Gαq在急性非感染性炎症中的作用与机制

项目名称： Gαq在急性非感染性炎症中的作用与机制

项目编号： No.81471534

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 石桂秀

作者单位： 厦门大学

项目金额： 80万元

中文摘要： 急性痛风是由尿酸钠单晶体（MSU）在关节腔内激活单核巨噬细胞和中性粒细胞并产生大量炎症因子，尤其是IL-1β，并造成单核巨噬细胞和中性粒细胞在炎症关节局部大量聚集而引起的急性炎症。故，单核巨噬细胞和中性粒细胞是急性痛风发生的关键炎症细胞。Gαq是由Gnaq基因编码的Gq蛋白的α功能亚单位，广泛表达于各种组织器官中。我们前期研究发现Gαq调控非特异性免疫细胞树突状细胞和中性粒细胞的迁移。预实验中发现痛风患者外周血PBMC中Gαq表达增高且Gαq的表达与IL-1β的表达呈正相关；Gαq基因敲除小鼠脾细胞IL-1β和TNF-α表达显著降低。我们推测，Gαq通过调控单核巨噬细胞和中性粒细胞的迁移和炎症因子的表达参与了痛风的发病。本研究将应用Gnaq-/-小鼠，结合痛风患者外周血，从疾病、细胞、动物三方面详细研究Gαq参与痛风发病的机制，并进一步探讨其作为痛风新治疗靶点的可能性。

中文关键词： 痛风；中性粒细胞；单核细胞；尿酸钠；G蛋白

英文摘要： Gout is an autoinflammatory disorder associated with deposition of monosodium urate (MSU) crystals in joints and periarticular tissues. Studies indicated that the responses of human neutrophils and monocytes to MSU crystals represent an integral part of this innate response and a key component of the acute in?ammatory response associated with gout. The proinflammatory factor Interleukin-1beta (IL-1β) is a key pathogenic factor in Gout development. Gαq, the alpha submit of Gq protein, encoded by GNAQ, is ubiquitously expressed in mammalians. Gq transduces many external signals into the cell, and controls many biological functions. Recent studies demonstrated the function and important roles of Gαq in the immune regulation and autoimmunity. Our previous data indicated that Gαq deficient neutrophils and dendritic cells (DCs) are defect in migration towards several chemokines. Therefore, Gαq may involve in the pathogenesis of Gout by regulating PMN and DC migration and function. To prove this hypothesis, we tested the expression of Gαq and IL-1β in PBMC from Gout patients, we have found that the expression of Gαq mRNA in the Peripheral blood mononuclear cells (PBMCs) from gout patients was significantly increased compared with that in healthy controls and the Gαq abnormal expression levels were significantly positive correlated with IL-1β. We also found that the expression of IL-1β and tumor necrosis factor alpha (TNF-α) were decreased in splenocytes of Gαq deficient mouse. Taking together, we hypothesized that Gαq is involved in the pathogenesis of gout by regulate neutrophils and monocytes chemotaxis and the expression of IL-1β. In this study, we will dissect the molecular mechnism of the neutrophils and monocytes chemotaxis in gout. Meanwhile, we will also explore the possibility of Gαq in regulating the expression of IL-1β. We intend to further reveal the mechnisms of Gαq in pathogenesis of gout and provide new clues to treat gout.

英文关键词： gout;polymorph nuclear;monocyte;monosodium urate;G protein