ER Stress and Diabetic Retinopathy

内质网应激和糖尿病视网膜病变

• 批准号: 8324762
• 负责人: Sarah X Zhang
• 金额: $ 5.37万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8324762
• 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; Injection of therapeutic agent; 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; 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).

糖尿病视网膜病变（diabetic retinopathy，DR）是糖尿病的主要并发症，是导致视力损害的主要原因 以及劳动年龄人口的减少。与糖尿病的其他微血管和大血管并发症相似， DR的发生和进展与糖尿病的持续时间相关。这 这一现象表明，糖尿病环境驱动的慢性细胞应激可能在糖尿病的发生中起作用。 我们最近发现内质网（ER）应激在视网膜中被激活， 糖尿病的几种模型。在本申请中，我们提出描绘ER应激在DR中的作用。 假设糖尿病诱导的内质网应激促进炎症，从而是一个中心驱动力 诱导导致DR的视网膜病变（例如，血-视网膜屏障的破坏、毛细血管细胞死亡，以及 视网膜中异常的新血管生长）。我们计划使用互补的体外和体内实验， 药物和基因干预，以及最先进的技术来测试我们的假设。在目标1中，我们 充分表征ER应激和未折叠蛋白反应（UPR），ER的保护机制， 两种不同糖尿病模型的视网膜，并说明糖尿病如何引起视网膜ER应激和改变 普遍定期审议。在目的2中，我们提出研究X-box结合的治疗效果和作用机制 蛋白1（XBP 1），一种内源性ER应激抑制剂，在减轻视网膜炎症和减少 在目标3中，使用新产生的细胞特异性XBP 1敲除小鼠， 模型，我们将描绘ER应激在特定视网膜细胞类型中的作用，并建立 内源性XBP 1在抵抗ER应激和炎症以及保护视网膜血管细胞免受 糖尿病损害总之，所提出的研究将确立ER应激的中心作用， 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，这项工作将确定一种新型保护剂的治疗潜力，以阻止发病和/或 DR的进展，这种疾病在美国接近流行病的比例。结果也可能 影响其他可能与ER应激有关的威胁视力的疾病，如年龄相关的 黄斑变性（AMD）。