基于Foxp3基因表观遗传修饰调控Treg细胞稳定性和功能,探讨乌头汤治疗RA的机制

The instability and dysfunction of regulatory T cell (Treg) in inflammatory milieu is of great significance in the pathogenesis of rheumatoid arthritis (RA), while the transcription factor FOXP3 plays a decisive role in the development and function of Treg. This study is on the basis of previous research findings that "Wutou Decoction can treat rats with Collagen Induced Arthritis (CIA) model and regulate epigenetic abnormalities in different segments of PBMC ". So we hypothesize that "Wutou Decoction may maintain the stability and normal function of Treg by regulating the epigenetic modifications of Foxp3 gene, thus taking effect in the treatment of RA ." We intend to establish the CIA model of mice to observe the change of FOXP3 expression, immunosuppressive function and transition to effector cells to investigate the role of Wutou Decoction from three aspects:1 The indirect effect of Wutou Decoction on CIA mice Treg in vivo .2 The direct effect of serum containing drug of Wutou Decoction on Treg of Foxp3cre-eGFP transgenic CIA mice in vitro.3 The therapeutic effect of Foxp3GFPTreg transfered to CIA mice after intervention with serum containing drug of Wutou Decoction. In addition, to explore its complex mechanism of multi-target therapy for RA we plan to observe the effect of Wutou Decoction on Foxp3 promoter, CNS2 methylation, histone modification and related regulatory proteases, providing scientific evidence for clinical treatment of RA.

炎症环境下调节性T细胞（Treg）不稳定性和功能异常是RA发病重要因素，而转录因子FOXP3对Treg发育和功能起决定性作用。本研究基于前期“乌头汤能治疗CIA大鼠，调控PBMC不同环节表观遗传异常”研究结果，提出“乌头汤可能通过调控Foxp3基因表观遗传修饰，维持Treg稳定性和正常功能，从而发挥对RA治疗作用”的假说，拟构建CIA模型，观察TregFOXP3表达、免疫抑制功能、向效应细胞转化的变化；从三个层面研究乌头汤的作用：乌头汤对体内CIA小鼠Treg的间接作用；乌头汤含药血清在体外对Foxp3cre-eGFPCIA小鼠Treg的直接作用；乌头汤含药血清干预后的Foxp3cre-eGFPTreg转输给CIA小鼠的治疗作用。另外观察乌头汤对Foxp3启动子、CNS2的甲基化及组蛋白修饰、相关调控蛋白酶等的影响，探索其治疗RA多靶点的复杂机制，为今后治疗RA提供科学依据。

调节性T细胞（Treg细胞）在类风湿关节炎（RA）的发病中发挥重要作用。在炎症环境中，Treg细胞的稳定性和正常功能多难以维持。本项目通过动物实验发现，乌头汤能够改善CIA模型小鼠脾脏Treg/Th17细胞平衡，增强炎症状态下Treg细胞的稳定性。进一步的细胞机制研究表明，乌头汤可以通过去甲基化调控Treg细胞TSDR区域甲基化水平，发挥增强炎症状态下Treg细胞的稳定性、促进Treg细胞重要膜分子TIGIT的表达、增强Treg细胞分泌抗炎因子IL10和TGFβ、增强Treg细胞对效应T细胞的抑制功能。本项目的主要研究结果表明，乌头汤能够通过稳定炎症状态下Treg细胞稳定性，增强Treg细胞免疫抑制功能，发挥治疗RA的作用。本项目主要研究结果为今后乌头汤和Treg细胞相关研究及临床应用奠定了坚实的基础。.项目资助发表相关SCI论文7篇，核心期刊论文2篇。项目在研期间，共培养博士研究生4名。本项目在研期间共投入直接经费55万元，已支出45.0574万元，结余9.9426万元。各项支出与项目预算基本相符。剩余经费将继续用于本项目后续研究的相关支出。

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