miR-124通过靶向Notch信号通路在阿尔茨海默氏病中发挥作用的分子机制研究

项目名称： miR-124通过靶向Notch信号通路在阿尔茨海默氏病中发挥作用的分子机制研究

项目编号： No.31200804

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、认识与心理学

项目作者： 孔岩

作者单位： 东南大学

项目金额： 26万元

中文摘要： 阿尔茨海默氏病（AD）是一种慢性神经退行性疾病。果蝇AD模型可表现出 神经退行性病变，是该病的有效研究工具。我们发现神经系统特异高表达的miR-124(一种microRNA)在AD果蝇中显著下降，提示其在该病中的重要作用。研究表明，miR-124水平降低导致Notch信号通路激活。据报道，Notch信号的过度激活可影响神经系统的结构与功能，而AD病人脑组织Notch信号处于激活状态。为阐明miR-124 、Notch和AD三者的关系，本课题拟用生物芯片、生物信息学分析及相关实验，筛选 Notch通路中miR-124的靶基因；通过果蝇AD模型及相应遗传学操作，从在体水平分析miR-124通过抑制Notch信号通路在AD中发挥作用的分子机制；通过体外实验在人和小鼠神经细胞中验证在果蝇中的发现。我们期望本课题的研究能够为以microRNA为靶点的AD干预和治疗研究提供新的思路和药物设计靶点。

中文关键词： 阿尔茨海默氏症；微小RNA；果蝇；miR-124；Notch

英文摘要： As a neurodegenerative disorder,Alzheimer's disease(AD) is the most common reason for old people's dementia. Although many microRNAs are found to be changed during progression of AD,their exact functions in vivo still need further investigation. With short life span and easy for genetic manipulation, Drosophila models could recapitulate many features of AD and are powerful tools to study this disease. miR-124 is a kind of microRNA expressed at high levels in the brain. We found that the expression of miR-124 is reduced in AD Drosophila. miR-124 knockout led to Notch signaling activation. It is reported that Notch singaling activation could increase neuronal vulnerability and accelarate neurodegenation, which were found in AD patients.In order to investigate the role of miR-124 in AD, molecular and cellular experiments as well as bioinformatic analysis will be performed to screen for the targets of miR-124 in Notch signaling pathway. We will use Drosophila AD model and mamalian neuronal cells to invesigate the role of miR-124 in AD by targeting Notch signaling molecules. We hope our study could contribute to the understanding of microRNAs in AD and provide new targets for drug desingn in AD prevention and treatment.

英文关键词： Alzheimer's disease；microRNA；Drosophila；miR-124；Notch