circSTAG1通过m6A RNA甲基化参与甲基苯丙胺急性中毒致脑星形胶质细胞活化的机制研究

以甲基苯丙胺（METH）为代表的毒品滥用引起的急性中毒是全球关注的公共卫生问题和危害严重的急危重症。在我国，METH已取代海洛因成为滥用人数最多的毒品。目前多数研究集中于其成瘾性，对于METH引起神经炎性反应介导急性脑损伤的机制探讨尚处于起步阶段。circSTAG1（简称CI）是前期通过高通量测序技术筛选获得的一条差异低表达于METH成瘾者血浆中、功能未知的环状RNA。验证显示CI低表达与成瘾者急性脑损伤发生相关、且在急性中毒小鼠模型的星形胶质细胞的分布显著降低。进一步研究发现circSTAG1可以靶向结合m6A去甲基化酶ALKBH5。故提出CI通过调控m6A修饰参与了METH急性中毒后脑星形胶质细胞活化过程的科学假说。本项目拟临床评价、模式动物、细胞生物学、分子生物学和示踪分析等手段，阐明CI参与METH致急性脑损伤的作用机制，为该类疾病有效治疗手段的研发提供新的理论依据和治疗靶标。

Acute poisoning caused by drug abuse represented by methamphetamine (METH) is a public health issue and a critical illness that is of global concern. In China, METH has replaced heroin as the most abused drug. Most of the current research focuses on its addiction, while the mechanism of METH-induced neuroinflammatory response-mediated acute brain injury remains need further elaboration. circSTAG1 is a circular RNA with unknown functions, which was obtained by high-throughput sequencing technology previously, and is low expressed in the plasma of METH addicts. Further expression level validation was performed by RT-PCR and we found that circSTAG1 is downregulated in distribution of astrocytes in a mouse model of METH acute poisoning, and low circSTAG1 expression is associated with the occurrence of acute brain injury in addicts. Further research found that circSTAG1 can target m6A demethylase ALKBH5. We therefore hypothesized that circSTAG1 could regulate m6A demethylase ALKBH5 expression to promote neuroinflammatory by acting as sponge of brain astrocytes. The current project aims to assess the mechanism between circSTAG1 expression level and METH-induced neuroinflammatory response-mediated acute brain injury through clinical evaluation, animal model, in vitro study, as well as molecular biology and tracer analysis. Our study offers and a new theoretical basis for the development and a new therapeutic target for the diagnosis and treatment of METH-induced acute brain injury.