转录因子YY1在类风湿性关节炎发病中的作用及其机制研究

Rheumatoid arthritis (RA) is a systemic inflammatory disease that involves hyperplasia of synovial tissues and structural damage to cartilage, bone, and ligaments. The etiology and pathogenesis of RA are still unclear, which lack of effective treatment. Therefore, study to explore new drug targets and effective intervention has important scientific significance and clinical applications. Previous studies have shown that the transcription factor YY1 has a dual function in inhibition and activation of transcription, which plays a key role in tumor development and is expected to be a potential target for cancer therapy. Nevertheless, whether YY1 has any effect on the inflammation process of RA, remains unknown. Our previous study has shown that YY1 was high-expressed in RA, however, whether this high-expression of YY1 was involved in the pathogenesis of RA, and if so, what is the mechanism, needs further study. The project intends to determine the expression of YY1 in RA patients and CIA mice firstly, further to prepare YY1 overexpression and RNA interference lentivirus to observe its effect on the incidence of CIA mice, finally, to explore the immunological mechanism of YY1 by promoting Th17 differentiation via IL-6 in the pathogenesis of RA. The findings of the study are expected to clarify the role of YY1 in the pathogenesis of RA, which may not only help to add a new layer into the pathogenesis of RA, but also providing theoretical and experimental basis for targeting YY1 in RA treatment.

类风湿性关节炎（Rheumatoid Arthritis RA）是一种慢性自身免疫性疾病，其发病机制尚不明确。探索其发病机制，寻找新的药物靶点并进行有效干预具有重要的科学意义和临床应用价值。以往研究表明转录因子YY1具有激活和抑制转录的双重功能，在肿瘤发生发展中起关键作用，是一个潜在的肿瘤治疗靶标。而目前尚未见关于YY1在RA中的报道。本研究前期结果表明 YY1在RA中高表达，它是否参与RA发病，其机制又是如何，尚待研究。本课题拟首先检测YY1在RA病人和CIA（collagen-induced arthritis）小鼠中的表达情况；进一步制备YY1过表达和RNA干扰慢病毒，观察其对CIA小鼠发病的影响；最后探讨YY1通过IL-6促进Th17细胞分化介导RA发病的免疫学机制。研究结果有望阐明YY1在RA发病中的作用，有助于拓展RA的发病机制，为临床靶向YY1治疗RA提供理论依据和实验基础。

类风湿关节炎（Rheumatoid Arthritis, RA）是一种慢性自身免疫性疾病，其发病机制尚不清楚。探索其发病机制，寻找新的药物靶点并进行有效干预具有重要的科学意义和临床应用价值。以往研究表明转录因子YY1具有激活和抑制转录的双重功能，在肿瘤发生发展中起关键作用，是一个潜在的肿瘤治疗靶标。而目前尚未见关于YY1在RA中的报道。我们的研究主要探讨转录因子YY1在RA发病中的作用机制。研究结果显示YY1在RA患者和CIA小鼠（RA的疾病动物模型）中表达升高。进一步，我们构建了YY1干扰慢病毒注射CIA小鼠，发现阻断YY1的作用可减缓CIA小鼠的炎症反应和关节损伤。通过信号通路分析（IPA分析），我们发现阻断YY1可抑制IL-6-JAK-STAT信号通路从而减少TH17细胞的数量，起到抑制RA炎症的作用。最后，我们发现YY1主要是通过结合在IL-6启动子区-1257 至 -1249和 -1480 至 -1472的位置，从而启动IL-6的转录表达。因此，转录因子YY1通过启动炎症因子IL-6的转录表达促进TH17细胞分化从而参与RA的炎症反应，靶向YY1可为RA的治疗提供新思路。