权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of fibroblast response to IL-1 in rheumatoid arthritis by the transmembrane heparane sulfate proteoglycan syndecan-4

跨膜硫酸乙酰肝素蛋白聚糖 syndecan-4 调节类风湿性关节炎中成纤维细胞对 IL-1 的反应

基本信息

批准号：
40956738
负责人：
Professor Dr. Thomas Pap
金额：
--
依托单位：
Institut für Muskuloskelettale Medizin
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2007
资助国家：
德国
起止时间：
2006-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/40956738?language=en
关键词：
Regulation fibroblast response IL rheumatoid

项目摘要

Fibroblast-like synoviocytes from patients with rheumatoid arthritis (RA-FLS) exhibit a stable activation that is associated with the imprinting of important pathogenic features including an altered response to extracellular signals. In the last funding period, we could show that the transmembrane heparan sulfate proteogylcan syndecan-4 (sdc4) not only is involved in the attachment of RA-FLS to cartilage, but also regulates the responsiveness of these cells to interleukin-1 (IL-1). We could demonstrate that IL-1 directly binds to sdc4 and leads to its dimerization, which is independent of the IL-1 receptor 1(IL-1R1). Strikingly, IL-1 induced dimerization of sdc4 regulates caveolin vesicle-mediated trafficking of the IL-1R. The loss of sdc4 or the inhibition of its dimerization by specific antibodies largely abolishes the surface presentation IL-1R1 on FLS in vitro and in vivo and reduces the severity of chronic destructive arthritis in mice. Based on these data, we now want to use recently generated mutants of sdc4 along with protein biochemical approaches and life cell imaging techniques to study the detailed mechanisms by which sdc4 controls IL-1R1 trafficking. In addition, we will analyse the in vivo relevance of our findings in our established animal models of RA. These data will provide new insights into inflammatory tissue remodelling in RA and contribute to the further development of our anti-sdc4 antibody strategy for the treatment of RA.

类风湿性关节炎（RA-FLS）患者的成纤维细胞样滑膜细胞表现出稳定的激活，这与重要致病特征的印记有关，包括对细胞外信号的反应改变。在最后的资助期内，我们可以证明跨膜硫酸肝素蛋白多糖syndecan-4 （sdc4）不仅参与RA-FLS与软骨的附着，而且还调节这些细胞对白细胞介素-1 （IL-1）的反应。我们可以证明IL-1直接与sdc4结合并导致其二聚化，这是独立于IL-1受体1（IL-1R1）的。引人注目的是，IL-1诱导的sdc4二聚化调节了小窝蛋白囊泡介导的IL-1R运输。在体外和体内实验中，sdc4的缺失或特异性抗体对其二聚化的抑制在很大程度上消除了FLS上IL-1R1的表面呈递，降低了小鼠慢性破坏性关节炎的严重程度。基于这些数据，我们现在希望使用最近生成的sdc4突变体以及蛋白质生化方法和生命细胞成像技术来研究sdc4控制IL-1R1运输的详细机制。此外，我们将分析我们的发现在我们建立的RA动物模型中的体内相关性。这些数据将为RA的炎症组织重塑提供新的见解，并有助于我们进一步开发抗sdc4抗体治疗RA的策略。