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: 8502551
• 负责人: Maria Bartolomeo Grant
• 金额: $ 42.41万
• 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/8502551
• 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率和发病率的主要原因。尽管最近使用药物疗法进展，但治愈糖尿病微血管并发症（MVC）尚未实现。必须识别新目标的概念和技术突破，而治愈这些并发症的策略至关重要。我们认为，我们的挑衅性初步数据以及最新的证据表明内皮祖细胞（EPC）在血管修复中的潜在作用以及发现肾素 - 血管紧张素系统（RAS）的血管保护轴的潜在作用，提供了这种突破。 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.在此提案中，我们利用视网膜病作为MVC来检验我们的假设，即EPC中的ACE/ACE2平衡决定了其修复能力，因此可以预测视网膜MVC的进展。如果已经存在MVC，则利用AAV技术来提高内源性ACE2水平的基因修饰EPC将增强其修复功能并反向MVC。我们提出了以下特定目的来检验我们的假设：目标1：研究EPC中ACE/ACE2的不平衡是否会预测MVC的进展。 AIM 2：检验假设，如果系统性脉管系统中缺乏ACE2会加速进展，而过表达将阻止发育和进展性视网膜血管并发症。 AIM 3：调查认为增加视网膜内ACE2/ANG-（1-7）表达的假设将刺激EPC的动员，归巢和修复潜力。在概念和技术上，这一综合性和多维建议在概念和技术上都是极具创新性的：（i）为我们的假设提供证据； （ii）建立了EPCS中ACE2/Ang-（1-7） - Mas受体轴激活的机制，可在糖尿病中持续细胞修复功能； （iii）确定EPC中RA的状态是否可以预测视网膜病的进展； （iv）使用高度创新的血管生成（Vesgen）技术来描述视网膜中的血管重塑，（iv）使我们处于使用遗传学或药理学的保护性RAS轴的细胞中，使我们处于过渡到临床领域的杰出位置