树鼩抗病毒先天免疫通路基因的挖掘与功能鉴定

项目名称： 树鼩抗病毒先天免疫通路基因的挖掘与功能鉴定

项目编号： No.U1402224

项目类型： 联合基金项目

立项/批准年度： 2015

项目学科： 管理科学

项目作者： 姚永刚

作者单位： 中国科学院昆明动物研究所

项目金额： 222万元

中文摘要： 树鼩作为具有潜在应用价值的新型实验动物，是灵长类动物的近亲，日渐受到重视。我们近期完成了树鼩基因组解析，全面获取了树鼩的遗传特性，解释了其用于人类疾病动物模型，尤其是病毒感染模型创建的遗传基础(Nature Communications 2013)。通过对树鼩2万多个基因的分析，我们发现其免疫系统基因存在特异性，如RIG-I基因缺失，这是否与树鼩能感染人类多种病毒，但某些病毒感染率低，极少形成持续性感染的现象直接相关，需要功能验证。本项目基于我们对树鼩基因组数据的深入挖掘和树鼩免疫系统基因的精细分析，以丙型肝炎病毒（HCV）感染为切入点，在细胞和动物感染层次全面解析树鼩RIG-I缺失后，其免疫系统RLR和TLR家族基因及相关通路的功能变化，阐明树鼩感染HCV，但难以形成持续感染的分子调控机制。研究结果将为树鼩HCV感染动物模型建立提供新的思路。

中文关键词： 树鼩基因组；先天性免疫；病毒感染；动物模型

英文摘要： The Chinese tree shrew (Tupaia belangeri chinensis), the closest relative of primates, possesses great potential as an experimental animal in biomedical research and has attracted increasing attention in modeling human diseases and therapeutic responses. We recently presented a publicly available annotated genome sequence for the Chinese tree shrew (Nature Communications 2013, 4: 1426). By characterizing key factors and signaling pathways in nervous and immune systems, we demonstrated that tree shrews possess both shared common and unique features, and provided a genetic basis for the use of this animal as a potential model for biomedical research. We found several uniquenesses of key antiviral innate immunity genes in Chinese tree shrew genome, such as absence of RIG-I. Whether the unique features of tree shrew antiviral innate immunity genes confer to the susceptibility of infection of human virus infection needs experimental characterization. In addition, in cases of tree shrew infection, experimental inoculations of several human viruses, such as hepatitis C virus (HCV), rarely led to sustained viremia, which for most human cases lasts for the entire course of infection. To understand the genetic basis for this phenomenon needs defined analysis. In this study, we investigated the property of gene interaction pathways involved in HCV infection and identified several unique genetic features by comparing tree shrew genome to primate and rodent genomes. Based on these initial discoveries in HCV infection signaling pathway, we aim to perform a comprehensive study to characterize functional alterations of specific genes of tree shrew retinoic acid-inducible gene-I-like receptors (RLRs) and toll-like receptors (TLRs)-dependent antiviral signaling pathways due to the absence of RIG-I at the cellular and animal model levels. Our study will uncover the mechanisms of tree shrew’s susceptibility to HCV infection but not sustained viremia, and will offer an opportunity to decipher the genetic basis of the tree shrews’ suitability as an animal model for studying viral infection, in particular for HCV infection.

英文关键词： Chinese tree shrew genome;Innate immune system;Viral infecion;Animal model