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

• 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
• 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

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）是糖尿病最常见的血管并发症。尽管最近 随着治疗和管理糖尿病的进展，DR仍然是严重糖尿病的主要原因。 60岁以下的人视力下降。越来越多的证据表明， 血管收缩、增殖、促炎和纤维化轴（血管紧张素转化 酶[ACE]/血管紧张素II [Ang II]/血管紧张素I型受体[AT 1 R]）， 血管紧张素系统（RAS）在DR的发病机制中起着重要作用， RAS轴的抑制剂尚未被证明在治疗和预防 DR在几个临床试验中，因此，一个概念上的突破是必要的，以确定新的 目标和治疗策略。我们相信我们的初步数据 最近的证据表明，最近发现的血管保护轴的保护作用， RAS提供了这样一个突破。RAS的保护轴涉及血管紧张素 转化酶2（ACE 2）通过产生血管紧张素-（1-7），血管紧张素-（1-7）通过受体发挥作用 Mas，减弱血管收缩，增殖，纤维化和肥大的影响， 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有害轴之间的微妙平衡， 对于维持正常的视网膜血管生理机能至关重要。任何损害 由糖尿病或其他危险因素引起的平衡，导致DR的发展。 血管保护轴活性的增加将克服视网膜神经元的不平衡。 RAS，保护DR的发生和发展，防止不良代谢产物的产生， 记忆我们的目标是：（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RAS研究 方法来恢复眼睛RAS的平衡;研究是否遗传缺失的Mas在 视网膜会加速糖尿病视网膜病变，并减弱ACE 2或Ang-（1-7）的保护作用; （2）探讨ACE/Ang Ⅱ/AT 1 R轴在视网膜局部高活动中的作用。 糖尿病在代谢记忆中的作用这些研究将（1）为我们的新发现提供证据。 （2）建立导致视网膜RAS慢性失调的机制 在糖尿病中;和（3）使我们处于一个强有力的地位，过渡到临床竞技场，以测试是否 ACE 2/Ang-（1-7）基因转移可能是治疗DR的有效方法。