挥之不去的环境铅污染所致神经毒性从备受全球关注的发育毒性效应跨越到严重威胁健康的神经退行性病变，其机制不明确，期待防治新靶点的广泛深入探究。突触可塑及其调节机制的研究为深入探讨铅神经毒性机制提供了神经生物学基础。基于前期研究基础，结合突触可塑信号通道最新研究，提出突触可塑信号通路中RyRs作为细胞内Ca2+信号枢纽介导突触可塑性可能是铅神经毒性作用的关键环节。拟采用激光共聚焦技术、多导离子通道检测技术、放射性配体结合技术、细胞定量分析技术以及siRNA、DNA重组等分子生物学技术，从实验和人群研究两方面，在整体、细胞和分子水平，从反向和正向以及Pb2+与RyRs作用方式上探讨RyRs调控细胞内钙信号介导突触可塑性在铅所致认知障碍中的作用及铅暴露人群外周血淋巴细胞RyRs等与铅所致认知障碍的关联。深入揭示铅神经毒性的分子机制，为发现新的防治靶标提供新线索和寻找铅所致危害的新兴标志提供新思路。

Neurotoxicity caused by ubiquitous and lingering lead has been showed to have a broad spectrum of toxic effects from developmental neurotoxicity of globally focused concern across to neurodegenerative diseases with a serious threat to the health. Extensive and intensive studies have been being urgently eager to elucidate its mechanism and discover a new target for its preventive and treatment. Synaptic plasticity and its regulation mechanisms provide the neurobiological basis for exploring the lead neurotoxicity mechanism intensively. On the basis of our feasibility investigations and the latest researches with signal pathway in synaptic plasticity. The hypothesis is proposed that RyRs as the hub of intracellular Ca2+ signals mediated synaptic plasticity may play a key role in the lead- induced cognitive impairment. In this project, applying Confocal Laser Scanning Microscope, Patch Clamp Amplifier System, Radioligand receptor binding assay and morphologic quantitative analysis, as well as cellular and molecular techniques of siRNA, DNA recombination and so on, we will try to elucidate the fundamental role of RYRs-regulated calcium signal mediated synaptic plasticity in lead- induced cognitive impairment from reverse and forward as well as the model of action between Pb2+ and RyRs in integral, cellular and molecular level from experimental and population-based studies, and the correlation between RyRs in peripheral blood lymphocytes of Pb2+ exposure human and lead- induced cognitive impairment. Our study will give additional information to reveal the lead neurotoxicity mechanism, provide new clues to discover the new target for lead intoxication prevention and treatment and offer new ideas to seek the emerging biomarker for lead hazards.