PTPN22基因启动子多态性影响1型糖尿病易感性的机制研究

项目名称： PTPN22基因启动子多态性影响1型糖尿病易感性的机制研究

项目编号： No.81500599

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： 孙成君

作者单位： 复旦大学

项目金额： 18万元

中文摘要： 1型糖尿病（T1D）是一种多基因遗传疾病，其中PTPN22为其重要的致病基因，但其确切致病机制不清。我们之前进行的大样本相关性研究显示汉族儿童PTPN22的启动子区域与T1D相关，提示PTPN22启动子可能具有导致疾病易感的生物学功能。我们进而检测了儿童外周血淋巴细胞的PTPN22表达，发现启动子-2.7k处多态性可影响淋巴细胞PTPN22表达；凝胶迁移及质谱鉴定提示该多态性可影响T细胞系中转录因子STAT3与启动子的结合力。基于此，本申请将深入研究PTPN22启动子内可改变PTPN22表达的基因多态性位点；并采用凝胶迁移、质谱鉴定影响PTPN22基因转录的转录因子，进而通过转录因子过表达及shRNA载体研究PTPN22的转录调节，分析免疫细胞细胞因子的变化，探究该启动子区域多态性对PTPN22的调控及产生自身免疫相关性的机制，为靶向调控该基因表达及其基础上进行免疫调节治疗方法提供新思路。

中文关键词： 免疫遗传；基因调控；自身免疫疾病

英文摘要： PTPN22 was one of the most important genes in the etiology of type 1 diabetes. Although PTPN22 was also associated with many other autoimmune diseases, the functional importance of this gene in disease susceptibility is not fully studied. In our previous large association study among Chinese Hans, we have identified that the association between PTPN22 and type 1 diabetes is located in the promoter region of the gene. In addition, variants in PTPN22 affect the expression of PTPN22 in peripheral blood. These results indicated that the promoter region of PTPN22 is likely involved in the regulation of PTPN22 expression which may further leads to altered susceptibility to autoimmune diseases. Therefore we proposed the current study to investigate the functional importance of genetic variations in this region regarding the regulation of PTPN22 expression. We will investigate the cis element in PTPN22 promoter and its binding transcriptional factors. Followed by investigation on the transcriptional regulation of the transcriptional factor, the proposed study can provide evidence on the expression regulation of PTPN22, which will line further a road to the intervention of immune regulation by manipulating the expression of PTPN22.

英文关键词： Immunogenetics;Genetic regulation;Autoimmune diseases