Ocular Renin Angiotensin System in Pathogenesis of Diabetic Retinopathy

项目总结： 糖尿病视网膜病变(DR)是糖尿病最常见的血管并发症。尽管最近 糖尿病的治疗和管理方面的进展，糖尿病视网膜病变仍然是严重糖尿病的主要原因 60岁以下人群中的视力丧失。越来越多的证据表明，人的多动 血管收缩、增殖、促炎和纤维化轴(血管紧张素转换 [血管紧张素转换酶/血管紧张素II/血管紧张素I型受体])。 血管紧张素系统(RAS)在DR的发病机制中起着核心作用。 这一RAS轴的抑制剂尚未被证明在治疗和预防 在几个临床试验中进行DR，因此必须在概念上取得突破，以确定新的 靶点和治疗策略。我们认为我们具有挑衅性的初步数据 随着最近发现的血管保护轴的保护作用的最新证据 RAS提供了这样一个突破。RAS的保护轴涉及血管紧张素 通过受体产生血管紧张素-(1-7)来转换酶2(ACE2) MAS，减弱血管收缩、增殖、纤维化和肥大的作用 血管紧张素II，RAS恶化轴的关键成员。我们的中心假设是 视网膜RAS的血管保护轴和有害血管轴之间的微妙平衡 对维持正常的视网膜血管生理至关重要。对这一点的任何损害 由糖尿病或其他危险因素引起的平衡会导致DR的发展，因此 血管保护轴活性的增加将克服视网膜的失衡 RAS，保护DR的发生发展，防止不良代谢 记忆。我们这项建议的目标是(1)研究血管保护轴的作用。 局部基因转移逆转糖尿病视网膜血管功能障碍的实验研究 恢复眼部RAS平衡的方法；研究MAS基因缺失是否在 视网膜会加速糖尿病视网膜病变，削弱ACE2或Ang-(1-7)的保护作用； 以及(2)检测血管紧张素转换酶(ACE)/血管紧张素转换酶II(Ang II)/血管紧张素Ⅱ受体(AT1R)轴局部视网膜过度活动的作用。 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 假说；(2)建立导致视网膜RAS慢性失调的机制 在糖尿病方面；以及(3)使我们处于有利地位，可以过渡到临床舞台上来测试 ACE2/Ang-(1-7)基因转移对DR有治疗作用。

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.