SGK1.1通过调节δENaC在抗癫痫中的作用研究

Epileptic susceptibility has been linked to abnormal neural network caused by changing of genes, which should be the important targets of antiepileptogenesis. In our previous study,we have revealed the relationship between abnormal neural network and intractable epilepsy (IE) by using cDNA microarray and proteomics technologies, and discovered 346 genes that had altered mRNA expression in brains of patients with IE and 89 genes were with changing of protein levels. SGK1 was one of these genes, which was significantly increased in IE brain tissues and presented a increased expression change in animal models. SGK1.1, a subtype of SGK1 which specifically expressed in neuron, has been proved to participate in regulating ENaC/DEC family genes, impacting neural excitation and forming abnormal neural network. Based on the previous study, with the combination of molecular biological and electrophysiological technologies, we aim to further investigate the interaction between SGK1.1 and δENaC, which is only expressed in neuron ,and clarify its role in neural excitation and abnormal neural network and provide a new therapeutic target for antiepileptogenesis.

癫痫易感性与异常神经网络有关，而参与异常神经网络形成的基因是抗癫痫的重要靶点。课题组前期在利用表达谱芯片，蛋白质组学等研究耐药性癫痫异常神经网络，寻找抗癫痫的靶点的过程中，发现了346个基因在耐药性癫痫患者脑组织表达存在差异，89个基因伴有功能蛋白异常。其中血清-糖皮质激素诱导蛋白激酶1（SGK1）在耐药性癫痫患者及癫痫动物模型脑组织中表达升高。脑内特有的SGK1亚型SGK1.1参与脑内上皮钠离子通道/退变素（ENaC/DEC）家族基因调节，影响神经兴奋性及异常神经网络形成。本项目在前期研究结果的基础上利用分子生物学，神经电生理学技术从细胞、动物模型到患者多个层面继续深入探讨癫痫中SGK1.1与唯一在神经元表达的上皮钠离子通道δ亚基（δENaC）的相关性，明确SGK1.1是否通过调节δENaC参与神经兴奋性调节及异常神经网络形成，为寻找抗癫痫新的作用靶点提供依据。

癫痫易感性与异常神经网络有关，参与异常神经网络形成的基因是抗癫痫的重要靶点。课题组在前期利用表达谱芯片和甲基化芯片对耐药性癫痫进行筛选异常基因的研究中发现SGK1在耐药性癫痫患者及癫痫动物模型脑组织中表达升高，5-HTR6在耐药性癫痫患者脑组织中甲基化程度降低，基因水平表达上调。脑内特有的SGK1亚型SGK1.1能调节δENaC影响兴奋性。我们利用分子生物学方法及神经电生理学技术研究发现SGK1.1及δENaC在癫痫脑组织中的表达表达增高，δENaC抑制剂干预可影响癫痫动物行为学，及大鼠脑片海马神经元的AP。5-HTR6是正常神经网络形成一个重要调节基因，能与mTOR作用参与神经兴奋性调节，我们利用分子生物学方法及神经电生理学技术研究发现5-HTR6在癫痫脑组织中的表达表达增高，5-HTR6抑制剂干预可影响癫痫动物行为学，5-HTR6作用于mTOR抑制癫痫放电。通过本研究证实δENaC及5-HTR6有可能作为抗癫痫的重要靶点，为以后的研究提供理论支持。