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

我们之前的研究表明，暴露于严重缺氧水平（<0.1% O2）的细胞会经历复制压力，从而导致DNA损伤反应（DDR）。对缺氧诱导的DDR的研究揭示了针对肿瘤中缺氧细胞的潜在治疗策略。这是一个重要的目标，因为它是肿瘤的低氧部分，最耐放疗，并导致肿瘤复发和预后不良。最近，我们已经意识到DDR也受到严重缺氧诱导的额外应激反应的影响，即未折叠蛋白反应（UPR）。然而，尽管有这些知识，我们没有考虑到癌细胞所经历的氧水平波动（循环缺氧），并且倾向于在恒定的氧水平下进行实验，这并不能准确地模拟肿瘤。该项目将侧重于了解暴露于辐射的细胞中DDR和UPR的相互作用，重要的是，这是如何受到生理相关氧气条件的影响。

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.