Ocular Renin Angiotensin System in Pathogenesis of Diabetic Retinopathy

描述(申请人提供)：糖尿病视网膜病变(DR)是最常见的糖尿病血管并发症。尽管最近在治疗和管理糖尿病方面取得了进展，DR仍然是60岁以下人群严重视力丧失的主要原因。越来越多的证据表明，肾素-血管紧张素系统(RAS)的血管收缩、增殖、促炎和纤维化轴(血管紧张素转换酶[ACE]/血管紧张素II[Ang II]/血管紧张素I型受体[AT1R])的高活性在DR的发病机制中起着核心作用。然而，在一些临床试验中，RAS轴的抑制剂尚未被证明在治疗和预防DR方面有效，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，加上最近发现的RAS血管保护轴的保护作用的最近证据，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)，通过产生血管紧张素-(1-7)，通过受体MAS作用，减弱血管紧张素II的收缩、增殖、纤维化和肥大的作用，血管紧张素II是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伤害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。糖尿病或其他危险因素引起的这种平衡的任何破坏都会导致DR的发生，因此血管保护轴的活性增加将克服视网膜RAS的失衡，保护DR的发生发展，防止不利的代谢记忆。我们的目标是(1)通过局部基因转移的方法，研究RAS的血管保护轴在逆转糖尿病视网膜血管功能障碍中的作用，以恢复眼RAS的平衡；研究视网膜中MAS的遗传缺失是否会加速糖尿病视网膜病变，并减弱ACE2或Ang-(1-7)的保护作用；以及(2)研究糖尿病诱导的局部视网膜ACE/Ang II/AT1R轴的过度活动在代谢记忆中的作用。拟议的研究将(1)为我们的新假说提供证据；(2)建立导致糖尿病患者视网膜RAS慢性失调的机制；以及(3)使我们处于有利地位，可以过渡到临床领域，以测试ACE2/Ang-(1-7)基因转移是否对DR具有治疗作用。 公共卫生相关性：本应用的总体目标是研究ACE2/Ang-(1-7)在通过眼部基因转移逆转糖尿病引起的视网膜血管功能障碍中的作用，确定ACE2/Ang1-7的保护机制，并检测眼部RAS在代谢记忆中的作用。这项拟议研究的结果将立即影响糖尿病视网膜病变患者的临床护理，并确定新的治疗干预机制和目标。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The overall goal of this application is to study the role of ACE2/Ang-(1-7) in reversing diabetes-induced retinal vascular dysfunctions using ocular gene transfer, identify the protective mechanism of ACE2/Ang1-7, and examine the role of ocular RAS in metabolic memory. The outcome of this proposed research will immediately impact the clinical care of patients with diabetic retinopathy, and identify novel mechanisms and targets for therapeutic intervention.