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

儿童时期暴露于有毒压力对健康有不利影响，包括疼痛和对阿片类镇痛剂成瘾。这个博士项目将测试暴露于早期生活压力（ELS）影响DNA甲基化的假设，从而改变基因表达，导致对阿片类镇痛药有害影响的脆弱性。该项目的目的将是确定机制和生物标志物，说明暴露于ELS的人对阿片类药物成瘾的脆弱性。这将通过探索发育过程中毒性应激对人诱导多能干细胞衍生神经元和小鼠的影响来实现。这两种模型将用于确定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差异DNA甲基化的变化。将在两种模型中使用基因编辑建立将压力与阿片类药物的有害影响联系起来的机制。

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.