ang1: Vascular Normalization and Neuroprotection for Diabetic Retinopathy

 描述（由申请人提供）：该项目的目标是有效预防糖尿病视网膜病变（DR）的进展。糖尿病高血糖对视网膜微血管系统具有毒性，导致周细胞凋亡，进而破坏视网膜血管内皮细胞-细胞连接的粘附钙粘蛋白：连环蛋白（例如VE-钙粘蛋白）成分的微血管细胞内运输。虽然 DR 的发病机制复杂，涉及各种相互交织的信号、系统和机制，但血-视网膜屏障功能障碍是一个关键因素，因为多种生长因子和细胞因子促进细胞连接溶解，破坏细胞与细胞接触和连接完整性，导致微血管渗漏、迁移和增殖。 内皮细胞。 DR 在很大程度上源于这种血管不稳定过程，导致炎症环境、血管生成、水肿、神经元损失和神经胶质增生。我们的中心假设是，COMP-Ang1（血管生成素-1 与软骨寡聚基质蛋白的短卷曲螺旋结构域相结合）的长期基因递送可有效促进视网膜缺血时的血管正常化和神经保护。这些实验将阐明 COMP-Ang1 血管正常化和神经保护能力的机制，定义优化 AAV.COMP-Ang1 基因递送到视网膜的配方的方法，特别是在 DR 的背景下，并确定 COMP-Ang1 是否通过增强内皮祖细胞整合和血管修复来促进血管再生。此外，该项目将增强我们对 DR 基本机制的理解。具体目标是确定是否： 1. AAV.COMP-Ang1 的拓宽趋向性改善其视网膜递送 2. COMP-Ang1 对糖尿病视网膜炎症、内皮血流反应性和神经元视网膜功能障碍的细胞内机制具有改善作用 3. COMP-Ang1 改善糖尿病视网膜病变的神经血管结构和功能 4. COMP-Ang1 的组成型表达增强内皮祖细胞（EPC）整合到糖尿病视网膜脉管系统中 该提案是根据美国-爱尔兰研发合作伙伴计划提交的，汇集了来自莫兰眼科中心（美国犹他大学）、生物技术学院（爱尔兰共和国都柏林城市大学）和实验医学中心（北爱尔兰贝尔法斯特女王大学）的研究人员。该项目通过提高三个国家研究人员在重点开发新治疗方法以加强疾病预防和医疗保健领域的合作研发水平，满足了美国-爱尔兰研发合作伙伴计划的要求。都柏林和贝尔法斯特拟议工作的资金将分别来自爱尔兰共和国（爱尔兰科学基金会）和北爱尔兰（研发办公室）。美国部分需要 NIH 资助。

 DESCRIPTION (provided by applicant): The goal of this project is to effectively prevent progression of diabetic retinopathy (DR). Diabetic hyperglycemia is toxic to the retinal microvasculature, causing pericyte apoptosis, which in turn disrupts microvascular intracellular trafficking of the adherent cadherin:catenin (e.g., VE-cadherin) components of retinal vascular endothelial cell-cell junctions. While the pathogenesis of DR is complex with a variety of interlacing signals, systems and mechanisms, blood-retinal barrier dysfunction is a key element, as multiple growth factors and cytokines promote dissolution of cell-junctions, disrupting cell-cel contact and junctional integrity, leading to leakage, migration, and proliferation of microvascular endothelial cells. DR derives in large part from this vascular-destabilization process, resulting i an inflammatory milieu, angiogenesis, edema, neuronal loss, and gliosis. Our central hypothesis is that long-term gene delivery of COMP-Ang1 (angiopoietin-1 combined with the short coiled-coil domain of cartilage oligomeric matrix protein) has efficacy in promoting vascular normalization and neuroprotection in the presence of retinal ischemia. These experiments will elucidate the mechanisms underlying the vascular normalizing and neuroprotective capabilities of COMP-Ang1, define methods for optimizing the formulation of AAV.COMP-Ang1 gene delivery to the retina, particularly within the context of DR, and establish whether COMP-Ang1 promotes vascular regeneration by enhancing endothelial progenitor cell integration and vascular repair. Further, this project will enhance our understanding of the underlying mechanisms of DR. The Specific Aims are to determine whether: 1. Broadening tropism of AAV.COMP-Ang1 improves its retinal delivery 2. COMP-Ang1 has an ameliorative impact on intracellular mechanisms of diabetic retinal inflammation, endothelial flow responsiveness, and neuronal retinal dysfunction 3. COMP-Ang1 improves neurovascular structure and function in diabetic retinopathy 4. Constitutive expression of COMP-Ang1 enhances endothelial progenitor cell (EPC) integration in diabetic retinal vasculature This proposal is being submitted under the US-Ireland R&D Partnership Programme, and brings together investigators from the Moran Eye Center (University of Utah, US), the School of Biotechnology (Dublin City University, Republic of Ireland) and the Centre for Experimental Medicine (Queen's University of Belfast, Northern Ireland). The project fulfills the requirements of the US-Ireland R&D Partnership Programme by increasing the level of collaborative R&D amongst researchers across the three nations in an area focused on the development of new therapeutic approaches for enhancing disease prevention and healthcare. Funding for the proposed work in Dublin and Belfast will come from the Republic of Ireland (Science Foundation Ireland) and Northern Ireland (R&D Office), respectively. NIH funding is requested for the US component.