Heparan sulfate in Degenerating Joint Diseases

硫酸乙酰肝素在退行性关节疾病中的作用

• 批准号: 169358254
• 负责人: Professorin Dr. Andrea Vortkamp
• 金额: --
• 依托单位: Abteilung Entwicklungsbiologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/169358254?language=en
• 关键词: Heparan; sulfate; Degenerating; Joint; Diseases

In this project we aim to investigate the role of heparan sulfate (HS) in degenerating joint diseases. Besides their structural function, HS of the extracellular proteoglycan network regulate growth factor signaling and bind to many extracellular proteins. Investigating a mouse line, in which the HS synthesizing enzyme Ext1 can be clonally deleted in chondrocytes, we found clones of hypertrophic cells in the articular surface, indicating a function HS in maintaining the joint surface. Here we plan to introduce cartilage degenerating diseases in Ext1 deficient mice. A hypomorpic allele of Ext1 will be used to generally decrease HS levels across the articular surface. In parralel clonal deletion of Ext1 will produce cells lacking HS. We will induce osteoarthritis (OA), rheumathoid arthritis (RA) and psoriasis arthritis (PsA) using crucial ligament dissections (OA) and the transgenic mouse lines hTNFtg and TTP-/- for RA and PsA, respectively. The progression of the disease will be followed using histological and molecular methods. Care will be taken to identify alterations in inflammation, protease levels and signaling factors implicated in joint diseases. The interaction of identified proteins with HS will be analyzed biochemically. As loss Syndecan-4, a carrier of HS in chondrocytes, has been shown to protect against OA, we will investigate OA progression in Ext1;Syndecan-4 mutants and in mutants with altered patterns of sulfation.

在本项目中，我们旨在探讨硫酸肝素（HS）在退行性关节疾病中的作用。除了其结构功能外，细胞外蛋白多糖网络的HS还调节生长因子信号并与许多细胞外蛋白结合。研究了一种小鼠系，其中HS合成酶Ext1可以在软骨细胞中克隆缺失，我们在关节表面发现了肥大细胞的克隆，表明HS在维持关节表面方面具有功能。我们计划在Ext1缺陷小鼠中引入软骨退行性疾病。Ext1的低等位基因通常会降低整个关节表面的HS水平。同时，克隆性缺失Ext1会产生HS缺失的细胞。我们将利用关键韧带解剖（OA）和转基因小鼠hTNFtg和TTP-/-分别诱导骨关节炎（OA）、类风湿性关节炎（RA）和牛皮癣关节炎（PsA）。将采用组织学和分子方法跟踪疾病的进展。将注意识别炎症、蛋白酶水平和与关节疾病有关的信号因子的改变。鉴定的蛋白质与HS的相互作用将进行生化分析。由于软骨细胞中HS的载体Syndecan-4缺失已被证明对OA有保护作用，我们将研究Ext1的OA进展；Syndecan-4突变体和磺化模式改变的突变体。