DNA碱基剪切修复在Gadd45a促CD4+T细胞DNA低甲基化中的作用及参与SLE发病的机制

项目名称： DNA碱基剪切修复在Gadd45a促CD4+T细胞DNA低甲基化中的作用及参与SLE发病的机制

项目编号： No.81472881

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： 李亚萍

作者单位： 中南大学

项目金额： 70万元

中文摘要： CD4+T细胞DNA低甲基化在系统性红斑狼疮（SLE）发生发展中起关键作用。我们证实SLE CD4+T细胞过度表达的Gadd45a能促进CD4+T细胞CD11a、CD70 DNA低甲基化，诱导自身免疫，但其分子机制不清楚。研究认为Gadd45a可能募集碱基剪切修复（BER）和/或核酸剪切修复（NER）参与DNA甲基化调控。我们发现NER修复途径在SLE CD4+T细胞中存在缺陷，推测Gadd45a可能通过募集BER元件启动BER途径去除甲基。我们拟开展研究：1、SLE患者和正常人是否存在BER元件表达差异？ 2、CD11a和CD70 基因是否通过Gadd45a募集BER修复元件发生DNA修复，去除甲基？ 3、BER途径和BER元件对CD4+T细胞Gadd45a介导的CD11a和CD70去甲基化的调控及在SLE发病中的作用。研究对阐释低甲基化分子机制和SLE的表观遗传学发病机制具有重要意义。

中文关键词： 系统性红斑狼疮；DNA修复；T细胞；DNA甲基化；Gadd45a

英文摘要： DNA hypomethylation of CD4+T cells plays a key role in the occurrence and development of systemic lupus erythematosus(SLE). Our previous studies have confirmed that Gadd45a is overexpressed in SLE CD4+ T cells, Gadd45a can promote DNA hypomethylation of CD11a and CD70, induce autoimmunity in CD4+T cells. However,it is unclear how Gadd45a promotes DNA hypomethylation of SLE CD4 + T cells. Studies have suggested that Gadd45a may promote DNA demethylation by recruiting base excision repair (BER) and/or nucleic acid excision repair (NER). We have identified that NER pathway is defective in CD4+T cells of SLE,thus we speculate that BER may be recruited by Gadd45a,then BER pathway may be activated to remove the methyl groups of CD11a and CD70. Research we plan to carry out as follows, 1.Is there any difference in the expression of BER elements between normal CD4+T cells and SLE CD4+T cells? 2. Are CD11a,CD70 promoter induced to be demethylated by Gadd45a recruiting BER elements and initiating BER to remove methyl group? 3. Study on regulation of BER pathway and BER elements on Gadd45a-mediated demethylation of CD11a,CD70 and their role in SLE pathogenesis. Our study will have important significance for explanation of demethylation molecular mechanisms and epigenetic pathogenesis of SLE.

英文关键词： systemic lupus erythematosus;DNA repair;T cells;DNA methylation;Gadd45a