阿尔茨海默病易感基因TREM2的精细作图及其致病机制研究

项目名称： 阿尔茨海默病易感基因TREM2的精细作图及其致病机制研究

项目编号： No.81471309

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： 郁金泰

作者单位： 青岛大学

项目金额： 90万元

中文摘要： 近期，两项大规模高加索人群二代测序研究发现TREM2为AD新的易感基因，其稀有变异R47H可增加患病风险3倍以上，这与APOEε4接近。我们前期率先证实TREM2与汉族人群AD易感性存在一定关联，但未检测到R47H变异，提示TREM2的SNP存在种族差异。同时，我们发现TREM2可参与调控小胶质细胞激活状态和功能，且其表达可能受Aβ影响。在此基础上，本项目拟对汉族AD患者和健康对照的TREM2重点区域进行第二代高通量测序，筛选出AD易感SNP，以全面揭示汉族人群TREM2与AD易感性的关系。此外，我们拟运用Aβ刺激离体和在体小胶质细胞，观察其对TREM2表达水平及下游信号转导的作用，同时运用慢病毒为载体的基因过表达/干扰技术，在细胞层面和活体层面对TREM2进行靶向干预，研究其对小胶质细胞激活状态及功能的调控和对AD病理特征及认知功能的影响，以全面阐明TREM2参与AD病理进程的分子机制。

中文关键词： 阿尔茨海默病；TREM2；第二代高通量测序；小胶质细胞；β-淀粉样蛋白

英文摘要： Recently, two large-scale studies have revealed that R47H, a rare variant within exon 2 of triggering receptor expressed on myeloid cells 2 (TREM2), increases susceptibility to late-onset Alzheimer's disease (LOAD) with an odds ratio similar to that of the apolipoprotein E ε4 allele in Caucasian population, suggesing that TREM2 represents an important susceptibility gene for LOAD. To date, the assoication of TREM2 with LOAD risk in Han Chinese remains unclear, and few studies have focused on the role of TREM2 in AD pathogenesis. In our preliminary studies, we provided the first evidence that TREM2 was associated with LOAD risk in Han Chinese, whereas the frequency and distribution of TREM2 variants were quite different with those in Caucasians, possibly due to the differences in genetic background. Meanwhile, we demonstrated that the expression of TREM2 might be affected by Aβ levels, and TREM2 was able to modulate the activation and function of microglia, the major type of macrophage in brain that was implicated in AD pathogenesis. Based on these findings, we intend to finely map TREM2 to identify risk variants for LOAD in a large Han Chinese cohort. In addition, to fully elucidate the role of TREM2 in AD pathogenesis, we investigate the impact of Aβ oligomer on the expresson and downstream signaling of TREM2 in vitro and in vivo first. Afterwards, we intend to manipulate TREM2 expression using lentivirus vectors to reveal its modulation on activation and function of microglia as well as AD-related neuropathology and congitive impairment. The completion of this project will provide theoretic support for early warning and diagnosis of AD in Han Chinese, and will offer novel target for therapies and durg development of this disease via uncovering its underlying pathogenesis.

英文关键词： Alzheimer's disease;TREM2;Next-generation sequencing;Microglia;β-amyloid