ERK信号转导通路在SLE表观遗传学基因表达调控机制中的作用探讨

项目名称： ERK信号转导通路在SLE表观遗传学基因表达调控机制中的作用探讨

项目编号： No.81201233

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学四处

项目作者： 米向斌

作者单位： 南方医科大学

项目金额： 23万元

中文摘要： 以DNA甲基化为核心的表观遗传学特征异常是SLE发病的重要因素。我们的研究发现SLE患者T细胞DNMT1基因表达减少和酶活性下降，CD70、IL-6等基因启动子甲基化程度降低，并导致该基因过度表达。最近文献报道，特异性ERK信号通路抑制剂可以抑制正常T细胞的DNMT1基因表达及酶活性并进而出现类似狼疮T细胞的免疫异常，而ERK信号转导通路活性降低正好也在狼疮T细胞中存在。故推测SLE患者T细胞中ERK信号转导通路缺陷可能在SLE表观遗传学特征异常中起关键作用。因此，我们拟利用高效液相色谱、流式、酶联免疫、蛋白印迹、免疫细胞化学等技术研究体内狼疮T细胞中ERK信号转导通路和表观遗传学特征异常的内在联系，用特异性ERK信号通路抑制剂、DNMT抑制剂处理T细胞研究体外ERK信号转导通路对狼疮T细胞表观遗传学特征的影响，从而进一步完善SLE发病机制中表观遗传学理论，为治疗SLE提供新思路和新靶点。

中文关键词： 系统性红斑狼疮；DNA甲基化；表观遗传；ERK1；

英文摘要： The epigenetic abnormalities characterized by DNA hypomethylation play an important role in the autoreactivity of lupus T cells and disease pathogenesis of systemic lupus erythematosus(SLE). Preliminary results from our group showed that DNA methyltransferase gene 1 (DNMT1) transcription decreased and CpG islands in promoter of some methylation-sensitive genes (CD70, IL-6) were unmethylated in different level which lead to the increased genes expression of in T cells from SLE patients and healthy T cells treated by DNA methylation inhibitor. Recently, special inhibitor of extmcelllllar regutated kinase（ERK） pathway which suppress gene expression of DNMT and cause epigenetic abnormalities in healthy T cells and autoimmunity like lupus T cells, while ERK pathway signaling abnormalities in lupus T cells were reported. Based on these observations, we hypothesis that the defect of ERK pathway might play an important role in epigenetic abnormalities in lupus T cells. So we try to elucidate the relationship between ERK pathway and epigenetic abnormalities of lupus T cells by high performance liquid chromatograph(HPLC), Flow cytomertry(FCM), Enzyme-Linked ImmunosorbentAssays (ELISA)，Western blot and immunocytochemistry(ICC) methods, and investigate the effect of ERK pathway of epigenetic abnormalities in T cells culture

英文关键词： Systemic lupus erythematosus；DNA methylation；Epigenetics；ERK1；