circRNA1463介导甲基苯丙胺致小胶质细胞自噬和凋亡的机制研究

Methamphetamine is one of the major substances were used worldwide. Despite the recognized impact of the methamphetamine abuse on the brain reward system especially monoamine transmitter, mechanisms underlying the ability of methamphetamine to enhance the neuroinflammation characterized by microglial activation remain elusive. Our pilot study indicated that administration of methamphetamine decreased the number of microglia in the hippocampus brain region. Furthermore, methamphetamine reduced the miR-9 level in the serum of abuser. On the basic of above outcome, we will focus on the non-coding circular RNA (circRNA) involved in the regulation of miRNA. We hypothesize that “circRNA1463 involved in the methamphetamine-mediated the microglial autophagy and apoptosis”. Therefore, we will investigate the mechanisms of methamphetamine induced microglial autophagy and apoptosis through circRNA1463/MiR-9/MCPIP1 pathway both in vitro to in vivo study using classic pharmacological methods along with the technology of bioinformatics and molecular biology. This proof of concept study will test the efficacy of blockage of circRNA1463/MiR-9/MCPIP1 pathway as a therapeutic strategy for ameliorating the microglial death induced by methamphetamine. This proposal is both novel and innovative in that the efficacy of circRNA1463/MiR-9/MCPIP1 blockage in abrogating microglial autophagy and apoptosis can be of value for methamphetamine-mediated neuroinflammation. Our study will understand the role of circRNA1463/MiR-9/MCPIP1 pathway in the microglial autophagy and apoptosis induced by methamphetamine providing insight for opening up novel therapeutic avenues for neuroinflammation induced by drug abuse and other neurological disorders.

传统的单胺学说难以解释甲基苯丙胺滥用引起的以小胶质细胞活化为特征的神经炎性反应。前期研究结果表明甲基苯丙胺成瘾者血清中miR-9表达水平降低，且离体和整体水平的实验也证实miR-9靶向调控MCPIP1。基于这些研究基础，申请人进一步关注对于miRNA自身调控的研究，如环状非编码RNA（circRNA）通过多种机制参与miRNA的调控。申请者提出“circRNA1463介导甲基苯丙胺致小胶质细胞的自噬和凋亡” 这一假说。拟用circRNA1463 siRNA的干预策略，探讨甲基苯丙胺致小胶质细胞自噬和凋亡的发生发展过程中，circRNA1463/miR-9/MCPIP1对小胶质细胞功能的调节，以及对缓解成瘾患者脑内的神经炎性损伤的作用。如果这一假设得到证实，将为治疗成瘾患者脑内的神经炎性损伤，减少并发症提供新的理论依据，对临床治疗策略的选择和治疗药物靶标的遴选提供新的视角。

药物成瘾已成为严重危害人类健康的疾病之一，给家庭和社会带来沉重的经济负担和巨额的财政支出。传统的单胺学说难以解释甲基苯丙胺滥用引起的神经炎性反应。因此，本项目结合神经炎性反应和表观遗传学研究，应用高通量技术分析神经炎性反应发生发展过程中非编码RNA的变化，从新的视角深入研究神经炎性反应发生发展的机制，选择关键靶标分子作为神经炎性反应及其相关重大神经系统疾病（如药物成瘾、脑卒中或抑郁症）的生物学客观标志物，为神经炎性反应及其相关重大神经系统疾病的早期诊断和治疗提供新思路和新策略。申请人紧密结合当前世界的研究热点，围绕神经炎性反应中的不同生物学事件，如胶质细胞异质性、血脑屏障完整性，阐明非编码RNA在神经炎性发生发展中的重要作用，为神经炎性反应的治疗提供新的策略，对预防和治疗神经炎性反应相关疾病具有重要意义。在该项目的资助下，目前已发表SCI论文10篇（IF：10分以上5篇），第一作者5篇，通讯作者1篇，包括Molecular Psychiatry，Microbiome，Autophagy，Journal of Neuroscience等本领域高水平期杂志。获得江苏省药理学会科学技术奖一等奖（2017）和中国药学会科学技术奖二等奖（2018）。