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

• 批准号: 7909809
• 负责人: Matthew Escobar
• 金额: $ 6.72万
• 依托单位: CALIFORNIA STATE UNIVERSITY SAN MARCOS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-31 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7909809
• 关键词: Affect; Alzheimer' 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; Operative Surgical Procedures; 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; oxidation; oxidative damage; prevent; programs; repaired; respiratory; response

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）是有氧代谢的必然结果。从阿尔茨海默氏病到糖尿病，ROS的积累和由此产生的氧化应激似乎是各种各样的人类病理。相反，健康个体的细胞通过合成抗氧化剂化合物，氧化损伤的快速修复以及细胞还原池的有效平衡有效地管理ROS。这些策略的后者是氧化还原平衡，主要是由于缺乏研究这种动态过程的生理相关动物模型。我们最近的工作表明，对拟南芥中无机氮营养的简单，生物学上现实的操纵可以迅速而可以预见，可以改变细胞氧化还原的状态，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的适应性变化。这些结果表明，thaliana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，该项目的主要目的是表征A. thaliana细胞对氮源诱导的细胞氧化还原状态变化的全局响应。为此，我们将利用基因组微阵列直接研究根细胞的转录组如何受细胞氧化还原状态改变的影响（特定的目标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对微阵列数据进行分析，并且我们特别有兴趣检查生产，细胞内分配和还原剂的氧化涉及的途径（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），每氧化脂质，以及抗氧化剂池的大小和氧化态（谷胱甘肽和抗坏血酸）（特定目标1）。总体而言，这些研究将使我们能够将细胞氧化还原状态的生理现实变化与氧化应激的定量评估和确定的转录反应联系起来。最终，这项工作将为蜂窝氧化还原平衡的全球，实验支持的模型提供信息，这对于维持人类健康至关重要。 从阿尔茨海默氏症到糖尿病的各种疾病都与细胞精致的“电子经济”中断产生的氧化应激有关。拟议的项目将使用植物拟南芥作为实验模型来阐明健康细胞如何动态调节其生理，以防止环境条件下的氧化应激。