结核分枝杆菌基因组甲基化修饰与其耐药和致病机制研究

项目名称： 结核分枝杆菌基因组甲基化修饰与其耐药和致病机制研究

项目编号： No.31471203

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 遗传学与生物信息学、细胞生物学

项目作者： 朱宝利

作者单位： 中国科学院微生物研究所

项目金额： 84万元

中文摘要： 结核分枝杆菌（TB）是肺结核的病原菌，其多耐药（MDR）和广泛耐药（XDR）菌株的出现给结核病的防治带来极大困难。TB的耐药性与致病性是TB研究中的难题，虽然多数情况下是由基因突变导致，但也有许多未知因素参与，只是目前还无法确认。对其他类病原菌的研究表明，细菌基因组表观修饰不但与细菌的致病性相关，也与细菌的耐药性相关。基于此，我们推测TB遗传表观修饰与致病性和耐药性有关联，因此拟以临床多耐药和毒力不同的TB菌株为研究对象，利用三代单分子DNA测序方法在基因组水平分析其甲基化修饰信息，并通过基因敲除和转录组分析等方法进行功能验证，明确甲基化修饰与TB多耐药表型和致病性的关联性。课题的前期实验在临床株中发现了两个全新的甲基转移酶，初步结果表明其可能参与了耐药和毒力相关基因的表达调控。课题研究将为TB多耐药表型的出现及其致病机理提供理论依据，为多耐药TB的治疗提供潜在的药物作用靶位点。

中文关键词： 结核分枝杆菌；表观遗传学；DNA甲基化

英文摘要： Mycobacterium tuberculosis(MTB) is one of serious infectious diseases worldwide. The emerging of multidrug resistance (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (TB) make its prevention and treatment tremendous difficulties. Present study showed that point mutation of the drug target genes responsible for most drug-resistant phenotype in MTB. But some drug-resistant phenotype can not be reasonably explained. Meanwhile pathogenesis of TB is not completely clear. Therefore, to reveal the pathogenesis of drug-resistant Mycobacterium tuberculosis is particularly urgent. Over the past two years, the third generation sequencing technology proveded its validity in the detection of methylation in genomic level in bacteria. And the epigenetic modification is potentially associated with drug resistance and virulence of bacteria. In this study, we obtained methylation information of the clinical multidrug-resistant and multi- sensitive Mycobacterium tuberculosis using the third generation genome sequencing technology, combined with bioinformatics analysis and functional verification of the methyltransferase, we are trying to reveal the association between the phenotype of multi- drug-resistant TB and its pathogenic mechanism. The results of this study will provide a potential drug target sites for MDR and XDR TB treatment.

英文关键词： mycobacteria tuboculosis;epigenetics;DNA methylation