以CysLT1为靶治疗类风湿性关节炎的机制研究

Cysteinyl leukotrienes receptor 1 (CysLT1) pathways are considered to play a key role in inflammatory diseases such as asthma. But their role in rheumatoid arthritis (RA) has not been deep researched in the world. In our previous studies we found that, in RA mice, CysLT1 is up-regulated in lymph node. Montelukast targeting CysLT1, effectively reduced the disease peak severity in RA mice. So in this project we will search the correlation between CysLT1 pathways and RA by detected the receptor expression level in RA mice tissue through real time-PCR and the ligand production level through ELISA. Subsequently we will test the efficacy of antagonist targeting CysLT1 in RA mice through the clinical score and pathological examination. We will then research the variation type of cell and cytokine in RA mice after treated with antagonist. Further we will study the mechanism of CysLT1 pathways involved in RA and the target of treating RA by interfering in the CysLT1 downstream pathways and the variation cytokine production pathways.

半胱氨酸-白三烯受体(CysLT1)信号通路主要参与一些炎症性疾病如哮喘的发病，而与RA发病之间的关系尚无人探究。申请人前期研究发现，RA小鼠体内淋巴结细胞CysLT1受体表达上调，给予CysLT1受体拮抗剂孟鲁司特后RA发病减轻，提示CysLT1信号通路参与RA的发病。因此本项目拟通过实时定量-PCR技术检测RA小鼠中CysLT1受体随RA病程的表达情况，ELISA检测RA小鼠中配体CysLTs的水平变化，寻找CysLT1信号通路与RA发病的相关性。给药RA小鼠CysLT1受体拮抗剂并通过临床评分及病理组织诊断确定药物疗效。进一步通过检测给药RA小鼠细胞变化类型或细胞因子变化情况，寻找可能受影响的细胞种类及其分泌的细胞因子。最后通过干预CysLT1下游信号通路及细胞因子信号通路来寻找RA发病的相关机制及药物作用靶点。

半胱氨酸-白三烯（Cysteinyl leukotrienes ，CysLTs) 在炎症性疾病如哮喘中扮演关键角色，半胱氨酸-白三烯的拮抗剂目前主要用于抗哮喘药物。CysLTs也参与其他炎症反应。在此，课题组报道在类风湿性关节炎小鼠中，半胱氨酸-白三烯受体（CysLT1 ）在后肢及淋巴中表达上调，与对照相比，血清中半胱氨酸-白三烯水平明显升高。靶向CysLT1的临床用药，孟鲁司特，可以有效的减轻类风湿性关节炎小鼠的发病率，病情严重程度及临床评分。免疫组化及免疫荧光实验表明给药孟鲁司特后炎症细胞浸润减轻，且细胞浸润以Th17细胞减少为主。进一步研究表明半胱氨酸-白三烯信号通路并不影响病理性T辅助细胞的分化。而半胱氨酸-白三烯信号通路极可能通过增加IL-17A的分泌和IL-17A的基因表达，诱导Th17细胞浸润到参与类风湿性关节炎的发病的。这些效应可以被半胱氨酸-白三烯信号通路阻断剂药孟鲁司特抑制。课题组的研究表明CysLT1受体阻断剂可能在临床用于治疗类风湿性关节炎。