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：
8964267
负责人：
Sarah X Zhang
金额：
$ 39.77万
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 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8964267
关键词：
Address Adult Age Angiogenic Factor Apoptosis Binding Proteins Biogenesis Biology Blindness Blood Vessels Blood capillaries Boxing Calcium Cell Survival Cells Cellular Stress Characteristics Chronic Data Defect Development Diabetes Mellitus Diabetic Retinopathy Dropout Drug Metabolic Detoxication Endoplasmic Reticulum Endothelial Cells Endothelium Environment Enzymes Event Excision Exhibits Extensive Stage Extravasation Failure Functional disorder Future GRP75 Gene Proteins Generations Glucose Glutathione Goals Grant Growth Homeostasis Immune response Inflammation Injury Knock-out Knockout Mice Lipid Peroxidation Manuscripts Mediating Membrane Membrane Potentials Metabolic Mitochondria Mus Neural Retina Oxidants Oxygen Pathway interactions Pericytes Preparation Process Production Proteins Proteomics Publishing Reactive Oxygen Species Regulation Retina Retinal Retinal Diseases Retinal Edemas Role Scheme Signal Pathway Stress Superoxides Testing Time Up-Regulation Vascular Diseases Vascular blood supply Work capillary combat diabetic effective therapy endoplasmic reticulum stress improved innovation lipid metabolism meetings mitochondrial membrane new therapeutic target novel overexpression oxidative damage prevent protective effect protein folding public health relevance release of sequestered calcium ion into cytoplasm response retina blood vessel structure retinal adaptation retinal damage stressor trafficking transcription factor transcriptome sequencing vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Retinal vascular dysfunction and degeneration are the early characteristics of diabetic retinopathy (DR). Compelling evidence suggests that the chronic diabetic milieu damages retinal endothelial cells and pericytes, resulting in loss of retinl capillaries. At the late stages, extensive capillary dropout leads to severe reduction in blood supply and defects in oxygen delivery to the neural retina. This, in turn, stimulates retinal expression and production of pro-angiogenic factors, which promote vascular leakage and new vessel growth leading to retinal edema and proliferative retinopathy. Clearly, retinal endothelial injury, if irreversibly leading to consequent capillary loss, is a central event in the development and progression of DR. However, to date, there is no effective therapy available to prevent diabetes-induced retinal vascular damage. The goal of our project is to address this critical gap by identifying and harnessing endogenous protective factors to enhance retinal cell survival and improve vascular function in diabetes mellitus. Our published and preliminary studies have revealed one such protective factor, namely X-box binding protein 1 (XBP1). XBP1 is a transcription factor in the core signaling pathways of the unfolded protein response (UPR) and is broadly implicated in ER biogenesis, protein folding, immune response, and lipid metabolism. Our data confirmed a fundamental role of the XBP1- mediated UPR in maintaining endothelial cell homeostasis against inflammation. In addition, we found that XBP1-null retinal cells are sensitive to oxidative damage and apoptosis. Strikingly, our new results suggest a novel function of XBP1 in regulation of mitochondrial remodeling and activity. Thus, we hypothesize that XBP1 is a central regulator of cell adaptation to diabetic stressors through coordinating ER and mitochondrial homeostasis. We propose 3 Specific Aims to test this hypothesis, focusing on XBP1's role in mitochondrial regulation in retinal endothelial cells. In Aim 1, we will examine if XBP1 is involved in mitochondrial remodeling and whether enhancing XBP1 expression can reverse diabetes-induced deficits in mitochondrial biogenesis. In Aim 2, we then will delineate if XBP1 regulates mitochondrial energy production through modulation of ER- mitochondrial contact and calcium trafficking. Finally, in Aim 3, we will establish whether XBP1 is essential for mitochondrial ROS detoxification, thereby reducing oxidative damage and apoptosis. This application is conceptually and technically innovative in that it will elucidate a novel function o XBP1, a traditional UPR protein induced by ER stress, in regulation of mitochondrial activities, and using novel RNA-seq and proteomic approaches to identify new XBP1-specific target genes and proteins that are critically involved in these processes. This project also has high translational potential by identifying novel therapeutic targets to enhance retinal cell adaptation to diabetic stresses and prevent/reverse retinal damage in diabetes.

描述（由应用提供）：视网膜血管功能障碍和变性是糖尿病性视网膜病（DR）的早期特征。令人信服的证据表明，慢性糖尿病环境会损害视网膜内皮细胞和周细胞，从而导致视网膜毛细血管丧失。在后期，广泛的毛细血管辍学会导致血液供应严重减少和氧递送到神经视网膜的缺陷。反过来，这刺激了视网膜表达和促血管生成因子的产生，这些因素促进了血管泄漏和新血管的生长，导致视网膜水肿和增殖视网膜病变。显然，视网膜内皮损伤（如果不可逆地导致毛细血管损失）是开发中的一个中心事件和DR的进展。但是，迄今为止，尚无有效的治疗可预防糖尿病诱导的视网膜血管损伤。我们项目的目的是通过识别和利用内源性保护因素来解决这一关键差距，以增强视网膜细胞存活并改善糖尿病中的血管功能。我们发表的初步研究表明，这样一个受保护的因子，即X-box结合蛋白1（XBP1）。 XBP1是展开的蛋白质反应（UPR）核心信号通路中的转录因子，并且广泛与ER生物发生，蛋白质折叠，免疫反应和脂质代谢有关。我们的数据证实了XBP1-介导的UPR在维持内皮细胞稳态抗炎中的基本作用。此外，我们发现XBP1无效的视网膜细胞对氧化损伤和凋亡敏感。令人惊讶的是，我们的新结果表明，XBP1在调节线粒体重塑和活性中的新功能。这就是我们假设XBP1是通过协调ER和线粒体稳态对细胞适应糖尿病应激源的中心调节剂。我们提出了3个特定旨在检验这一假设的特定旨在，重点是XBP1在视网膜内皮细胞中线粒体调节中的作用。在AIM 1中，我们将检查XBP1是否参与线粒体重塑以及增强XBP1表达是否可以逆转糖尿病诱导的线粒体生物发生中的缺陷。在AIM 2中，如果XBP1通过调节线粒体接触和钙运输来调节线粒体能量的产生，我们将描述。最后，在AIM 3中，我们将确定XBP1是否对线粒体ROS排毒，从而减少了氧化损伤和凋亡。该应用在概念上和技术上是创新的，因为它将阐明一种新型功能O XBP1，这是一种由ER应力，通过调节线粒体活性引起的传统UPR蛋白，并使用新型的RNA-SEQ和蛋白质组学方法来识别XBP1特异性的靶基因和蛋白质与这些过程中有关的新型XBP1特异性靶基因和蛋白质。该项目还通过识别新的治疗靶标具有高转化潜力糖尿病应力并防止糖尿病中的残留损害。