精神分裂症相关蛋白dysbindin 的磷酸化修饰调节其功能并参与精神分裂

项目名称： 精神分裂症相关蛋白dysbindin 的磷酸化修饰调节其功能并参与精神分裂

项目编号： No.81460215

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 费尔康

作者单位： 南昌大学

项目金额： 47万元

中文摘要： Dysbindin 是精神分裂症易感基因之一，其在脑中表达水平降低与精神分裂症发病密切相关。我们以及其他实验室的研究发现dysbindin 调节突触囊泡释放相关蛋白synapsin I 的表达以及神经突起的生长，参与树突棘的发育。但目前对于dysbindin 上述功能的调节机制仍然未知。我们在预实验中发现dysbindin 可以被蛋白激酶Akt1 在S10 位点磷酸化。本项目将在原代神经元中鉴定调节Akt/dysbindin 上游通路的信号因子，同时研究磷酸化对其下游突触相关功能的调节，探讨dysbindin 的磷酸化调节自身功能的分子机制。最后在dysbindin 缺陷小鼠（Sandy mice）中探索其磷酸化在体内对突触功能的调节作用，以期阐明dysbindin 的磷酸化修饰在精神分裂症发生发展中的意义，为其治疗提供新的思路。

中文关键词： dysbindin；精神分裂症；Akt；磷酸化

英文摘要： DTNBP1 is a susceptibility gene of schizophrenia, and its product, dysbindin, is reduced in the prefrontal cortex and hippocampus of schizophrenic patients. Our previous studies found that dysbindin regulates synapsin I expression and neurite outgrowth. And dysbindin was also reported to regulate dendritc spine development by other groups. However, little is known about the mechanisms underlying regulation of dysbindin functions. In our preliminary study, we found that Akt1 phosphorylates dysbindin at Ser10. In this study, we will identify the upstream signaling pathway that activates Akt/dysbindin and investigate if phosphorylation of dysbindin regulates its synaptic functions in primary neuronal cultures. Moreover, we will explore the molecular mechanisms by which phosphorylation of dysbindin regulates its functions. Finally, the role of phosphorylation of dybindin in the pathogenesis of schizophrenia will be characterized in Sandy mice, the dysbindin-null mice. This study will be helpful for the further understanding of the pathogenic mechanisms of dysbindin in schizophrenia, and could possibly lead to strategy for the effective treatment of schizophrenia.

英文关键词： dysbindin;Schizophrenia;Akt;Phosphorylation