Vascular Reparative Mechanism by ACE2/Ang-(1-7)in Diabetes

ACE2/Ang-(1-7)在糖尿病中的血管修复机制

• 批准号: 8189558
• 负责人: Maria Bartolomeo Grant
• 金额: $ 46.87万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8189558
• 关键词: Age; Angiopoietin-2; Angiotensin II; Angiotensins; Attenuated; Blood Vessels; Blood capillaries; Bone Marrow; CD34 gene; Cell Therapy; Cell physiology; Cells; Chimera organism; Clinical; Clinical Research; Coupled; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Retinopathy; Endothelial Cells; Equilibrium; Functional disorder; Generations; Homing; Individual; Intention; Ischemia; Knock-out; Lead; Link; Messenger RNA; Morbidity - disease rate; Mus; Outcome; Peptidyl-Dipeptidase A; Pharmacotherapy; Phase; Positioning Attribute; Renin-Angiotensin System; Reperfusion Therapy; Retina; Retinal; Retinal Diseases; Role; Stem cells; Technology; Testing; Vascular remodeling; Vascularization; angiotensin I (1-7); attenuation; base; capillary; diabetic; diabetic patient; glycemic control; improved; injured; innovation; member; mortality; novel; overexpression; prevent; proliferative diabetic retinopathy; receptor; repaired; research study; retinal ischemia; sex; vector

DESCRIPTION (provided by applicant): Vascular complications are a leading cause of mortality and morbidity in diabetic individuals. Despite recent advances using pharmacotherapy, a cure for diabetic microvascular complications (MVC) has yet to be realized. A conceptual and technical breakthrough is imperative to identify novel targets, and a strategy to cure these complications is paramount. We believe that our provocative preliminary data coupled with recent evidence of a potential role of endothelial progenitor cells (EPCs) in vascular repair and the discovery of the vasoprotective axis of the renin-angiotensin-system (RAS) offer such a breakthrough. The protective axis of the RAS involves the angiotensin converting enzyme 2 (ACE2) which is present in both endothelial cells and EPCs and generates angiotensin-(1-7) which acting through the Mas, attenuates the vasoconstrictive, proliferative, fibrotic and hypertrophic effects of angiotensin II, the key member of the deleterious axis of RAS. In this proposal we utilize retinopathy as the MVC to test our hypothesis that the ACE/ACE2 balance within EPCs dictates their reparative capability and can therefore predict progression of retinal MVC. If MVC are already present, then genetically modifying EPCs utilizing AAV technology to increase endogenous levels of ACE2 will enhance their reparative function and reverse MVC. We put forth the following Specific Aims to test our hypothesis: Aim 1: Investigate whether the ACE/ACE2 imbalance within EPCs will predict progression of MVC. Aim 2: Test the hypothesis if the absence of ACE2 in the systemic vasculature will accelerate progression while overexpression will prevent development and progression retinovascular complications. Aim 3: Investigate the hypothesis that increased ACE2/Ang-(1-7) expression within the retina will stimulate mobilization, homing and reparative potential of EPCs. This integrative and multidimensional proposal is extremely innovative both conceptually and technically because it will: (i) provide evidence for our hypothesis; (ii) establish the mechanism by which the activation of the ACE2/Ang-(1-7)-Mas receptor axis within EPCs sustains cellular reparative function in diabetes; (iii) determine whether the state of the RAS in EPCs can predict the progression of retinopathy; (iv) use the highly innovative VESsel GENeration (VESGEN) technology to delineate vascular remodeling in the retina and (iv) put us in an outstanding position to transition into the clinical arena using cells that have their protective RAS axis activated, either genetically or pharmacologically, for treatment of diabetic retinopathy PUBLIC HEALTH RELEVANCE: The focus of our proposal is to investigate if the balance of vasoprotective axis vs. vasodeleterious axis of the RAS within EPCs can predict progression of MVC in diabetes. Furthermore we will study if correction of this imbalance in the EPCs of diabetic patients would prevent the progression/attenuation of MVC. Outcome of these experiments will be a significant advancement in the use of ACE/ACE2 ratio as a predictor of diabetic patients and development of novel stem cell-based therapy to prevent MVC, single most important cause of diabetes-linked mortality and morbidity.

描述（由申请人提供）：血管并发症是糖尿病患者死亡和发病的主要原因。尽管药物疗法最近取得了进展，但糖尿病微血管并发症（MVC）的治愈方法尚未实现。概念和技术上的突破对于确定新靶标至关重要，而治愈这些并发症的策略至关重要。我们相信，我们的令人兴奋的初步数据加上内皮祖细胞（EPC）在血管修复中潜在作用的最新证据以及肾素血管紧张素系统（RAS）血管保护轴的发现提供了这样的突破。 RAS 的保护轴涉及血管紧张素转换酶 2 (ACE2)，它存在于内皮细胞和 EPC 中，并产生血管紧张素-(1-7)，血管紧张素-(1-7) 通过 Mas 起作用，减弱血管紧张素 II 的血管收缩、增殖、纤维化和肥大作用，血管紧张素 II 是 RAS 有害轴的关键成员。在本提案中，我们利用视网膜病变作为 MVC 来检验我们的假设，即 EPC 内的 ACE/ACE2 平衡决定其修复能力，因此可以预测视网膜 MVC 的进展。如果 MVC 已经存在，那么利用 AAV 技术对 EPC 进行基因改造以增加 ACE2 的内源水平将增强其修复功能并逆转 MVC。我们提出以下具体目标来检验我们的假设： 目标 1：研究 EPC 内的 ACE/ACE2 失衡是否可以预测 MVC 的进展。目标 2：检验以下假设：系统血管系统中 ACE2 的缺失是否会加速进展，而过度表达是否会阻止视网膜血管并发症的发生和进展。目标 3：研究视网膜内 ACE2/Ang-(1-7) 表达增加将刺激 EPC 的动员、归巢和修复潜力的假设。这个综合性和多维的提议在概念和技术上都极具创新性，因为它将：（i）为我们的假设提供证据； (ii) 建立EPCs内ACE2/Ang-(1-7)-Mas受体轴的激活维持糖尿病细胞修复功能的机制； (iii) 确定 EPC 中 RAS 的状态是否可以预测视网膜病变的进展； (iv) 使用高度创新的 VESsel GENeration (VESGEN) 技术来描绘视网膜中的血管重塑，并且 (iv) 使我们处于有利地位，可以利用通过遗传或药理学激活其保护性 RAS 轴的细胞来过渡到临床领域，以治疗糖尿病视网膜病变 公共健康相关性：我们提案的重点是研究 EPC 内 RAS 的血管保护轴与血管损害轴的平衡是否可以预测糖尿病 MVC 的进展。此外，我们将研究纠正糖尿病患者 EPC 的这种不平衡是否会阻止 MVC 的进展/减弱。这些实验的结果将是在使用 ACE/ACE2 比率作为糖尿病患者的预测因子以及开发基于干细胞的新型疗法来预防 MVC 方面取得重大进展，MVC 是糖尿病相关死亡率和发病率的最重要原因。