ER Stress and Diabetic Retinopathy

内质网应激和糖尿病视网膜病变

基本信息

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
项目类别：
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

项目摘要

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）：糖尿病性视网膜病（DR）是糖尿病的主要并发症，是工作年龄人群的视力障碍和损失的主要原因。与糖尿病的其他微和宏血管并发症类似，DR的发育和进展已充分证明与糖尿病的持续时间相关。这种现象表明，由糖尿病环境驱动的慢性细胞应激可能在DR的发病机理中起作用。我们最近发现，在几种糖尿病模型的视网膜中激活内质网应激。在此应用中，我们建议描述ER应力在DR中的作用。我们假设糖尿病诱导的ER应激会促进炎症，从而引起视网膜病理学的中心驱动力，导致DR（例如，血液 - 视网膜屏障，毛细血管细胞死亡的崩溃，视网膜中的异常血管生长）。我们计划使用互补的体外和体内实验，药物和遗传干预措施以及最先进的技术来检验我们的假设。在AIM 1中，我们将在两种不同模型的糖尿病模型的视网膜中充分表征ER应激和ER的保护蛋白反应（UPR），并解决糖尿病如何引起视网膜ER应力并改变UPR。在AIM 2中，我们建议研究X-box结合蛋白1（XBP1）（一种内源性ER应力抑制剂）的治疗作用和作用机理，以减轻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基因敲除小鼠模型，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在抵消ER应力和炎症中的重要性，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应力的核心作用以及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，这项工作将确定一种新型保护剂的治疗潜力，以阻止DR的发作和/或进展，DR的发作和/或正在接近美国流行病的疾病。结果还可能影响其他威胁视力的疾病，其中可能涉及ER应力，例如与年龄相关的黄斑变性（AMD）。