AD易感基因RPL13的作用机制研究

项目名称： AD易感基因RPL13的作用机制研究

项目编号： No.81500940

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 周合江

作者单位： 中国科学院昆明动物研究所

项目金额： 17.5万元

中文摘要： 阿尔兹海默症（AD）是临床表现为认知和记忆功能损伤的神经退行性疾病。AD的发病机理存在多种假说，但具体机制至今未明，目前尚无控制AD发展进程的药物和治疗方法。因此，深入研究AD发生发展的分子机制是新药开发和疾病诊治的基础。我们基于现有数据库数据挖掘分析和功能实验发现，核糖体蛋白L13（RPL13）在AD患者海马和有神经纤维缠结（AD显著病理特征之一）的神经元中高表达； RPL13单核苷酸多态位点rs3211567与AD发病显著相关，且风险基因型TT显著降低大脑组织中的该基因表达水平。本项目拟在此基础上，进一步明确RPL13表达水平的调控及RPL13表达量与AD发生的关系，分析RPL13对神经元凋亡的调控，并鉴定出与RPL13相互作用的蛋白，阐明RPL13的信号通路作用机制。通过以上研究，深入探讨RPL13与AD发生发展的分子机制，为AD临床诊治提供新的视角。

中文关键词： 核糖体蛋白L13；阿尔兹海默症；基因调控；凋亡；遗传易感

英文摘要： Alzheimer’s disease (AD) is a neurodegenerative disorder with a clinical manifestation of cognitive and memory function damage. Insights into the mechanisms of the progression of AD are needed to develop new drug and therapeutic treatments for AD. So far, there is few effective drugs to prevent the aggravation due to elusive pathogenesis of AD. In our recent (unpublished) study, we found that Ribosome protein L13 (RPL13) could be considered as an AD susceptibility gene. Gene expression analysis in AD using the Gene Expression Omnibus (GEO) database showed that RPL13 mRNA is highly expressed in the hippocampus of AD patients and entorhinal cortex neurons containing neurofibrillary (which is typical of AD pathology). Genetic association analyses based on 1633 AD samples showed that single nucleotide polymorphism (SNP) rs3211567 in the RPL13 gene conferred AD genetic susceptibility. Moreover, expression Quantitative Trait Locai data indicated that risk genotype TT of rs3211567 was significantly associated with a reduced RPL13 mRNA level. In this study, we aim to further characterize the roles of RPL13 in AD pathogenesis. We will (1) elucidate the regulation of RPL13 expression at the genetic level and define the relationship between expression quantity of RPL13 and the progression of AD; (2) define the roles of RPL13 in the regulation of apoptosis and function of neurons; (3) identify new factor(s) regulating in the progression of AD through RPL13 pathway. Our results will uncover the mechanism of the RPL13 gene during the progression of AD, and will (potentially) help with the therapeutic interventions of AD.

英文关键词： RPL13;Alzheimer’s disease;Genetic expression; Apoptosis;Genetic susceptibility