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: 8325567
• 负责人: Maria Bartolomeo Grant
• 金额: $ 44.54万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325567
• 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

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。尽管最近在药物治疗方面取得了进展，但治疗糖尿病微血管并发症（MVC）的方法尚未实现。概念和技术上的突破是确定新靶点的必要条件，而治疗这些并发症的策略是至关重要的。我们相信，我们令人振奋的初步数据，加上最近内皮祖细胞（EPCs）在血管修复中的潜在作用的证据，以及肾素-血管紧张素系统（RAS）血管保护轴的发现，提供了这样一个突破。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内皮细胞中，并产生血管紧张素-(1-7)，血管紧张素-通过Mas作用，减弱血管紧张素II的血管收缩、增殖、纤维化和肥厚作用，血管紧张素II是RAS有害轴的关键成员。在这个建议中，我们利用视网膜病变作为MVC来验证我们的假设，即EPCs内的ACE/ACE2平衡决定了它们的修复能力，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EPCs进行基因修饰以增加内源性ACE2水平将增强其修复功能并逆转MVC。我们提出了以下具体目的来验证我们的假设：目的1：研究EPCs内ACE/ACE2失衡是否会预测MVC的进展。目的2：验证系统血管中ACE2的缺失是否会加速进展，而过表达是否会阻止视网膜血管并发症的发生和进展。目的3：探讨视网膜内ACE2/Ang-(1-7)表达增加是否会刺激EPCs的动员、归巢和修复潜能。这一综合和多维的建议在概念和技术上都极具创新性，因为它将：(1)为我们的假设提供证据；（ii）建立EPCs内ACE2/Ang-(1-7)- mas受体轴激活维持糖尿病细胞修复功能的机制；（iii）确定EPCs中RAS的状态是否可以预测视网膜病变的进展；（iv）使用高度创新的血管生成（VESGEN）技术来描绘视网膜中的血管重塑，（iv）使我们处于一个突出的位置，可以过渡到临床领域，使用具有保护性RAS轴激活的细胞，无论是遗传还是药理学，用于治疗糖尿病视网膜病变