Translational regulation of gene expression during oxidative stress conditions

氧化应激条件下基因表达的翻译调控

• 批准号: 2110626
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2110626
• 关键词: Translational; regulation; gene; expression; during

Our research efforts are aimed at understanding the responses of eukaryotic cells to oxidative stress using the yeast Saccharomyces cerevisiae as a model organism. All aerobic organisms are exposed to reactive oxygen species (ROS) during the course of normal aerobic metabolism or following exposure to radical-generating compounds. ROS can cause wide-ranging damage to cells and an oxidative stress is said to occur when the cellular survival mechanisms are unable to cope with the ROS or the damage caused by them. Oxidative damage is associated with various disease processes including cancer, ageing and neurodegenerative disorders and it is also of particular concern to industry including biotech, brewing and baking. This means that understanding the causes and the molecular responses to oxidative stress is of broad fundamental importance. This specific focus of this project is the role of translation in regulating gene expression in response and adaptation to oxidative stress conditions. The yeast Saccharomyces cerevisiae has a wide variety of industrial applications many of which are impacted upon by its capacity to synthesis proteins under conditions of stress. Thus identifying and characterizing regulatory mechanisms that control protein production during stress conditions will benefit industrial researchers, interested in maximising protein production from biological systems for biotechnological and biopharmaceutical applications.Although the regulation of the transcription of selected genes has been extensively studied, there is growing appreciation that the selection of the mRNA to be translated is also tightly regulated. Translation initiation is a crucial step for this selection and misregulation of this process has been linked with a plethora of diseases. Cells typically respond to an oxidative stress by inhibiting translation initiation. This reduction in protein synthesis prevents continued gene expression during potentially error-prone conditions as well as allowing for the turnover of existing mRNAs and proteins whilst gene expression is reprogrammed to deal with the stress. Although oxidative stress is widely inhibitory to protein synthesis, translational induction of specific mRNAs is critically important for adaptation to it. This project will use cutting edge technology to examine how oxidative stress regulates translation focussing on identifying and characterizing examples of mRNA-specific regulation which are required for oxidative stress tolerance. Using the yeast model, we have preliminary evidence supporting a regulatory role for the evolutionarily conserved eIF4G translation initiation factor in regulating the translational response to oxidative stress. This project aims to understand the role of eIF4G during oxidative stress which is important since its dysregulation has been implicated in many disease processes and ageing.

我们的研究工作旨在了解真核细胞对氧化应激的反应，以酿酒酵母为模式生物。所有需氧生物在正常的有氧代谢过程中或在暴露于产生自由基的化合物后，都会暴露在活性氧物种(ROS)中。ROS可以对细胞造成广泛的损害，当细胞的生存机制无法应对ROS或由其造成的损害时，就会发生氧化应激。氧化损伤与包括癌症、衰老和神经退行性疾病在内的各种疾病过程有关，它也是生物技术、酿造和烘焙等行业特别关注的问题。这意味着了解氧化应激的原因和分子反应具有广泛的基础重要性。这个项目的重点是翻译在调节基因表达方面的作用，以响应和适应氧化应激条件。酿酒酵母具有广泛的工业应用，其中许多应用受到其在胁迫条件下合成蛋白质的能力的影响。因此，识别和表征在胁迫条件下控制蛋白质产生的调控机制将有利于工业研究人员，他们有兴趣最大限度地提高生物技术和生物制药应用中生物系统的蛋白质产量。尽管对选定基因的转录调控已经进行了广泛的研究，但人们越来越认识到，要翻译的mRNA的选择也受到严格的调控。翻译启动是这一选择的关键步骤，而对这一过程的错误调控与一系列疾病有关。细胞通常通过抑制翻译启动来对氧化应激做出反应。这种蛋白质合成的减少阻止了在潜在容易出错的条件下继续基因表达，并允许现有mRNAs和蛋白质的周转，同时基因表达被重新编程以应对压力。虽然氧化应激对蛋白质合成具有广泛的抑制作用，但特定mRNAs的翻译诱导对于适应氧化应激至关重要。这个项目将使用尖端技术来研究氧化应激如何调节翻译，重点是识别和表征氧化应激耐受所需的特定mRNA调节的例子。使用酵母模型，我们有初步的证据支持进化上保守的eIF4G翻译起始因子在调节氧化应激的翻译反应中的调节作用。该项目旨在了解eIF4G在氧化应激过程中的作用，这一点很重要，因为它的失调与许多疾病过程和衰老有关。