RIP3介导程序性坏死在甲基苯丙胺神经毒性中的作用及分子机制研究

甲基苯丙胺（methamphetamine，METH）是代表性的新型毒品，滥用广泛。METH神经毒性诱导的细胞损伤是引起精神神经症状的重要病理基础，但具体机制不明。前期研究发现，METH急性染毒引起的神经元损伤可被程序性坏死阻断剂Nec-1抑制，进一步研究表明程序性坏死关键分子RIP3表达及磷酸化水平增高，且RSK分子与RIP3存在结合；提示RIP3介导程序性坏死参与METH神经毒性，而RSK磷酸化调控RIP3途径可能与神经元程序性坏死密切相关。因此，本项目拟在前期工作基础上，基于实验动物及体外细胞模型，采用基因干扰技术、生物传感技术、经典分子生物学方法等手段，阐释RIP3介导程序性坏死在METH急性神经毒性中的作用特点，并围绕核心元件RIP3解析上游分子RSK调控RIP3的精细机制。通过本研究，可为法医病理、毒理学相关研究及诊断提供理论基础，为解毒、戒毒相关干预靶点选择提供参考。

Methamphetamine (METH) is one of the widely abused illicit drugs with serious negative effects. However, the molecular mechanism of nervous system damage remains unclear. It showed that early neuronal necrosis was found by an acute single dose METH administration and part of necrosis can be inhibited by Nec-1 (programmed necrosis blocker). Increased RIP3 protein expression was found and RSK combined with RIP3 by immune coprecipitation test in further study. Accordingly, the project plans to confirm whether RIP3 mediated programmed necrosis as a key molecular, identifying if RSK specially targets RIP3 phosphorylation, and explore the molecular mechanism of RSK/RIP3 pathway in METH-induced acute toxicity of neurons. Gene interference technology, morphology and cellular biology method would be applied in our project. What’s more, biosensor technology would be used to detect the level of dopamine and glutamic acid in our research. Though the project, the programmed necrosis and its molecular mechanism in METH induced acute neuronal damage would be preliminarily interpreted and theory basis can be provided for screening molecular markers and early clinical intervention targets of METH-induced programming necrosis.