Cellular Redox Balancing and Oxidative Stress: Assembling a Global Model

细胞氧化还原平衡和氧化应激：组装全局模型

基本信息

批准号：
7883389
负责人：
Matthew Escobar
金额：
$ 11.1万
依托单位：
CALIFORNIA STATE UNIVERSITY SAN MARCOS
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7883389
关键词：
Affect Alzheimer&apos s Disease Ammonium Animal Model Antioxidants Apoptotic Assimilations Biochemical Biochemical Pathway Biochemical Reaction Cell Cycle Cell Death Cell Respiration Cell model Cell physiology Cells Complex Cues Cytosol Data Development Diabetes Mellitus Electrons Environment Enzymes Equilibrium Experimental Models Face Foundations Future Gene Expression Gene Expression Profile Gene Expression Regulation Gene Family Generations Genome Glutathione Goals Health Homeostasis Human Human Pathology Hydrogen Peroxide Individual Laboratories Link Lipid Peroxidation Lipids Maintenance Membrane Lipids Mitochondria Modeling Mouse-ear Cress NADP Necrosis Nitrates Nitrogen Nutritional Organism Oxidation-Reduction Oxidative Stress Pathway interactions Pattern Physiology Plant Roots Plants Plastids Play Process Production Reaction Reactive Oxygen Species Reducing Agents Regulation Research Respiratory Chain Role Series Software Design Soil Source Study models System Work ammonium nitrate ascorbate cell growth regulation cost environmental change human disease interest nutrition operation oxidation oxidative damage prevent programs repaired respiratory response

项目摘要

DESCRIPTION (provided by applicant): Reactive oxygen species (ROS) are an inevitable consequence of aerobic metabolism. The accumulation of ROS, and resulting oxidative stress, appear to underlie a diverse array of human pathologies, from Alzheimer's disease to diabetes. In contrast, the cells of healthy individuals effectively manage ROS through the synthesis of antioxidant compounds, the rapid repair of oxidative damage, and the efficient balancing of cellular reductant pools. The latter of these strategies, redox balancing, is poorly understood, primarily due to the lack of physiologically relevant animal models to study this dynamic process. Our recent work has shown that simple, biologically realistic manipulations of inorganic nitrogen nutrition in Arabidopsis thaliana can rapidly and predictably alter cellular redox status, leading to adaptive changes in the expression and activity of several redox balancing enzymes in the mitochondrial respiratory chain. These results demonstrate that A. thaliana can serve as a unique model for studies of redox balancing and its role in ROS management. Thus, the primary objective of this project is to characterize the global response of A. thaliana cells to nitrogen source-induced changes in cellular redox status. Toward this end, we will utilize genome microarrays to directly examine how the transcriptome of root cells is affected by alterations in cellular redox status (Specific Aim 2). Microarray data will be analyzed using software designed to identify and statistically quantify the coordinated regulation of biochemical pathways, and we are particularly interested in examining the pathways involved in the production, intracellular partitioning, and oxidation of reductant (i.e. potential redox balancing pathways). In addition to studying redox balancing at the level of gene expression, we will also directly examine how nitrogen source affects cellular ROS levels (H2O2), lipid per oxidation, and the size and oxidation state of antioxidant pools (glutathione and ascorbate) (Specific Aim 1). Overall, these studies will allow us to link a physiologically realistic change in cellular redox state to quantitative assessments of oxidative stress and a defined transcriptional response. Ultimately, this work will inform the development of a global, experimentally-supported model of cellular redox balancing, a process which is central to the maintenance of human health. A variety of diseases, from Alzheimer's to diabetes, are related to the oxidative stress that arises from disruptions in the cell's delicate "electron economy". The proposed project will elucidate how healthy cells dynamically adjust their physiology to prevent oxidative stress under changing environmental conditions, using the plant Arabidopsis thaliana as an experimental model.

描述（由申请人提供）：活性氧（ROS）是有氧代谢的不可避免的结果。活性氧的积累以及由此产生的氧化应激似乎是从阿尔茨海默病到糖尿病等多种人类病理的基础。相比之下，健康个体的细胞通过抗氧化化合物的合成、氧化损伤的快速修复以及细胞还原剂池的有效平衡来有效管理ROS。后者，即氧化还原平衡，人们知之甚少，主要是由于缺乏生理相关的动物模型来研究这一动态过程。我们最近的工作表明，对拟南芥无机氮营养进行简单、符合生物学的操作可以快速且可预测地改变细胞氧化还原状态，从而导致线粒体呼吸链中几种氧化还原平衡酶的表达和活性发生适应性变化。这些结果表明拟南芥可以作为研究氧化还原平衡及其在 ROS 管理中的作用的独特模型。因此，该项目的主要目标是表征拟南芥细胞对氮源诱导的细胞氧化还原状态变化的整体反应。为此，我们将利用基因组微阵列直接检查根细胞的转录组如何受到细胞氧化还原状态变化的影响（具体目标 2）。将使用旨在识别和统计量化生化途径的协调调节的软件来分析微阵列数据，我们特别感兴趣的是检查还原剂的产生、细胞内分配和氧化所涉及的途径（即潜在的氧化还原平衡途径）。除了研究基因表达水平的氧化还原平衡外，我们还将直接研究氮源如何影响细胞ROS水平（H2O2）、脂质过氧化以及抗氧化剂池（谷胱甘肽和抗坏血酸）的大小和氧化态（具体目标1).总的来说，这些研究将使我们能够将细胞氧化还原状态的生理学实际变化与氧化应激的定量评估和明确的转录反应联系起来。最终，这项工作将为开发全球性的、实验支持的细胞氧化还原平衡模型提供信息，这是维持人类健康的核心过程。从阿尔茨海默病到糖尿病，多种疾病都与细胞微妙的“电子经济”破坏所产生的氧化应激有关。该项目将利用拟南芥植物作为实验模型，阐明健康细胞如何在不断变化的环境条件下动态调整其生理机能以防止氧化应激。