Investigating the effect of ionising radiation on cyclic hypoxia-induced replication catastrophe and genome instability in tumours

研究电离辐射对周期性缺氧诱导的肿瘤复制灾难和基因组不稳定性的影响

• 批准号: 2745245
• 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: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2745245
• 关键词: Investigating; effect; ionising; radiation; cyclic

Our previous research has demonstrated that cells exposed to severe levels of hypoxia (<0.1% O2) experience replication stress which in turn leads to a DNA damage response (DDR). The study of the hypoxia-induced DDR has illuminated potential therapeutic strategies to target hypoxic cells in tumours. This is an important goal as it is the hypoxic fraction of tumours which are most resistant to radiotherapy and lead to tumour reoccurrence and poor prognosis. Most recently, we have become aware that the DDR is also impacted by an addition al stress response induced in response to severe hypoxia, the unfolded protein response (UPR). Despite this knowledge however, we have failed to consider the fluctuation in oxygen levels experienced by cancer cells (cyclic hypoxia) and have tended to carry out experiments in constant levels of oxygen which do not accurately mimic the tumour. This project will focus on the understanding of the interaction of the DDR and UPR in cells exposed to radiation and importantly, how this is impacted by physiologically relevant oxygen conditions.

我们以前的研究已经证明，暴露于严重缺氧水平（<0.1%O2）的细胞会经历复制应激，这反过来会导致DNA损伤反应（DDR）。对缺氧诱导的DDR的研究已经阐明了靶向肿瘤中缺氧细胞的潜在治疗策略。这是一个重要的目标，因为它是肿瘤的缺氧部分，对放射治疗最有抵抗力，并导致肿瘤复发和预后不良。最近，我们已经意识到DDR也受到响应于严重缺氧而诱导的另外的应激反应，未折叠蛋白反应（UPR）的影响。然而，尽管有这些知识，我们未能考虑癌细胞所经历的氧水平的波动（循环缺氧），并且倾向于在不能准确模拟肿瘤的恒定氧水平下进行实验。该项目将侧重于了解DDR和UPR在暴露于辐射的细胞中的相互作用，以及重要的是，这是如何受到生理相关氧气条件的影响。