Ca2+/PKC通路在PFOS诱导的小胶质细胞炎性活化中的意义

项目名称： Ca2+/PKC通路在PFOS诱导的小胶质细胞炎性活化中的意义

项目编号： No.21507063

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 化学工业

项目作者： 聂晓科

作者单位： 南通大学

项目金额： 21万元

中文摘要： 环境污染物PFOS具有明显的神经毒性，但其作用机制尚未明确。课题组前期的研究发现，低剂量PFOS可激活脑内的小胶质细胞，上调其胞浆内Ca2+的水平，同时发现依赖于Ca2+的PKC的活性也明显上调，基于此课题组提出PFOS的神经毒性是通过激活小胶质细胞，提高胞浆Ca2+水平，继而引发下游区PKC的活化并通过依赖于PKC的信号转导而产生神经毒性的假设。本研究拟以PFOS处理大鼠，观察其对小胶质细胞激活、胞浆内Ca2+水平及PKC活性的影响；分析PFOS上调胞浆Ca2+与PKC活性以及调节PKC信号转导的机制；通过用PFOS处理小胶质细胞后的培养基处理原代神经元24小时，分析小胶质细胞分泌的炎症因子对神经元的毒性作用。最后，通过抑制Ca2+内流和PKC活性，探索降低PFOS神经毒性的药物靶点。本课题的研究将为阐明PFOS的神经毒性的机制提供实验基础，对预防和治疗PFOS的神经毒性具有重要的意义。

中文关键词： 全氟辛烷磺酸；Ca2+；PKC；小胶质细胞；神经毒性

英文摘要： Environmental pollutant PFOS has obvious neurotoxicity, but the mechanism is not clear. Our previous studies have found that low dose of PFOS promotes the activation of microglia. PFOS up-regulates the intracellular concentration of free Ca2+ of microglia as well as the activation of Ca2+-independent PKC, through which PFOS might mediate the activation of microglia and subsequent neurotoxicity. Topics to be first in the rats treated with PFOS, to observe the intracellular concentration of free Ca2+ and the activation of PKC as well as the activation of microglia; then analysis the mechanism in microglia through which PFOS up-regulates the intracellular concentration of free Ca2+ and the activation, to adjust PKC-independent molecular signaling. Through treating primary neurons for 24 h with PFOS-treated microglial conditioned medium, analysis the neurotoxic effect of cytokines secreted by microglia. Finally, through inhibiting the Ca2+ influx and PKC activation, find out the target point of medicine healing the neurotoxicity of PFOS. This research will provide experimental basis for elucidating the mechanism of PFOS’s neurotoxicity, and provide a theoretical basis for the prevention and treatment of PFOS’s neurotoxicity.

英文关键词： PFOS;Ca2+;PKC;microglia;neurotoxicity