ER Stress and Diabetic Retinopathy

内质网应激和糖尿病视网膜病变

• 批准号: 8542852
• 负责人: Sarah X Zhang
• 金额: $ 36.25万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 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/8542852
• 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; macular edema; mouse model; multicatalytic endopeptidase complex; new therapeutic target; non-diabetic; novel; preconditioning; prevent; protective effect; public health relevance; research study; response; response marker; retinal damage; stressor; vascular inflammation

DESCRIPTION (provided by applicant): 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 macro vascular 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).

描述（由申请人提供）：糖尿病视网膜病变（DR）是糖尿病的主要并发症，是工作年龄人群视力受损和丧失的主要原因。与糖尿病的其他微血管和大血管并发症类似，DR的发生和进展与糖尿病的持续时间相关。这一现象表明，慢性细胞应激驱动的糖尿病环境可能在DR的发病机制中发挥作用。我们最近发现，内质网（ER）应激激活的视网膜中的几个模型的糖尿病。在本申请中，我们提出描绘ER应激在DR中的作用。我们假设糖尿病诱导的ER应激促进炎症，从而是诱导视网膜病理导致DR的中心驱动力（例如，血视网膜屏障的破坏、毛细血管细胞死亡和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，药物和遗传干预，以及最先进的技术来验证我们的假设。在目标1中，我们将全面描述两种不同糖尿病模型视网膜中的ER应激和未折叠蛋白反应（UPR）（ER的一种保护机制），并解决糖尿病如何引起视网膜ER应激并改变UPR。在目标2中，我们提出研究X-box结合蛋白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与DR相关的血管病理中的治疗效果和作用机制。在目标3中，使用新产生的细胞特异性XBP 1敲除小鼠模型，我们将描述ER应激在特定视网膜细胞类型中的作用，并确定内源性XBP 1在对抗ER应激和炎症以及保护视网膜血管细胞免受糖尿病损伤中的重要性。总之，所提出的研究将确立ER应激的中心作用以及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。此外，这项工作将建立一种新型保护剂的治疗潜力，以阻止DR的发作和/或进展，DR是一种在美国接近流行病比例的疾病。这些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，如年龄相关性黄斑变性（AMD）。