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）：糖尿病性视网膜病（DR）是最常见的糖尿病血管并发症。尽管最近的治疗和管理糖尿病进展，但博士仍然是六十岁以下人群严重视力丧失的主要原因。不断增长的证据表明，血管收缩，增殖性，促炎和纤维化轴（血管紧张素转化酶[ACE]/Angiotensin II [ANG II]/血管紧张素I型受体[ANG II] II [ANG II]型I型肾素 - 血管紧张素 - 血管紧张素系统（RAS）的过度动力（ANG II] II [ANG II] II [ANG II] II [ANG II] [ANG II] II [ANG II] [ANG II]）中心作用。然而，在多个临床试验中，对这种RAS轴的抑制剂尚未证明在治疗和预防DR方面有效，因此，必须进行概念突破，即确定新颖的目标和治疗策略。我们认为，我们的挑衅性初步数据以及最近发现的RAS血管保护轴保护性作用的最新证据提供了如此突破。 RAS的保护轴涉及通过产生通过受体MAS起作用的血管紧张素2（ACE2）的血管紧张素转化酶2（ACE2），从而减轻了血管紧张，纤维化，纤维化，纤维化和肥大效应的血管紧张，血管紧张素II，是Ras eleterious Axis的关键成员。我们的中心假设是，视网膜RAS的血管保护和血管畸形轴之间的微妙平衡对于维持正常的视网膜血管生理学至关重要。糖尿病或其他危险因素引起的这种平衡的任何损害都会导致DR的发展。因此，血管保护轴活动的增加将克服视网膜RAS的失衡，保护DR的发展和进展，并防止不良代谢记忆。该提案的目标是（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使用局部基因转移方法恢复眼睛RAS平衡的作用；研究MAS在视网膜中的遗传耗竭是否会加速糖尿病性视网膜病变并钝化ACE2或ANG-（1-7）的保护作用； （2）检查由糖尿病在代谢记忆中诱导的ACE/ANG II/AT1R轴的局部视网膜多动症的作用。拟议的研究将（1）为我们的新假设提供证据； （2）建立导致糖尿病中视网膜RAS慢性失调的机制； （3）使我们处于过渡到临床领域的强烈位置，以测试ACE2/ANG-（1-7）基因转移是否对DR具有治疗性。 公共卫生相关性：该应用的总体目标是研究ACE2/ANG-（1-7）在使用眼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，并确定ACE2/ANG1-7的保护机制，并检查Ocular Ras在代谢记忆中的作用。这项拟议的研究的结果将立即影响糖尿病性视网膜病患者的临床护理，并确定治疗干预的新型机制和靶标。