Axl受体酪氨酸激酶在系统性红斑狼疮单核/巨噬细胞极化调控中机制的研究

项目名称： Axl受体酪氨酸激酶在系统性红斑狼疮单核/巨噬细胞极化调控中机制的研究

项目编号： No.81471600

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： 苏茵

作者单位： 北京大学

项目金额： 71万元

中文摘要： 系统性红斑狼疮（SLE）是以复杂的免疫学异常为主要特征的全身性自身免疫病，其发病过程中伴有凋亡细胞清除障碍并产生多种自身抗体，最终导致多系统、多器官的免疫损伤。研究发现，Axl受体酪氨酸激酶（TK）在凋亡细胞清除、炎症因子释放以及单核/巨噬细胞活化等方面都有重要作用，但其在SLE发病中的作用及作用机制至今仍然不清。本课题将利用Axl TK基因敲除小鼠进一步探讨Axl TK对体内、外单核/巨噬细胞的极化作用及作用机制；通过质粒转染和小干扰RNA技术探讨Axl TK与其它亚家族成员间的相互调节作用；利用人CD14+单核/巨噬细胞，探讨Axl TK在SLE凋亡细胞清除以及炎症反应中的作用机制；进而从分子水平、细胞水平、动物模型三方面探讨Axl TK对SLE单核/巨噬细胞极化的调控机制，为探索SLE新的治疗靶点提供实验依据。

中文关键词： 系统性红斑狼疮；Axl受体酪氨酸激酶；单核巨噬细胞；极化；分子机制

英文摘要： Systemic Lupus Erythematosus is a systemic autoimmune disease with complex immunological abnormalities characterized by elevated levels of autoantibodies and deficient clearance of apoptotic debris leading to multiorgan involvement.Axl receptor tyrosine kinase plays an important role in promoting apoptosis,regulating release of inflammatory cytokines,and polarizing monocyte/macrophage. Mer TK and Tyro3 TK can be cross-talked and trans-activated by Axl TK,suggesting functional interaction among TAM TK family on immunological regulation.However, at present there are few studies on the interaction of Axl TK with Mer TK and Tyro3 TK.In our study, AXL TK gene knockout female mice are used to explore the polarization function of Axl TK signaling pathway on monocyte/macrophage subtypes firstly. For the interaction between Axl TK and Mer TK or Tyro3 TK, plasmid transfection and siRNA interference will be performed .Then monocyte/macrophage culturing system will be applied to studying the mechanism of Axl TK in clearance of apoptotic cells and inflammatory response of innate immune system .In summary, this study will explore the regulatory function of Axl receptor tyrosine kinase on monocyte/macrophage from molecular level, celluar level and animal level, trying to provide new evidence for selectively targeting it for SLE therapies.

英文关键词： Systemic Lupus Erythematosus;Axl receptor tyrosine kinase;Monocyte/Macrophage;polarization;Molecular mechanism