FOXP3基因甲基化修饰促进动脉粥样硬化进程的机制研究

动脉粥样硬化（AS）是由于免疫失衡所致的慢性炎症性疾病，调节性T细胞（Treg）缺失是AS发生发展的重要因素。FOXP3主要表达于Treg，是关系Treg发育和功能的关键因子。而FOXP3去甲基化状态决定其稳定表达，对维持Treg功能和数量有重要意义，也是Treg的特异性标志物。本课题前期研究首次表明外周血FOXP3基因甲基化水平与AS的严重程度密切相关，细胞学研究提示FOXP3基因甲基化修饰调控AS进程。本研究拟在已有的工作基础上，通过双向性队列研究及动物学实验，明确FOXP3基因甲基化水平改变能否协助预测AS和诊断疾病；通过分子生物及细胞学实验，探明是否多种AS的危险因素均可诱发FOXP3基因甲基化而引起免疫失衡；通过构建FOXP3基因去甲基化的CD4+T细胞，观察其对AS形成、发展及斑块稳定性的影响，进一步印证FOXP3基因异常甲基化改变促进AS进程，并为AS的细胞免疫治疗提供依据。

Atherosclerosis is characterized by chronic inflammatory response due to the imbalance between pathogenic immunity and immunologic tolerance. Regulatory T cells (Tregs) are powerful inhibitor of atherosclerosis. It has been noted that a stable FOXP3 expression is a prerequisite for the maintenance of the development and suppressive properties of Tregs. Stable expression of FOXP3 in Tregs requires DNA methylation-based regulation. Demethylation analysis of the FOXP3-Treg-specific demethylated region has been regarded as a marker for Tregs. Our preliminary study first demonstrated that methylaiton of FOXP3 gene in peripheral blood is associated with the severity of atherosclerosis; epigenetic suppression of FOXP3 might play an important role in the progression of atherosclerosis. Based on our previous data, we proposed to confirm the methylation level of FOXP3 gene in the peripheral blood as a specific marker to predict and diagnosis coronary artery disease, by prospective and retrospective study and animal experiment; further demonstrate that multiple risk factors cause atherosclerosis is through the methylaiton of FOXP3; verify that the methylation of FOXP3 accelerate the progression of atherosclerosis by preparing FOXP3 demethylated CD4+T cells, observing their effect on the development of atherosclerosis and the stability of plaque, which will provide basis for the immune cell therapy to treat atherosclerosis.