环境铅毒物导致儿童学习记忆下降等认知功能障碍，小胶质细胞的炎性激活在其中起着重要作用。NLRP3炎症小体活化是小胶质细胞激活的关键环节，细胞内钙稳态改变和线粒体功能紊乱可引起NLRP3炎症小体活化，但其在铅诱导的神经毒性中的作用和分子调控机制尚不清楚。前期预实验发现，铅可激活小鼠脑部海马区的小胶质细胞，并使TNF-α、IL-1β因子和NLRP3蛋白表达升高。本研究拟利用动物模型和细胞模型，采用免疫荧光、电生理和慢病毒转染等技术，对NLRP3、caspase-1等NLRP3炎症小体相关蛋白的丰度进行检测和调节，探讨小胶质细胞激活及其释放的炎性因子在铅暴露造成学习记忆损伤和神经行为改变中的作用；揭示NLRP3炎症小体活化是铅诱导小胶质细胞炎性激活的关键环节；阐明铅暴露诱导的钙稳态改变和线粒体功能紊乱与NLRP3炎症小体活化之间的关系，为后期调控小胶质细胞功能应用于铅神经毒性的防治奠定坚实基础。

Lead exposure induces impaired learning, memory and other cognitive behavior in children, in which the activation of microglial cells plays a vital role. The activation of NLRP3 inflammasome signaling pathway has recently been recognized as a key step in activating microglia and generating pro-inflammatory factors. Both mitochondrial dysfunction and disruption of calcium homeostasis are closely associated with NLRP3 inflammatory activation. However, whether and how lead induces NLRP3 inflammatory activation remains to be unraveled. In our preliminary studies, we found that lead induces microglial activation in mouse hippocampus and the expression of TNF-α, IL-1β and NLRP3 is upregulated in BV2 microglial cells after lead exposure. In this project, we propose to investigate the impact of lead exposure on NLRP3 inflammasome in microglial activation using in vivo and in vitro models. Next, we propose to investigate the role of NLRP3 inflammasome in microglial activation via modifying the expression of NLRP3 and caspase-1. We will further explore the association of mitochondrial dysfunction and disruption of calcium homeostasis induced by lead in the context of NLRP3 inflammatory activation. Our investigation will not only reveal the role of NLRP3 inflammasome in lead-induced neurotoxicity, but also shed light on the prevention and protection of lead-induced neurotoxicity.