The role of DNA methylation in the detrimental effects of early life adversity on the use of opioid analgesics

儿童时期暴露在有毒压力下会对健康造成有害影响，包括疼痛和对阿片类镇痛剂的上瘾。这个PHD项目将测试这一假说，即暴露在早期生活应激(ELS)下会影响DNA甲基化，导致基因表达改变，从而容易受到阿片类镇痛剂的有害影响。该项目的目的将是确定暴露于ELS的人易受阿片成瘾影响的机制和生物标记。这将通过探索发育过程中的毒性应激对人类诱导的多能干细胞来源的神经元和小鼠的影响来实现。这两个模型将被用来建立1)人类神经生理学和2)小鼠对阿片类药物的行为反应以及相关的差异DNA甲基化的变化。在这两个模型中，都将使用基因编辑来建立应激与阿片类药物有害影响之间的联系。

Exposure to toxic stress during childhood has detrimental effects on health, including pain and addiction to opioid analgesics. This PhD project will test the hypothesis that exposure to early life stress (ELS) affects DNA methylation resulting in altered gene expression leading to vulnerability to the detrimental effects of opioid analgesics. The aim of the project will be to identify mechanisms and biological markers that account for vulnerabilities to opioid addiction in those exposed to ELS. This will be achieved by exploring the effects, of toxic stress during development on human induced pluripotent stem cell derived neurones and mice. These two models will be used to establish changes in 1) human neurophysiology and 2) mouse behavioural responses to opioids as well as associated differential DNA methylation. Mechanisms linking stress to detrimental effects of opioids will be established using gene editing in both models.