ER Stress and Diabetic Retinopathy

内质网应激和糖尿病视网膜病变

• 批准号: 8324632
• 负责人: Sarah X Zhang
• 金额: $ 6.32万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-12-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8324632
• 关键词: Abbreviations; Address; Adhesions; Adult; Age; Age related macular degeneration; Applications Grants; Arts; Attenuated; Binding Proteins; Blindness; Blood Vessels; Blood capillaries; Blood-Retinal Barrier; Boxing; CCAAT-Enhancer-Binding Proteins; Cell Adhesion Molecules; Cell Death; Cells; Cellular Stress; Chemicals; Chronic; Complement; Complications of Diabetes Mellitus; Data; Defect; Dependovirus; Development; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Disease; Endoplasmic Reticulum; Endothelial Cells; Environment; Epidemic; Eukaryotic Initiation Factors; Extravasation; Eye; Fibroblast Growth Factor; GRP78 gene; Genetic Models; Glucose; Goals; Growth; Homologous Protein; Hyperglycemia; Hypoxia; Impairment; In Vitro; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Intercellular adhesion molecule 1; Kinetics; Knockout Mice; Mediating; Modeling; Molecular Chaperones; Mus; Nuclear; Outcome; Pathogenesis; Pathology; Pharmacologic Substance; Play; Population; Production; Protective Agents; Proteins; Reactive Oxygen Species; Reporting; Retina; Retinal; Retinal Neovascularization; Rodent; Role; Signal Pathway; Streptozocin; TNF gene; Techniques; Testing; Therapeutic; Therapeutic Effect; Vascular Endothelial Cell; Vision; Work; activating transcription factor; capillary; cell injury; cell type; diabetic; driving force; endoplasmic reticulum stress; gene therapy; glucose-regulated proteins; in vivo; inhibitor/antagonist; intravitreal injection; macrovascular disease; macular edema; mouse model; multicatalytic endopeptidase complex; new therapeutic target; non-diabetic; novel; preconditioning; prevent; protective effect; research study; response; response marker; retinal damage; stressor; vascular inflammation

Diabetic retinopathy (DR), a major complication of diabetes, is the leading cause of vision impairment and loss in the working age population. Similar to other micro- and macrovascular complications of diabetes, the development and progression of DR is well documented to correlate with the duration of diabetes. This phenomenon suggests that chronic cellular stress driven by a diabetic milieu may play a role in the pathogenesis of DR. We recently discovered that endoplasmic reticulum (ER) stress is activated in the retinas of several models of diabetes. In this application, we propose to delineate the role of ER stress in DR. We hypothesize that diabetes-induced ER stress promotes inflammation and is thereby a central driving force inducing retinal pathology leading to DR (e.g. breakdown of the blood-retinal barrier, capillary cell death, and aberrant new vessel growth in the retina). We plan to use complementary in vitro and in vivo experiments, pharmaceutical and genetic interventions, and state-of-art techniques to test our hypothesis. In Aim 1, we will fully characterize ER stress and the unfolded protein response (UPR), a protective mechanism of the ER, in the retinas of two different models of diabetes and address how diabetes causes retinal ER stress and alters the UPR. In Aim 2, we propose to study the therapeutic effects and mechanism of action of X-box binding protein 1 (XBP1), an endogenous ER stress inhibitor, in mitigating retinal inflammation and reducing the vascular pathology associated with DR. In Aim 3, using newly generated cell-specific XBP1 knockout mouse models, we will delineate the role of ER stress in specific retinal cell types and to establish the importance of endogenous XBP1 in counteracting ER stress and inflammation and protecting retinal vascular cells from diabetic damage. In summary, the proposed studies will establish the central role of ER stress and the importance of the UPR in the development of diabetes-driven inflammation and retinal vascular pathology. In addition, this work will establish the therapeutic potential of a novel protective agent to block the onset and/or progression of DR, a disease that is approaching epidemic proportions in the US. The outcomes may also impact other vision-threatening diseases in which ER stress is potentially implicated, such as age-related macular degeneration (AMD).

糖尿病病变（DR）是糖尿病的主要并发症，是视力障碍的主要原因 和工作年龄人口的损失。类似于糖尿病的其他微血管并发症， DR的发展和进展已充分证明与糖尿病的持续时间相关。这 现象表明，由糖尿病环境驱动的慢性细胞应激可能在 Dr的发病机理我们最近发现内质网（ER）应力在视网膜中激活 几种糖尿病模型。在此应用中，我们建议描述ER应力在DR中的作用。我们 假设糖尿病引起的ER应力会促进炎症，从而是中央驱动力 诱导视网膜病理学导致DR（例如，血液视网膜屏障，毛细血管死亡和 视网膜中异常的新容器生长）。我们计划使用互补的体外和体内实验， 药物和遗传干预措施以及检验我们假设的最先进技术。在AIM 1中，我们将 充分表征ER应力和未展开的蛋白质反应（UPR），ER的保护机制 两种不同模型的糖尿病模型的视网膜，并解决糖尿病如何引起视网膜ER应力和改变 UPR。在AIM 2中，我们建议研究X-box结合的治疗效果和作用机理 蛋白质1（XBP1），一种内源性ER应激抑制剂，可缓解视网膜炎症并减少 与DR相关的血管病理。在AIM 3中，使用新生成的细胞特异性XBP1敲除鼠标 模型，我们将描述ER应力在特定的视网膜细胞类型中的作用，并确定 内源性XBP1在抵抗ER应力和炎症中，并保护视网膜血管细胞免受 糖尿病损害。总而言之，拟议的研究将确定ER应力和 UPR在糖尿病驱动的炎症和视网膜血管病理学发展中的重要性。在 此外，这项工作将确定新型保护剂的治疗潜力，以阻止发作和/或 DR的进展，这种疾病正在接近美国的流行比例。结果也可能 影响其他威胁视力的疾病，其中可能涉及ER压力，例如与年龄相关的疾病 黄斑变性（AMD）。