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Gpx3 Targeting and Extracellular Oxidative Stress

Gpx3 靶向和细胞外氧化应激

基本信息

批准号：
8286340
负责人：
RAYMOND F. BURK
金额：
$ 37.27万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8286340
关键词：
ABCC1 gene Affect Antibodies Antioxidants Basement membrane Binding Biochemical Blood Urea Nitrogen Cells Colitis Colon Data Disease Enzymes Epididymal duct structure Epithelial Cells Epithelium Gallbladder Gamma-glutamyl transferase Genes Glutathione Glutathione Disulfide Glutathione Metabolism Pathway Goals Health Hydrogen Peroxide In Situ Hybridization Inflammation Inflammatory Injury Intestines Ischemia Kidney Kidney Diseases Kidney Transplantation Knock-out Knockout Mice Learning Light Liquid Chromatography Liver Methods Modeling Multidrug Resistance Associated Protein 1 Mus NF-E2-related factor 2 Nature Organ Oxidative Stress Phosphate Buffer Physiological Physiology Plasma Preparation Reactive Oxygen Species Reduced Glutathione Renal tubule structure Reperfusion Therapy Research Design Response Elements Reverse Transcriptase Polymerase Chain Reaction Saline Selenium Small Intestines Sodium Dextran Sulfate Source Sulfhydryl Compounds Superoxide Dismutase Tissues bile duct cell injury extracellular glutathione peroxidase immunocytochemistry in vivo insight interstitial kidney cell neutrophil research study selenoprotein tandem mass spectrometry transcription factor

项目摘要

DESCRIPTION (provided by applicant): Extracellular glutathione peroxidase (Gpx3) is produced primarily by the proximal convoluted tubule (PCT) cells of the kidney. Gpx3 catabolizes H2O2 and other hydroperoxides outside cells using GSH as its reducing substrate. Thus, Gpx3 functions as an extracellular antioxidant. We have developed immunocytochemistry methods to detect Gpx3 and have used them to show that Gpx3 binds specifically to the basement membranes of kidney tubules, small intestine, colon, and other absorptive epithelia. It does not bind to basement membranes in most tissues. We have also acquired mice with the Gpx3 gene deleted. Using these mice, we have found that extracellular glutathione metabolism is sharply affected by Gpx3 deletion with plasma glutathione concentration being almost tripled. This finding supports GSH as being the reducing substrate of Gpx3. We have also shown that Gpx3 is not involved in the regulated transport of selenium. We hypothesize that Gpx3 protects basement membranes and their associated epithelial cells in kidney and intestine from damage by oxidative stresses. We propose to characterize the relationship of Gpx3 with basement membranes and to assess its effect on oxidative stresses in intestine, kidney, and liver. We also propose to characterize the effect of the kidney on the presence and function of Gpx3 in other tissues. These studies are designed to provide insight into Gpx3 function and to assess how kidney disease might deprive other tissues of Gpx3 and thereby render them susceptible to injury from oxidative stress. PUBLIC HEALTH RELEVANCE: Extracellular glutathione peroxidase (Gpx3) is an antioxidant enzyme. Our preliminary data show that Gpx3 binds to basement membranes in the intestine and in other tissues. We produced mice with Gpx3 deleted and will assess Gpx3 protection against oxidative stress in those mice to shed light on some diseases.

描述（由申请人提供）：细胞外谷胱甘肽过氧化物酶（Gpx3）主要由肾脏的近曲小管（PCT）细胞产生。 Gpx3 使用 GSH 作为还原底物在细胞外分解 H2O2 和其他氢过氧化物。因此，Gpx3 起到细胞外抗氧化剂的作用。我们开发了免疫细胞化学方法来检测 Gpx3，并用它们证明 Gpx3 与肾小管、小肠、结肠和其他吸收性上皮细胞的基底膜特异性结合。它不与大多数组织的基底膜结合。我们还获得了 Gpx3 基因缺失的小鼠。使用这些小鼠，我们发现细胞外谷胱甘肽代谢受到 Gpx3 缺失的急剧影响，血浆谷胱甘肽浓度几乎增加了两倍。这一发现支持 GSH 作为 Gpx3 的还原底物。我们还表明 Gpx3 不参与硒的调控运输。我们假设 Gpx3 可以保护肾脏和肠道的基底膜及其相关上皮细胞免受氧化应激的损害。我们建议表征 Gpx3 与基底膜的关系，并评估其对肠道、肾脏和肝脏氧化应激的影响。我们还建议描述肾脏对其他组织中 Gpx3 的存在和功能的影响。这些研究旨在深入了解 Gpx3 功能，并评估肾脏疾病如何剥夺其他组织的 Gpx3，从而使它们容易受到氧化应激的伤害。公共卫生相关性：细胞外谷胱甘肽过氧化物酶 (Gpx3) 是一种抗氧化酶。我们的初步数据显示 Gpx3 与肠道和其他组织的基底膜结合。我们培育了 Gpx3 缺失的小鼠，并将评估 Gpx3 对这些小鼠氧化应激的保护作用，以揭示某些疾病。