类风湿关节炎(RA)是临床难治病，国医大师周仲瑛治疗RA的验方（滋肾通络方）疗效确切，新近研究表明miRNAs（miR）介导Th细胞可塑性分化具整体性和多环节作用，与中医药疗效特点相契合，可能是该方重建RA免疫稳态的重要机制。预实验发现该方调控RA多种异常表达的miR，且部分与Th分化相关。由此提出假说：滋肾通络方功效单元靶向不同miR，通过调控基因和微环境，介导Th可塑性分化平衡，协同增效达到“标本兼治”效果。项目采用RA阴虚络热证患者外周血和CIA小鼠的Th细胞，运用miR功能获得性/缺失性实验技术，筛选调控分化的关键miR，揭示“miR表达-Th分化-临床表型”内在联系；从免疫系统不同层面（免疫器官、循环、关节局部）、Th分化不同环节（初始分化、再分化），研究复方和滋肾养阴、祛风除湿、化痰祛瘀功效单元的个体效应和整体调节机制，阐明其组方配伍机制和治法方药的科学内涵，指导临床组方用药。

Rheumatoid arthritis (RA) is one of the clinical refractory diseases. Zishentongluo recipe, which has an accurate efficacy in curing RA, is one of the empirical formulas designed by the famous doctor- Zhou Zhong-ying. Recent studies suggest that miRNAs- mediated Th cells plasticity have features of totality and multi- link, which fit for the features of traditional Chinese medicine curing diseases. The mediated effects may be the mechanism of the recipe reconstructing the immune homeostasis. Our previous results showed that the recipe could regulate the expressions of some miRNAs that were abnormal in RA, and eight miRNAs among them may have relations with Th cells differentiation. Based on the results, this project presents a hypothesis that the three efficacy units of Zishentongluo recipe act on the different miRNAs targets and mediate the Th cells differentiation and plasticity through regulating the target genes and the micro enviorenment. The combination of the different efficacy units strengthen the overall effect on both the symptoms and root cause. To verify the hypothesis, we will collect the peripheral blood of RA patients which have “Yinxuluore” syndromes and found the collagen-induced arthritis models in mice. Then we will set up the method for the miRNA study of Gain-of-function and Loss-of-function. The key miRNAs that regulating Th cells differentiation will be investigated, and the interactions of miRNAs expression, Th cells differentiation and phenotypes will also be analyzed. Based on the results, the effects of Zishentongluo recipe and its “Zishenyangyin”, “Qufengchushi” and “Huatanquyu” units on the miRNAs-regulated Th cells plasicity will be observed from the different parts of the immune system (immune organs, circulation, local tissues) and the different links of Th cells differentiation (initial differentiation, redifferentiation). Through the studies, we can understand the differences and relevances between the different efficacy units and the recipe, and then explain the molecular mechanisms of Zishentongluo recipe on reconstructing immune homeostasis in RA. That will help to clarify the scientific nature of the prescription so as to provide scientific basis for clinical treatment.