细胞因子对ERK1/2和ERK5信号通路在孤独症中的调控和致病机制的研究

项目名称： 细胞因子对ERK1/2和ERK5信号通路在孤独症中的调控和致病机制的研究

项目编号： No.81201060

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 神经系统疾病、精神疾病

项目作者： 杨堃

作者单位： 青岛大学

项目金额： 24万元

中文摘要： 孤独症是一种严重的神经发育障碍性疾病，其发病机制尚不明确。我们的前期研究发现ERK1/2和ERK5信号通路在孤独症患者和BTBR孤独症模型小鼠的大脑皮质中都存在异常激活的现象，并对神经元的迁移、发育、突触传递功能以及树突棘的成熟产生了影响，但是其激活机制仍不清楚。大量研究表明，免疫功能紊乱和多种细胞因子表达升高与孤独症的发生密切相关，提示我们ERK1/2和ERK5通路的激活可能与这些细胞因子有关。本项目拟在现有研究成果的基础上，以BTBR小鼠和B6小鼠作为研究对象，利用过表达和RNA干扰慢病毒从体内和体外两方面深入探讨细胞因子对ERK1/2和ERK5通路在孤独症中的调控机制，同时观察对小鼠孤独症相关行为学以及小鼠大脑皮质神经元的发育、凋亡、突触可塑性的调节作用，为进一步明确孤独症的发病机理，探索新的治疗方法提供理论基础和实验依据。

中文关键词： 孤独症；白介素-6；ERK5信号通路；神经发育；行为学

英文摘要： Autism is a severe neurodevelopmental disorder and the pathogenesis of this disorder is unknown. Our recent work showed that ERK1/2 and ERK5 signaling pathways were significantly up-regulated in the cortex of autistic individuals and in the BTBR murine model of autism and we found that ERK1/2 up-regulation in cortical neurons could alter neural cell migration, inhibit neurogenesis, as well as affect synaptic transmission and dendritic spine maturation. However, the exact activation mechanism of ERK1/2 and ERK5 signaling pathways remains undefined. A number of studies have shown that immune dysfunction and various cytokines upregulation are associated with autism, which suggests that the upregulation of ERK1/2 and ERK5 signaling activities in autism could result from increased cytokines. Based on these findings, we propose to upregulate and downregulate cytokines expression in the cortex of B6 mice, a highly social control strain, and BTBR mice respectively both in vitro and in vivo with a lentivirus approach and conduct studies to investigate the modulation of ERK1/2 and ERK5 pathways by cytokines and determine the effect of cytokine alteration on autism-like behavior in mice and mouse neural cell migration, development, apoptosis and synaptic plasticity. The importance of this application is that completion of

英文关键词： Autism；Interleukin-6；ERK5 signaling pathway；Neural development；Behavior