Ocular Renin Angiotensin System in Pathogenesis of Diabetic Retinopathy

眼部肾素血管紧张素系统在糖尿病视网膜病变发病机制中的作用

基本信息

批准号：
8404011
负责人：
Qiuhong Li
金额：
$ 34.79万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8404011
关键词：
Age Angiopoietin-2 Angiotensin II Angiotensins Animal Model Attenuated Blindness Blood Vessels Chronic Clinical Clinical Trials Coupled Data Development Diabetes Mellitus Diabetic Angiopathies Diabetic Retinopathy Equilibrium Functional disorder Gene Delivery Gene Expression Gene Transfer Genes Genetic Goals Hyperactive behavior Hyperglycemia Inflammatory Maintenance Mediating Memory Metabolic Mus Outcome Pathogenesis Pathology Patients Peptidyl-Dipeptidase A Physiology Play Positioning Attribute Prevention Renin-Angiotensin System Research Retina Retinal Risk Factors Role Signal Transduction Small Interfering RNA Streptozocin Testing Therapeutic Therapeutic Intervention adeno-associated viral vector angiotensin I (1-7)clinical care diabetes management diabetic diabetic rat equilibration disorder inhibitor/antagonist member new therapeutic target novel prevent protective effect receptor small hairpin RNA

项目摘要

Project Summary: Diabetic retinopathy (DR) is the most common diabetic vascular complication. Despite recent advances in therapeutics and management diabetes, DR remains the leading cause of severe vision loss in people under age of sixty. Growing evidence indicates that hyperactivity of the vasoconstrictive, proliferative, pro-inflammatory, and fibrotic axis (angiotensin-converting enzyme [ACE]/angiotensin II [Ang II]/angiotensin type I receptor [AT1R]) of the renin- angiotensin-system (RAS) plays a central role in the pathogenesis of DR. Nevertheless, inhibitors to this axis of RAS have not proven to be effective in the treatment and prevention of DR in several clinical trials, thus a conceptual breakthrough is imperative to identify novel targets and therapeutic strategies. We believe that our provocative preliminary data coupled with recent evidence of the protective role of the recently discovered vasoprotective axis of the RAS offer such a breakthrough. The protective axis of the RAS involves the angiotensin converting enzyme 2 (ACE2) by generating angiotensin-(1-7) which acts through the receptor Mas, attenuates the vasoconstrictive, proliferative, fibrotic and hypertrophic effects of angiotensin II, the key member of the deleterious axis of RAS. Our Central Hypothesis is that a delicate balance between the vasoprotective and vasodeleterious axis of retinal RAS is critical to the maintenance of normal retinal vascular physiology. Any impairment of this balance, induced by diabetes or other risk factors, leads to the development of DR. Thus an increase in the activity of the vasoprotective axis will overcome the imbalance of the retinal RAS, protect the development and progression of DR, and prevent the adverse metabolic memory. Our goal of this proposal is to (1) investigate the role of the vasoprotective axis of the RAS in reversing diabetes-induced retinal vascular dysfunctions using local gene transfer approach to restore the balance of ocular RAS; study whether genetic depletion of Mas in the retina will accelerate diabetic retinopathy and blunt the protective effects of ACE2 or Ang-(1-7); and (2) examine the role of local retinal hyperactivity of ACE/Ang II/AT1R axis induced by diabetes in metabolic memory. The proposed studies will (1) provide evidence for our novel hypothesis; (2) establish the mechanism that leads to a chronic dysregulation of the retinal RAS in diabetes; and (3) put us in a strong position to transition into the clinical arena to test whether ACE2/Ang-(1-7) gene transfer would be therapeutic for DR.

项目概要：糖尿病视网膜病变（DR）是最常见的糖尿病血管并发症。尽管最近随着糖尿病治疗和管理的进步，DR 仍然是严重糖尿病的主要原因六十岁以下的人视力丧失。越来越多的证据表明，过度活跃血管收缩轴、增殖轴、促炎轴和纤维化轴（血管紧张素转换轴）肾素酶 [ACE]/血管紧张素 II [Ang II]/血管紧张素 I 型受体 [AT1R]）血管紧张素系统（RAS）在 DR 的发病机制中发挥着核心作用。尽管如此， RAS 轴抑制剂尚未被证明可有效治疗和预防 DR 已在多项临床试验中进行，因此，必须在概念上进行突破，以识别新的目标和治疗策略。我们相信我们的挑衅性初步数据加上最近发现的血管保护轴的保护作用的最新证据 RAS 提供了这样的突破。 RAS 的保护轴涉及血管紧张素通过生成血管紧张素-(1-7) 来转化酶 2 (ACE2)，血管紧张素-(1-7) 通过受体发挥作用 Mas，减弱血管收缩、增殖、纤维化和肥大作用血管紧张素II，RAS有害轴的关键成员。我们的中心假设是视网膜 RAS 的血管保护轴和血管破坏轴之间的微妙平衡对于维持正常的视网膜血管生理至关重要。对此的任何损害由糖尿病或其他危险因素引起的平衡会导致 DR 的发生。因此血管保护轴活性的增加将克服视网膜的不平衡 RAS，保护DR的发生和进展，预防不良代谢记忆。我们该提案的目标是（1）研究血管保护轴的作用 RAS 利用局部基因转移逆转糖尿病引起的视网膜血管功能障碍恢复眼部 RAS 平衡的方法；研究 Mas 的遗传缺失是否视网膜会加速糖尿病视网膜病变并削弱 ACE2 或 Ang-(1-7) 的保护作用； (2)检查ACE/Ang II/AT1R轴局部视网膜过度活跃的作用代谢记忆中的糖尿病。拟议的研究将（1）为我们的小说提供证据假设; (2) 建立导致视网膜RAS慢性失调的机制患有糖尿病； (3) 让我们处于有利的地位，可以过渡到临床领域，以测试是否 ACE2/Ang-(1-7) 基因转移可治疗 DR。