纳米颗粒对中枢神经元的潜在毒性及分子机制研究

项目名称： 纳米颗粒对中枢神经元的潜在毒性及分子机制研究

项目编号： No.30870680

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 金属学与金属工艺

项目作者： 孙皎

作者单位： 上海交通大学

项目金额： 32万元

中文摘要： 由于脑组织有可能是纳米颗粒作用的潜在靶器官，因此纳米颗粒的神经毒性效应已成为研究热点。本课题针对三种常用的无机纳米颗粒（TiO2-NPs、SiO2-NPs和Fe3O4-NPs）进行研究，发现它们在脑组织中有分布、聚集、滞留及导致海马、纹状体的氧化应激损伤的情况发生。另外课题分别探讨了直接接触和间接接触途径对神经元的致损伤机制，发现纳米颗粒通过直接损伤DNA，影响多巴胺能神经元的细胞周期，导致P53/p21/Gadd45 信号通路的激活，最终导致神经元凋亡；通过激活小胶质细胞，活化以NF-κ#20026;主的炎症信号途径，释放NO、趋化因子、细胞因子，从而间接导致神经元死亡及其分子机制。同时，结合整体和细胞水平上的研究，从不同层面上，分析了纳米颗粒对神经元损伤作用和相关性，发现了颗粒诱发帕金森病的潜能，填补了国内外在研究纳米颗粒诱导中枢神经元毒性的作用途径及其机制方面的空白，为纳米材料的研发和应用提供理论依据，为保障人类健康创造前提。

中文关键词： 纳米颗粒；中枢神经元；小胶质细胞；细胞毒性；神经退行性病变

英文摘要： To date, little is known concerning the accumulation, retention and potential adverse effects on the brain associated with the exposure to nanoparticles. This project investigated the effects of three nanoparticles (TiO2-NPs, SiO2-NPs and Fe3O4-NPs) on the brain, illustrating their biodistribution/accumulation/retention patterns and oxidative injuries induced in the striatum and hippocampus.Attempts were also made to elucidate the damage response to dopaminergic neurons through direct and in direct pathways: a. All the three nanoparticles could lead to DNA damage directly, affect cell cycle, activate the p53/p21/Gadd45 and finally causing apoptosis in PC12 cells;b.All the nanoparticles could stimulate microglial cells, activate inflammatory cell signal pathway mainly about NF-κ lead to NO/chemalkines/cytokines releasing, and finally causing death of PC12 cells. Meanwhile, we combined study at whole body level with that at cellular level to illuminate damage effects between different levels, and interpreted the potential inducibility that nano-particles might have in parkinson ' s disease. This project filled the gaps at home and abroad in the field of research on the action pathway and the mechanism of nano-particles' cytotoxicity to central neuron, layed theoretical basis for research, development and application of nano-materials, furthermore, it provided the prerequisite for ensuring human health.

英文关键词： nano-particle; central neuron; microglia; cytotoxicity; neurodegenerative disease