精神疾病致病基因NPAS3对VGF转录调控机制的研究

批准号:
81201044
项目类别:
青年科学基金项目
资助金额:
23.0 万元
负责人:
沙丽
依托单位:
学科分类:
H1005.精神分裂症及精神病性障碍
结题年份:
2015
批准年份:
2012
项目状态:
已结题
项目参与者:
周世昱、孙月吉、吴心灵、陶俊杰、张文博、王智、李晓丹
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中文摘要
精神分裂症是一种常见的精神疾病,严重影响患者的健康水平和生活质量,是一个严重的全球化的社会健康问题。申请者的博士导师所带领的团队在一对苏格兰患有精神分裂症及轻度学习障碍的母女染色体中首次发现了异常的NPAS3基因。NPAS3与精神分裂症、双向障碍及严重抑郁症存在密切联系,是bHLH-PAS转录调控因子家族成员之一。申请者在博士期间对其功能及其转录调控进行了深入的研究,揭示了该基因与神经再生、能量代谢及生物时钟调控的联系,还发现VGF可以被NPAS3显著上调。与NPAS3相似,VGF具有很多对于精神疾病来说非常重要的特征:受生物时钟的调节;参与了代谢调控;在成年神经再生中发挥作用;与神经和精神疾病有着密切的关联。本项目将着重研究NPAS3对VGF的调控机制以及VGF在神经再生过程中的作用,其结果将对深入了解精神疾病的病理机制,进而为开发新的药物及基因治疗提供更多的理论支持和崭新思路。
英文摘要
Schizophrenia is a neuropsychiatric disorder, which affects about 4-6 in a thousand individuals. The basic helix-loop-helix PAS domain transcription factor gene NPAS3 is a risk factor for psychiatric disorders. Disruption of NPAS3 gene as a result of a chromosomal abnormality carried by a mother and daughter diagnosed with schizophrenia...The regulatory profile of NPAS3 was identified by my previous microarray analysis. The most highly up-regulated NPAS3 target gene, VGF, encodes secretory peptides with established roles in neurogenesis, depression and schizophrenia. It is a highly relevant target gene as it shares a number of key feathers with NPAS3: regulation by circadian rhythm, involvement in metabolic control, contribution to adult neurogenesis and association with neurological diseases and several psychiatric disorders...The VGF promoter contains several specific regions including E-Box, which can be identified by NPAS3. A human VGF promoter fragment, containing promoter, exon1, inron1 and part of exon2, was cloned into a pGL3 basic vector. The activity of the VGF promoter was analysed using a dual luciferase assay in NPAS3 over-expression and control cells. In HEK293 and SHSY5Y cells, the luciferase activities of VGF promoter are significantly increased in the NPAS3 over-expressed cells...The mechanism of transcriptional regulation on VGF promoter by NPAS3 will be further revealed in this study using Dual lucifersae Assay, Illumina Microarray and other Bench work. HEK293 cells, SHSY5Y cells and primary mouse hippocampus progenitor cells will be used in this project. In this project, I will described experiments designed to study the transcriptional regulation on VGF promoter and the biological functions of VGF in hippocampus neuronal progenitor cells. ..This work will detail how transcription factors are involved in biological processes linked to psychiatric illness and will increase our understanding of aspects of neurogenesis relevant to mental illness and may explain the innate and medication-induced susceptibility to diabetes reported in psychiatric patients.
精神疾病易感基因NPAS3与精神分裂症及双相障碍密切相关。它是包含bHLH和PAS 结构域的转录调控因子,参与了神经形成的调控。Npas3敲除小鼠的行为及神经形成过程异常,但其机制不详。申请者对NPAS3转录谱的研究发现NPAS3可以调控神经因子VGF的转录。VGF是连接精神疾病、神经形成及突触活性的关键因子。本研究针对NPAS3对VGF的转录调控进行深入研究,发现:1)在神经干细胞中NPAS3可以上调VGF的表达,并阐明了其具体机制;2)同时结合本研究结果及以往文献,提出了一个由多个与神经形成及精神疾病密切相关的因子(NPAS3、VGF、NF-κB、BDNF及NGF)组成的网络;3)还发现NPAS3可以通过VGF来调控神经细胞的增殖。;4)揭示了了NPAS3介导的神经细胞增殖的下游信号通路。研究精神疾病易感基因NPAS3与VGF的转录调控机制,对与揭示精神疾病致病机理及神经形成的分子机制至关重要,为开创新的治疗方法提供理论依据。
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