Systems biology of the oxidative stress response

氧化应激反应的系统生物学

• 批准号: 8632655
• 负责人: DIETER A WOLF
• 金额: $ 37.05万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632655
• 关键词: Address; Amyotrophic Lateral Sclerosis; Benchmarking; Biological Models; Blood Vessels; Cell Death; Cell Respiration; Cells; Chronic Disease; Complications of Diabetes Mellitus; Data; Data Set; Defense Mechanisms; Diabetes Mellitus; Disease; Down-Regulation; Drug Targeting; Ensure; Equilibrium; Eukaryota; Fission Yeast; Gene Expression; Homeostasis; Human; Hydrogen Peroxide; Hydroxyl Radical; Inflammatory; Kinetics; Lead; Link; Malignant Neoplasms; Mammalian Cell; Messenger RNA; Modeling; Motor Neurons; Mutation; Neurodegenerative Disorders; Nitrogen; Oxidative Stress; Oxygen; Patients; Phagocytosis; Plant Roots; Process; Production; Proteins; Quality Control; Recovery; Relative (related person); Ribosomes; Role; Shapes; Signal Transduction; Simulate; Stress; Stress-Induced Protein; System; Systems Biology; Testing; Time; Translations; Up-Regulation; Validation; age related; biological adaptation to stress; cost; dopaminergic neuron; endoplasmic reticulum stress; feeding; fitness; mRNA Stability; mRNA Transcript Degradation; macromolecule; macrophage; mathematical model; microorganism; novel; oxidative damage; programs; public health relevance; response; simulation

Project Summary This project addresses the fundamental question of how cells adjust their gene expression program in response to oxidative stress (OS) in order to ensure survival. OS, inflicted upon cells either as an intrinsic cost of aerobic metabolism or by extraneous conditions, is intimately linked to a variety of ageing-related diseases, including neurodegenerative disorders, inflammatory conditions, cancer, and the vascular complications of diabetes. OS is known to trigger a transcriptional program primarily geared toward recovery, but triggering cell death if the damage is irreparable. Whereas this program is relatively well characterized at the level of mRNA abundance, almost nothing is known about the coordination with posttranscriptional layers of gene expression control. This application explores the overarching hypothesis that gene expression in response to OS is shaped by an integrated multi-layered program that precisely coordinates transcriptional and posttranscriptional mechanisms to maximize survival. The aim is to describe these mechanisms quantitatively and validating them experimentally both by acquiring global gene expression datasets and by formalizing the connections in mathematical terms. Specifically, a novel model of integrated control is addressed that was inspired by preliminary studies which highlighted the limitations of predicting protein changes from changes in mRNA levels. Mathematical simulations suggested critical roles for control at the levels of mRNA and protein stability during stress that lead to the following propositions: a) Increased synthesis of stress-induced proteins coincides with increased oxidative damage and hence increased proteolytic clearance as a quality control mechanism. b) OS-triggered rapid translational shutdown leads to downregulation of OS-suppressed mRNAs but not proteins in order to liberate ribosome capacity for the efficient translation of OS-induced mRNAs. Within the realm of the proposed project, these predictions will be put to scrutiny by acquiring unique system-wide datasets that will feed into an iterative process of mathematical modeling and experimental validation to arrive at a comprehensive framework of stress-regulated gene expression. The studies also address the general applicability of the OS models for gene expression in response to other forms of environmental stress and to mammalian cells.

项目摘要 该项目解决了细胞如何调节其基因表达的根本问题。 程序，以应对氧化应激(OS)，以确保生存。OS，对细胞造成的影响 无论是有氧代谢的内在成本，还是外部条件的影响，都是密切相关的 各种与衰老有关的疾病，包括神经退行性疾病、炎症性疾病 疾病、癌症和糖尿病的血管并发症。已知操作系统会触发 转录程序主要是为了恢复，但如果损伤引发细胞死亡 是无法挽回的。鉴于该程序在信使核糖核酸水平上具有较好的特征 丰富，几乎什么都不知道与转录后层次的协调 基因表达调控。这个应用程序探索了最重要的假设 响应操作系统的表达是由集成的多层程序塑造的，该程序准确地 协调转录和转录后机制以最大限度地提高存活率。我们的目标是 为了定量地描述这些机制并通过实验验证它们， 获取全局基因表达数据集，并通过将数学中的联系形式化 条款。具体地说，提出了一种新的集成控制模型，该模型的灵感来自 强调从变化中预测蛋白质变化的局限性的初步研究 在信使核糖核酸水平。数学模拟表明，在以下级别的控制中具有关键作用 应激期间的mRNA和蛋白质稳定性导致以下命题：a)增加 应激诱导蛋白质的合成与氧化损伤的增加相一致，因此 作为一种质量控制机制，增加了蛋白质降解清除量。B)操作系统触发的快速 翻译关闭导致OS抑制的mRNAs下调，但不下调蛋白质 以释放核糖体能力，以便高效翻译OS诱导的mRNAs。在 在提议的项目领域，这些预测将通过获取Unique 系统范围的数据集，将提供给迭代的数学建模过程和 获得应激调节基因综合框架的实验验证 表情。这些研究还讨论了操作系统模型对基因的普遍适用性 在其他形式的环境压力和哺乳动物细胞中的表达。