冷诱导RNA结合蛋白CIRBP在铅暴露导致突触可塑性改变中的作用及机制

Lead is one of the major environmental chemical risk factors that seriously harm human health, leading to cognitive impairment and neural development retardation. Lead exposure may elevate the LTP threshold of the hippocampus neurons, decrease the amplitude and duration of the LTP and thus influence the synaptic plasticity of the hippocampus neurons. According to previous studies, the lead induced LTP dysfunction may be related to the disorders of calcium metabolism. Thus, promoting calcium internal flow and improving calcium related kinase function may be a potential method to protect hippocampus function under lead exposure. CIRBP is a kind of major environmental stress protein, which may play neuroprotective under series of environmental stresses. In previous studies, we found that decreased CIRBP expression as well as disabled hippocampus LTP in the lead exposed rats. Besides, in the CIRBP knockout rats, the expression of calcium channel protein and related kinases significantly reduced, indicating that CIRBP may play an important role in the regulation of calcium channel protein and related kinases. Herein in this study, we will explore the influence of CIRBP expression upon calcium concentration and LTP in hippocampus neurons, by establishing the lead exposed rats and cell models, reveal the potential mechanism of CIRBP regulating hippocampus neuronal calcium channel proteins and related kinases, and thus provide some new insights into the neuroprotection under lead exposure.

铅是严重危害人类健康的主要环境化学危险因素之一，会影响智力发育，导致机体认知功能障碍。其机制与海马体神经元突触可塑性损伤密切相关。既往研究证实，铅暴露对海马神经元突触可塑性的影响可能与钙离子代谢紊乱有关，因此促进钙离子内流或提升钙离子相关激酶功能是回转海马功能的有效方法。CIRBP是一类具有神经保护作用的重要环境应激蛋白。我课题组既往研究发现，铅暴露毒大鼠模型CIRBP表达降低，并伴有海马神经元突触可塑性异常。CIRBP敲除大鼠离子通道蛋白表达显著降低，提示CIRBP可能参与调控钙离子通道蛋白和钙离子相关激酶的表达，进而影响海马神经元突触可塑性。本研究通过建立铅暴露大鼠模型与细胞模型，探究CIRBP表达对海马神经元内钙离子浓度与突触可塑性功能的影响，揭示CIRBP调控海马神经元突触可塑性的潜在机制，为铅暴露诱导认知功能损伤的防治研究提供新思路。

铅是环境中广泛存在的污染物，铅暴露严重危害人类健康，尤其是影响智力发育，导致机体认知功能障碍。过往的研究认为铅暴露引起的认知功能损伤与海马神经元突触可塑性损伤密切相关，而铅诱导的细胞钙离子紊乱与突触可塑性损伤有关，但是其机制并不清楚。该项目研究证实铅暴露导致海马神经元突触结构和功能损伤。铅暴露导致CIRBP表达降低参与了突触可塑性的损伤；CIRBP敲除对突触功能的影响和铅暴露产生类似的效果，导致突触可塑性及钙震荡受损；最后，通过结构信息学分析CIRBP下游分子，发现铅暴露通过CIRBP调节的钙通道蛋白CACNB3的mRNA稳定性影响突触钙活动及神经细胞突触可塑性的形成。在该项目的资助下，发表JCR1区SCI论文一篇。获得发明专利1项，软件著作权证书3项。培养研究生2名。