Investigation of the contribution of redox stress to the therapy resistance of cells experiencing cycling oxygen levels

研究氧化还原应激对经历循环氧水平的细胞的治疗抵抗力的贡献

• 批准号: 2437099
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2437099
• 关键词: Investigation; contribution; redox; stress; therapy

Hypoxia is a major barrier to successful cancer treatment as the more hypoxic a tumour, the less well patients respond. This project will focus on the physiologically relevant condition of cyclic hypoxia in which cancer cells experience fluctuations in oxygen levels as opposed to constant exposure to hypoxia. Recent findings from the Hammond lab suggest that the cellular response to cyclic hypoxia differs significantly from constant exposure and that this includes the contribution of changes in REDOX in the cyclic conditions. Understanding the dynamics of REDOX elements in biological systems is of major importance because of its roles in basic biology, agriculture, disease and medicine. However, quantifying changes in REDOX elements remains a major challenge for chemical biology. Key elements involved in defining the cellular REDOX environment include reactive oxygen species (ROS), reactive nitrogen species (RNS), sulfur-containing molecules including H2S and glutathione (GSH), hypoxia (lower than normal [O2]), and post-translational modification of amino acid residues in proteins. The relative concentration and interaction of these components defines the cellular REDOX environment, which is intrinsically linked to metabolism through processes such as glycolysis and oxidative phosphorylation. Cellular metabolism and REDOX state are in turn linked to epigenetic regulation, because modifications to chromatin involve consumption of important metabolites and REDOX-active molecules. Consequently, both metabolism and the REDOX environment can affect transcription through chromatin remodelling, and therefore cell fate decisions are closely linked to changes in metabolic activity and the REDOX environment. This project will investigate REDOX stress in cyclic hypoxia and how this contributes to biological response and sensitivity to cancer therapies. Specific approaches will include, for example, gene expression analysis (RNA-seq) of cells in both constant and cyclic hypoxia. This project will also benefit from early access to probes being generated in the Conway lab which will allow characterisation of REDOX stress.

缺氧是癌症治疗成功的主要障碍，因为肿瘤越缺氧，患者的反应就越差。该项目将重点关注周期性缺氧的生理相关条件，在这种情况下，癌细胞经历氧气水平的波动，而不是持续暴露于缺氧中。哈蒙德实验室最近的研究结果表明，细胞对循环缺氧的反应与持续暴露有很大不同，这包括循环条件下氧化还原的变化。了解生物系统中氧化还原元素的动力学是非常重要的，因为它在基础生物学，农业，疾病和医学中的作用。然而，量化氧化还原元素的变化仍然是化学生物学的主要挑战。定义细胞氧化还原环境的关键因素包括活性氧（ROS）、活性氮（RNS）、含硫分子（包括H2S和谷胱甘肽（GSH））、缺氧（低于正常[O2]）和蛋白质中氨基酸残基的翻译后修饰。这些成分的相对浓度和相互作用决定了细胞氧化还原环境，这与糖酵解和氧化磷酸化等代谢过程有着内在的联系。细胞代谢和氧化还原状态反过来与表观遗传调控有关，因为染色质的修饰涉及重要代谢物和氧化还原活性分子的消耗。因此，代谢和氧化还原环境都可以通过染色质重塑影响转录，因此细胞命运的决定与代谢活性和氧化还原环境的变化密切相关。本项目将研究循环缺氧中的氧化还原应激及其对癌症治疗的生物学反应和敏感性。具体的方法将包括，例如，基因表达分析（RNA-seq）细胞在恒定和周期性缺氧。该项目还将受益于康威实验室生成的探针的早期访问，这将允许表征氧化还原应力。