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: 8244746
• 负责人: Qiuhong Li
• 金额: $ 36.63万
• 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/8244746
• 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

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.

描述（由申请人提供）：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，但DR仍然是导致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]）的过度活跃在DR的发病机制中起着核心作用。然而，在一些临床试验中，RAS这一轴的抑制剂尚未被证明在治疗和预防DR中有效。因此，概念上的突破是必要的，以确定新的靶点和治疗策略。我们相信，我们令人振奋的初步数据，加上最近发现的RAS血管保护轴的保护作用的证据，提供了这样一个突破。RAS的保护轴通过产生血管紧张素-(1-7)参与血管紧张素转换酶2 (ACE2)，血管紧张素-(1-7)通过受体Mas起作用，减弱血管紧张素II的血管收缩、增殖、纤维化和肥厚作用，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有害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。任何由糖尿病或其他危险因素引起的这种平衡的损害都会导致DR的发生，因此血管保护轴活性的增加将克服视网膜RAS的不平衡，保护DR的发生和进展，并防止不良的代谢记忆。我们的目标是：(1)研究RAS的血管保护轴在逆转糖尿病诱导的视网膜血管功能障碍中的作用，使用局部基因转移方法恢复眼部RAS的平衡；研究视网膜中Mas基因缺失是否会加速糖尿病视网膜病变，削弱ACE2或Ang-的保护作用（1-7）；(2)探讨糖尿病诱导的局部视网膜ACE/Ang II/AT1R轴高活性在代谢记忆中的作用。提出的研究将(1)为我们的新假设提供证据；(2)建立导致糖尿病视网膜RAS慢性失调的机制；(3)使我们处于一个强有力的位置，可以过渡到临床领域，以测试ACE2/Ang-(1-7)基因转移是否可以治疗DR。