COMP-Ang1: Vascular Normalization and Neuroprotection for Diabetic Retinopathy

 描述（由申请人提供）：本项目的目标是有效预防糖尿病视网膜病变（DR）的进展。糖尿病性高血糖症对视网膜微血管系统是有毒的，引起周细胞凋亡，这进而破坏粘附的钙粘蛋白：连环蛋白（例如，VE-钙粘蛋白）组成的视网膜血管内皮细胞-细胞连接。虽然DR的发病机制是复杂的，具有各种交织的信号、系统和机制，但是血-视网膜屏障功能障碍是关键因素，因为多种生长因子和细胞因子促进细胞连接的溶解，破坏细胞-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在很大程度上源自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-Ang 1（血管生成素-1结合软骨寡聚基质蛋白的短卷曲螺旋结构域）的长期基因递送在视网膜缺血的情况下具有促进血管正常化和神经保护的功效。这些实验将阐明C 0 MP-Ang 1的血管正常化和神经保护能力的潜在机制，定义用于优化AAV. C 0 MP-Ang 1基因递送至视网膜的制剂的方法，特别是在DR的背景下，并确定C 0 MP-Ang 1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，这个项目将提高我们对DR的潜在机制的理解。具体目的是确定是否：1。扩大AAV. COMP-Ang 1的向性改善其视网膜递送2。COMP-Ang 1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-Ang 1改善糖尿病视网膜病变的神经血管结构和功能4. COMP-Ang 1的组成型表达增强糖尿病视网膜血管系统中内皮祖细胞（EPC）的整合该提案是根据美国-爱尔兰研发合作计划提交的，并汇集了来自Moran眼科中心的研究人员。（美国犹他州大学）生物技术学院（都柏林城市大学，爱尔兰共和国）和实验医学中心（贝尔法斯特女王大学，北方爱尔兰）。该项目满足了美国-爱尔兰研发合作伙伴计划的要求，提高了三国研究人员在一个专注于开发新的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。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）和北方尔兰（研发办公室）。NIH的资金被要求用于美国部分。

 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.