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: 8588328
• 负责人: Qiuhong Li
• 金额: $ 35.89万
• 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/8588328
• 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; Vascular Diseases; 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.

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