ER Stress and Diabetic Retinopathy

描述(申请人提供)：糖尿病视网膜病变(DR)是糖尿病的主要并发症，是劳动年龄人口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，糖尿病视网膜病变的发生和发展与糖尿病病程相关。这一现象表明，由糖尿病环境驱动的慢性细胞应激可能在DR的发病机制中发挥作用。我们最近发现，内质网(ER)应激在几种糖尿病模型的视网膜中被激活。在这一应用中，我们建议描绘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，从而是导致DR的视网膜病理(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)的中心驱动力。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，我们将充分描述内质网应激和内质网的一种保护机制--未折叠蛋白反应(UPR)在两种不同糖尿病模型的视网膜中的特征，并解决糖尿病如何导致视网膜内质网应激和改变UPR。在目的2中，我们建议研究内源性ER应激抑制剂X盒结合蛋白1(XBP1)在减轻视网膜炎症和减少与DR相关的血管病变方面的疗效和作用机制。在目的3中，我们将利用新建立的细胞特异性XBP1基因敲除小鼠模型，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XBP1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，拟议的研究将确定内质网应激的核心作用以及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的发病和/或进展，DR是一种在美国正接近流行比例的疾病。这一结果也可能影响到其他可能与ER应激有关的威胁视力的疾病，如老年性黄斑变性(AMD)。 公共卫生相关性：糖尿病视网膜病变(DR)是糖尿病的主要并发症，是劳动年龄人口视力受损和丧失的主要原因。这项拨款申请的目标是描述内质网(ER)应激在糖尿病视网膜血管病理发展中的作用，并测试一种新型保护剂在对抗内质网应激和DR视网膜细胞炎症损伤方面的治疗潜力。这些目标的实现有望确定支持糖尿病视网膜并发症的新机制，并为预防/治疗这种威胁视力的疾病铺平道路。

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). PUBLIC HEALTH RELEVANCE: Diabetic retinopathy (DR), a major complication of diabetes, is a leading cause of vision impairment and loss in the working age population. The goals of this grant application are to delineate the role of endoplasmic reticulum (ER) stress in the development of retinal vascular pathology in diabetes, and to test the therapeutic potential of a novel protective agent in counteracting ER stress and inflammatory damage of retinal cells in DR. The realization of these goals is anticipated to identify a novel mechanism underpinning the retinal complications of diabetes and pave the way for new therapies to prevent/treat this sight-threatening disease.