甲基苯丙胺诱导神经血管单元损伤的内质网应激机制研究

项目名称： 甲基苯丙胺诱导神经血管单元损伤的内质网应激机制研究

项目编号： No.81471822

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 马春玲

作者单位： 河北医科大学

项目金额： 73万元

中文摘要： 甲基苯丙胺（MA）是目前广泛滥用、危害严重的一种新型毒品，可导致大脑出现与阿尔茨海默病和帕金森病等神经退行性病变相类似的改变。神经血管单元（NVU）是中枢发挥正常功能的结构基础，并作为一个功能模块，日益成为中枢损伤性疾病研究的重要靶点，而 MA 对 NVU 内在功能及其相互作用关系的影响未见相关报道。本研究将从 NVU 的三维角度对 MA 的中枢毒性及其机制进行系统研究，明确 MA 在神经损伤进程中 NVU 功能的动态变化及其相互作用关系；并探讨内质网应激（ERS）是否可作为 MA 引起 NVU 发生级联损伤反应的共同机制，阐明 ERS 通过 IRE1/ASK1/JNK及TRAF2/IRE1/IKK/NF-kB 通路介导MA 致 NVU 发生炎症反应、细胞凋亡等过程的相关分子机制，期待为 MA 滥用后相关疾病的治疗提供新的药物干预靶点和脑保护措施。

中文关键词： 法医毒理学；甲基苯丙胺；脑损伤；神经血管单元；内质网应激

英文摘要： Methamphetamine (MA) is a widely abused new-type drug with serious hazard. It could induce the similar pathologic change as neurodegeneration in alzheimer's disease and Parkinson's disease. Nerve Vascular Unit (NVU) is the structure foundation of normal central function, and as a function module, it has become an important therapeutic target of brain damage disease. However, no report focuses on the effect of MA on interaction and internal function of NVU. The present study aims to investigate the toxic effects of MA on central nervous system and its mechanisms from the three-dimensional perspective, as well as to observe the dynamic change of NVU functions and the interaction of each part in NVU. Furthermore, we will explore whether the endoplasmic reticulum stress (ERS) could be used as a common mechanism of MA induced cascade injury of NVU. The molecular mechanism of MA-induced inflammation and apoptosis of NVU, and the effect of MA on IRE1/ASK1/JNK and TRAF2/ IRE1/IKK/NF-kB signal pathway will also be cleared. We're looking forward to find a new therapeutic target and protective medication in the treatment of MA abuse.

英文关键词： Forensic toxicology;Methamphetamine;Brain damage;Nerve Vascular Unit;Endoplasmic Reticulum Stress