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; 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.

项目摘要： 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 治疗和管理糖尿病的进步，博士仍然是严重的主要原因 六十岁以下的人的视力丧失。越来越多的证据表明 血管收缩，增生，促炎和纤维化轴（血管紧张素转换） 肾素 - 血管紧张素系统（RAS）在DR的发病机理中起着核心作用。尽管如此， 该RA轴的抑制剂尚未证明在治疗和预防方面有效 DR在几个临床试验中，因此必须进行概念突破 目标和治疗策略。我们相信我们的挑衅性初步数据耦合 最近有证据表明最近发现的血管保护轴的保护作用 Ras提供了如此突破。 RA的保护轴涉及血管紧张素 通过产生通过受体作用的血管紧张素（1-7）来转换酶2（ACE2） MAS，减轻血管收缩，增生，纤维化和肥厚的作用 血管紧张素II，RAS有害轴的主要成员。我们的中心假设是 视网膜RAS的血管保护和血管置轴之间的微妙平衡是 维持正常的视网膜血管生理学至关重要。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。因此 血管保护轴活动的增加将克服视网膜的失衡 RAS，保护DR的发展和发展，并防止不良代谢 记忆。该提议的目标是（1）研究该提案的作用 RA使用局部基因转移逆转糖尿病引起的视网膜血管功能障碍 恢复眼睛RA的平衡的方法；研究MAS在 视网膜将加速糖尿病性视网膜病，并钝化ACE2或Ang-（1-7）的保护作用； （2）检查ACE/ANG II/AT1R轴局部视网膜多动的作用 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 假设; （2）建立导致视网膜RAS慢性失调的机制 在糖尿病中； （3）使我们处于过渡到临床领域的强烈立场，以测试是否是否 ACE2/Ang-（1-7）基因转移将为DR提供治疗。