Systems biology of the oxidative stress response

项目摘要 这个项目解决了细胞如何调节其基因表达的基本问题 计划，以应对氧化应激（OS），以确保生存。OS，施加于细胞 无论是作为有氧代谢的内在代价，还是外部条件， 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 转录程序主要面向恢复，但如果损伤 是无法弥补的然而，这个程序在mRNA水平上得到了比较好的表征， 丰富，几乎没有什么是已知的协调与转录后层的 基因表达调控这个应用程序探讨了一个总体假设，即基因 响应操作系统的表达是由一个集成的多层程序形成的， 协调转录和转录后机制以最大化存活。目的是 定量地描述这些机制，并通过实验验证它们， 获取全球基因表达数据集，并通过数学形式化的连接， 届具体而言，一种新的模型的综合控制解决的灵感来自 初步研究强调了从变化预测蛋白质变化的局限性， 在mRNA水平。数学模拟表明，控制在以下水平上起着关键作用： 应激过程中mRNA和蛋白质的稳定性导致以下命题： 应激诱导蛋白的合成与氧化损伤的增加相一致， 增加蛋白水解清除率作为质量控制机制。B）OS触发的快速 翻译关闭导致OS抑制的mRNA下调，但不是蛋白质。 以释放核糖体的能力，用于OS诱导的mRNA的有效翻译。内 在拟议项目的范围内，这些预测将通过获得独特的 系统范围内的数据集，这些数据集将输入到数学建模的迭代过程中， 实验验证，以达到一个全面的框架，压力调节基因 表情这些研究还解决了基因OS模型的普遍适用性 表达，以响应其他形式的环境应激和哺乳动物细胞。

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.