NEDL1动物模型的神经生物学功能及机制的在体研究

项目名称： NEDL1动物模型的神经生物学功能及机制的在体研究

项目编号： No.81471329

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 邹丽萍

作者单位： 中国人民解放军总医院

项目金额： 80万元

中文摘要： 儿童常见的神经系统疾病常有共患现象，提示它们存在共同致病通路。泛素连接酶NEDL1 mRNA优先表达于神经组织，我们研究证明NEDL1(又称HECW1)能抑制mTOR通路的激活，NEDL1敲低的斑马鱼显示脑组织细胞特异性死亡，予拯救实验后，其导致的脑细胞死亡表型消失，提示NEDL1是脑神经系统发生所必须蛋白。本课题将在前期研究基础上，利用NEDL1敲除动物模型，以mTOR通路为切入点，采用细胞生物学、神经生理学等方法，检测NEDL1敲除动物有关脑区神经环路中的分子及生化信息传递变化，证实NEDL1在神经元及突触形态和功能异常中的作用；通过建立NEDL1敲除鼠的癫痫及孤独症模型, 结合神经行为学及电生理研究，对其分子、突触、细胞、环路各层次进行相关分析，揭示有关基因及突变体在神经元发育环路的形成和功能中的作用及机理，为临床上常见儿童神经系统疾病的治疗提供新的研究方向、理论依据以及药物治疗靶点

中文关键词： 泛素连接酶；NEDL1；HECW1；癫痫；孤独症

英文摘要： The comorbidity is common in the nervous system diseases in children which tells these nervous system diseases have the same pathogenic pathway. Neural precursor cell-expressed developmentally down-regulated gene 4 (NEDD4)-like ubiquitin ligase 1 (NEDL1,also known as HECW1)expresses in the nervous system preferentially. In our previous study, we have found NEDL1 can inhibit mTOR signal pathway; in the zebra fish with NEDL1 knockdown, brain cells happened necrosis which can be inverted by rescue experiment. So, it is can be concluded that NEDL1 is the necessary protein for the occurrence and development of center nervous system. In this research, we will investigate the changes of molecule and biochemistry information transfer in the neural circuit of related brain region by a combination of in vitro and in vivo approaches including cell biology, electroneurophysiology and rescue experiment based on the NEDL1 knockout/knockdown animal and mTOR signal pathway, to confirm what kind of role that NEDL1 plays in the formation and disfunction of neurons and synapses; meanwhile, we will deliberate the contribution and mechanism of the related gene and mutant in the formation and function of neuron circuit by neuroethologic and electrophysiologic methods and analysis of molecule, synapse, cell and circuit based on the autism spectrum disorder and epilepsy mice model with NEDL1 knockout. This study will help us figure out the potential pathogenesy in autism spectrum disorder and epilepsy, and provide new research directions, logic proofs and new targets in searching drug treatment of nervous system diseases in children.

英文关键词： ubiquitin;NEDL1;HECW1;epilepsy;autism