METTL14介导的lncRNA HOTAIR调控PP1甲基化参与羟考酮成瘾的机制研究

羟考酮（Oxycodone）作为阿片类镇痛药，长期使用易导致药物成瘾。近来，成瘾记忆被认为是引起药物滥用的主要因素之一，长链非编码RNA（lncRNA）在该过程中发挥重要作用。课题组前期研究发现，羟考酮上调海马内RNA甲基化转移酶（METTL14）与组蛋白甲基化（H3K4me2）水平；敲除lncRNA HOTAIR可阻断羟考酮诱导的记忆抑制分子（PP1）表达降低。结果提示，HOTAIR所参与的表观遗传学调控可能在羟考酮成瘾中扮演重要角色。本项目在前期工作基础上，拟综合运用CRISPR/Cas9基因编辑技术、ChIP、RNA免疫共沉淀和动物模型等多种手段，研究HOTAIR与羟考酮成瘾的相关性；阐明RNA甲基化修饰调控HOTAIR的作用机理；揭示HOTAIR调控PP1启动子区域组蛋白甲基化的分子机制。本项目可为羟考酮成瘾的早期诊断、风险评估和新药研发提供科学的理论依据。

Oxycodone, as an opioid analgesic, can lead to drug addiction after long-term use. Recently, addictive memory is considered to be one of the main factors causing drug abuse, and long non-coding RNA (lncRNA) plays an important role in this process. In our previous study, we found that oxycodone upregulated the levels of RNA methyltransferase (METTL14) and histone methylation (H3K4me2) in the hippocampus; knockout of lncRNA HOTAIR blocked oxycodone-induced decrease in memory suppressor molecule (PP1). The results suggested that the epigenetic regulation of HOTAIR may play an important role in oxycodone addiction. On the basis of previous work, this project plans to comprehensively use CRISPR/Cas9-based genome editing technology, chromatin immunoprecipitation, RNA immunoprecipitation and animal models to study the correlation between HOTAIR and oxycodone addiction; to clarify the mechanism of RNA methylation in the regulation of HOTAIR; to reveal the molecular mechanism of HOTAIR in regulating histone methylation at the PP1 promoter region. Hopefully, this project may provide a scientific theoretical basis for early diagnosis, risk assessment and new drugs of oxycodone addiction.