ER Stress and Diabetic Retinopathy

糖尿病视网膜病变(DR)是糖尿病的主要并发症，是导致视力障碍的主要原因 以及劳动年龄人口的损失。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的病程有很好的相关性。这 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.的发病机制我们最近发现内质网(ER)应激在视网膜被激活 糖尿病的几种模型。在这一应用中，我们建议描绘内质网应激在Dr.We中的作用 假设糖尿病诱导的内质网应激促进炎症，从而是中心驱动力 诱发视网膜病变导致DR(例如血-视网膜屏障破裂，毛细血管细胞死亡，以及 视网膜中新血管的异常生长)。我们计划使用体外和体内的互补实验， 药物和基因干预，以及最先进的技术来验证我们的假设。在目标1中，我们将 充分表征内质网应激和未折叠蛋白反应(UPR)，这是内质网的一种保护机制，在 两种不同糖尿病模型的视网膜，并解决糖尿病如何导致视网膜内质网压力和改变 普遍定期审议。在目标2中，我们建议研究X-box结合的治疗作用和作用机制 蛋白1(XBP1)，一种内源性内质网应激抑制物，在减轻视网膜炎症和减少 在AIM 3中，使用新产生的细胞特异性XBP1基因敲除小鼠，研究了与DR相关的血管病理 模型，我们将描述内质网应激在特定视网膜细胞类型中的作用，并确定 内源性XBP1拮抗内质网应激和炎症反应及保护视网膜血管细胞 糖尿病损伤。总之，拟议的研究将确立内质网应激和内质网压力的核心作用。 UPR在糖尿病引起的炎症和视网膜血管病理发展中的重要性。在……里面 此外，这项工作将建立一种新型保护剂的治疗潜力，以阻止发病和/或 糖尿病视网膜病变的进展，这是一种在美国接近流行比例的疾病。结果也可能是 影响其他可能与内质网应激有关的威胁视力的疾病，如与年龄有关的 黄斑变性(AMD)。

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).