SDF-1/CXCR4异构复合体在关节软骨炎症损伤/干细胞修复功能平衡中的作用

项目名称： SDF-1/CXCR4异构复合体在关节软骨炎症损伤/干细胞修复功能平衡中的作用

项目编号： No.81472082

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： 陈安民

作者单位： 华中科技大学

项目金额： 61万元

中文摘要： SDF-1/CXCR4轴既能促MSCs动员、定向分化，进而修复损伤关节软骨；又能激活细胞外信号调节酶(Erk)及p38MAPK通路造成软骨损伤，这两个相反的功能如何平衡？ SDF-1具有相反作用的异构体α和β；而SDF/CXCR4复合体下游可激活G蛋白依赖转导通路和非G蛋白依赖通路。故推测：1.SDF-1的α和β异构体分别表现出软骨炎症损伤及修复作用，该区别由于活性基团的磷酸化状态不同；2.α异构体通过G蛋白依赖通路发挥软骨炎症损伤效应；β异构体通过非G蛋白依赖通路发挥干细胞修复效应。 为验证假设,1.我们采用蛋白质组学检测方法，检测SDF-1两个异构体的蛋白质二级和三级构象以及磷酸化活性基团的不同，研究α和β异构体的功能；2.分别研究α和β异构体的炎症性和趋化性的表达机制及其对MSC的趋化诱导作用；3.S/C轴调控MSCs在受损软骨部位定植的机制。为精确调控MSC分化,促软骨重建提供依据

中文关键词： 异构复合体；关节软骨；修复；炎症损伤；平衡

英文摘要： Mesenchymal stem cell (MSC) can be regulated and directed to differentiate into steady-state precartilaginous stem cells (PCSC). The MSC were anchored in specific nest, whose de-adhesion-homing-colonization is the critical factor to activate the reparation of the damaged cartilage. Stromalcell-derivedfactor-1(SDF-1)/ CXCchemokinereceptor4(CXCR4) axis is the main induced signal for MSC homing to repair the damaged cells. Meanwhile, this axis can also trigger the RC inflammatory injury. The mechanism about the regulation of the two contradictory functions and how MSC can firmly colonize to the target region is still unclear. We speculate that: (1) the phosphorylation state of the active groups between inflammatory SDF-1 and chemotactic SDF-1 is different. They can form different active groups complex with CXCR4; ②The downstream activation pathways of the two complex is different: the former can lead to the cartilage damage through the G protein-dependent signaling pathway；however, the latter can induce the cartilage reparation through the non-G-protein-dependent signaling pathway；(3) the latter also activates of MSC superficial specific affinity and adhesion molecule to realize the colonization purpose. To proof the assumptions, the project intends to adopt proteomics method to detect inflammation、secondary structure and tertiary structure of chemotactic SDF-1 protein, and phosphorylation state of active groups; to detect subsequent activation pathway of each active S/C complex; and finally to detect the active effect of this axis to MSC adhesion molecule. The research may validate the mechanism that the S/C axis can induce MSC colonization. The research will provide theoretical basis for precise regulation of MSC differentiation and promotion reconstruction of cartilage.

英文关键词： complexus;arthrodial cartilage;repair;Inflammatory injury;balance