JAK2/STAT3信号通路及Klotho基因在镉暴露对认知功能影响中的作用机制研究

Recent studies suggested that the effect of cadmium on the cognitive function has being a research focus but its mechanisms still not completely understood. The latest studies showed that Klotho gene was closely related to cognitive function ，which could affect cognitive function through JAK2/STAT3 signaling pathway. Thus we hypothesize that, weather the exposure to cadmium impairs cognitive function through regulation of the expression of Klotho gene and JAK2/STAT3 signaling pathway or not? In this study, firstly the local residents were divided into groups according to the level of environmental exposed to cadmium and their cognitive function and the components of JAK2/STAT3 signaling pathway were determined. Through this environment epidemiological survey in cadmium polluted area of Guangxi, the effect of chronic exposure to cadmium on the cognitive function and its relationship with Klotho gene and JAK2/STAT3 signaling pathway will be explored. Secondly, the animal experiment with cadmium exposed will be adopted to confirm the effect of exposure to cadmium on the cognitive function, explore the mechanism of JAK2/STAT3 signaling pathway in this progress. The results of this study will provide theoretical basis for prevention the toxic effect of cadmium.

近年来镉对认知功能的影响成为研究热点, 但其作用机制则少见文献报导。最新研究表明Klotho基因与认知功能密切相关， Klotho基因可通过JAK2/STAT3信号传导通路影响认知功能。由此我们提出假设，镉暴露是否可能通过影响Klotho基因的表达，进而使JAK2/STAT3信号通路受到影响，损伤认知功能？本研究首先采用环境流行病学方法，拟在广西镉污染地区对当地居民按镉暴露程度不同分组，对其进行认知功能的检测，并通过对JAK2/STAT3信号通路相关因子进行分析，初步探讨不同镉水平的环境暴露对人群认知功能的影响及与JAK2/STAT3信号通路、Klotho基因的关系。然后通过镉染毒动物实验，进一步验证JAK2/STAT3信号通路在镉暴露对认知功能影响的作用。研究结果将为更好的预防镉的毒作用危害提供理论依据。

本研究在广西镉污染地区对当地居民按镉暴露程度不同分组，对其进行认知功能的检测，并通过对JAK2/STAT3信号通路相关因子进行分析，初步探讨不同镉水平的环境暴露对人群认知功能的影响及与JAK2/STAT3信号通路、Klotho基因的关系。通过镉染毒动物实验，进一步验证JAK2/STAT3信号通路在镉暴露对认知功能影响的作用。研究发现：1. 镉暴露可以对人群血液系统、肝肾功能、认知功能产生影响，镉暴露引起的Klotho基因甲基化程度升高可能在其中发挥一定的作用。2. 慢性镉染毒引起大鼠的空间学习记忆能力下降，与 可能与JAK2/STAT3信号通路激活，klotho 表达下降有关。3. 镉可以通过激活PC12细胞 JAK2/STAT3信号通路介导胆碱能系统活性下降，导致PC12细胞的凋亡。4. 高剂量的镉可引起PC12细胞内Klotho蛋白表达量降低，可能导致与其相关功能受损。