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: 8725220
• 负责人: Maria Bartolomeo Grant
• 金额: $ 43.66万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 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/8725220
• 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 Retinopathy; Endothelial Cells; Equilibrium; Functional disorder; Generations; Homing; Individual; Intention; Ischemia; Knock-out; Lead; Link; Messenger RNA; Microvascular Dysfunction; 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。尽管最近使用药物治疗取得了进展，但糖尿病微血管并发症（MVC）的治愈尚未实现。一个概念和技术上的突破是确定新的目标势在必行，治疗这些并发症的策略是至关重要的。我们相信，我们的挑衅性的初步数据，加上最近的证据表明，内皮祖细胞（EPCs）在血管修复中的潜在作用和血管保护轴的发现的肾素-血管紧张素系统（RAS）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（ACE 2），其存在于内皮细胞和EPCs中并产生血管紧张素-（1-7），其通过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。在这个提议中，我们利用视网膜病变作为MVC来测试我们的假设，即EPC内的ACE/ACE 2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技术遗传修饰EPCs以增加内源性ACE 2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：研究内皮祖细胞内ACE/ACE 2失衡是否可以预测MVC的进展。目标二：检验系统血管中缺乏ACE 2是否会加速进展，而过度表达是否会预防视网膜血管并发症的发生和进展。目标三：研究视网膜内ACE 2/Ang-（1-7）表达增加将刺激EPCs的动员、归巢和修复潜力的假设。这一综合性和多方面的建议在概念和技术上都是非常创新的，因为它将：（i）为我们的假设提供证据;（ii）建立EPCs内ACE 2/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VESsel GENeration（VESGEN）技术来描绘视网膜中的血管重塑，以及（iv）使我们处于一个突出的位置，以过渡到临床竞技场，使用具有其保护性RAS轴激活的细胞，无论是遗传性的还是非遗传性的，用于治疗糖尿病视网膜病变