重金属低剂量复合污染是当今环境污染面临的重大难题，其中铅、镉、砷和汞是能在一般人群血液中检测到的典型神经毒物。但其联合暴露所致健康损害及机制尚不明确。我们前期发现当单个重金属浓度为一般人群血液负荷相关水平（低于NOAELs）时，这四种重金属联合暴露可产生协同神经毒性而引起树突棘损伤致神经行为异常，且树突棘消长泛素化通路Snk-SPAR和磷酸化通路PAK1-LIMK1-Cofilin在其中均起一定作用。研究证实这两条通路均可被钙结合蛋白CIB1调控。因此我们假设铅、镉、砷和汞模拟钙与CIB1结合进而调控树突棘消长泛素化和磷酸化双通路致神经行为异常。本项目拟从动物、细胞及分子水平，探究重金属离子与CIB1的结合作用，挖掘CIB1在低剂量重金属联合暴露致神经行为异常中的作用，并阐明CIB1调控树突棘消长泛素化/磷酸化双通路在其中的分子机制。研究将为防治重金属污染所致神经系统疾病提供新的干预靶点。

Low level heavy metal mixture pollution has become a severe issue of environmental pollution, among which lead (Pb), cadmium (Cd), arsenic (As) and mercury (Hg) are typical neurotoxins that can be detected simultaneously in the blood of the general population. However, the combined impacts of these heavy metals on human health as well as the mechanism are still unclear. Our previous studies had found that Pb, Cd, As and Hg combined exposure evoked synergistic neurotoxicity when their individual metals were below no observed adverse effect levels (NOAELs) and at the related levels of these metals in the blood of population, and induced dendritic spines injuries and finally caused neural behavior abnormalities, and both dendritic spine related ubiquitination pathway Snk-SPAR and phosphorylation pathway PAK1-LIMK1-Cofilin played some part in that process. Studies have confirmed that both of these two pathways can be regulated by calcium binding protein CIB1. Therefore, we hypothesized that Pb2+, Cd2+, As3+ and Hg2+ mimics Ca2+ binding to CIB1 to regulate the ubiquitination and phosphorylation binary pathways of dendritic spines, leading to neural behavior abnormalities. In our study, we explore the binding effect of these four heavy metal ions with CIB1, then excavate the influence of CIB1 expression changes on neural behavior abnormalities caused by combined exposure of low-level heavy metals, and further to elucidate the molecular mechanisms of CIB1 regulated dendritic spines related ubiquitination and phosphorylation binary pathways in low level heavy metal combined exposure induced abnormal neural behavior. This study will provide new intervention strategies for the prevention and treatment of nervous system diseases caused by heavy metal pollution.