系统性红斑狼疮新易感基因WDFY4在B细胞发育中的作用及其致病机制研究

项目名称： 系统性红斑狼疮新易感基因WDFY4在B细胞发育中的作用及其致病机制研究

项目编号： No.81471602

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： 刘奇迹

作者单位： 山东大学

项目金额： 90万元

中文摘要： 申请者利用全基因组关联研究发现WDFY4基因是系统性红斑狼疮（SLE）的易感基因，进一步分析发现该基因在病例与对照中表达有差异，且主要在脾脏、骨髓等组织的B细胞中高表达，可能影响了细胞的自噬、增殖与凋亡，但具体的机制及其在SLE发生中的作用尚不清楚。由于其同家族基因是自噬相关基因，据此我们提出假说：WDFY4可能通过参与自噬而影响了B细胞的发育分化进而参与了SLE的发生发展。为验证此假说，申请者启动了WDFY4条件性基因敲除小鼠的构建，拟与EIIa-Cre杂交得到全身敲除小鼠，系统分析小鼠表型。与CD19-Cre小鼠杂交得到B细胞条件性敲除Wdfy4的小鼠，分析其对B细胞的自噬、发育的影响，深入揭示该基因的生物学功能。同时，将Wdfy4敲除小鼠与MRL/lpr狼疮鼠杂交，通过分析小鼠的表型，明确其在SLE发生中的作用，为理解其生物学功能及寻找新的治疗靶点提供理论依据进行积极的探索。

中文关键词： 系统性红斑狼疮；自身免疫性疾病；基因敲除小鼠；WDFY4；自噬

英文摘要： Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by pathogenic autoantibody formation, immune complex deposition, and end organ damage. A growing body of evidence supports the key role of the B cell in SLE pathogenesis. Our previous GWAS identified WDFY4 as a novel susceptibility gene of SLE. Although its function is unknown, it predominantly expressed in immune tissues such as lymph node, spleen, thymus and tonsil. Its closest paralog is WD repeat and FYVE domain containing 3 (WDFY3), which was reported to be involved in autophagy. Similar to WDFY3,WDFY4 does contain WD40 domains and a BEACH (Beige and chediak-kigashi) domain. WD40 domain is found in a number of eukaryotic proteins that over a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly, while the BEACH domains are implicated in membrane trafficking. Also, our previous results demonstrated that WDFY4 expressed highly in B cells and implicated in autophagy, cell apoptosis and proliferation. Based on these preliminary findings, we hypothesize that WDFY4 might plays an essential role in SLE pathogenesis by affecting B cell development or differentiation through involving in autophagy process. To test the hypothesis, we are constructing the conditional knock out mouse model. In vitro and in vivo studies are employed to investigate the potential role of WDFY4 in B cell behaviour and the mechanisms in SLE pathogenesis. Our proposed study might help elucidate the biological function of WDFY4 and identify the potential SLE therapy target.

英文关键词： Systemic Lupus Erythematosus;Autoimmune disease;Gene knockout;WDFY4;Autophagy