ADHESION MOLECULES IN THE PATHOGENESIS OF MURINE RHEUMATIOD ARTHRITIS

这些研究的目的是阐明 类风湿性关节炎的炎症，重点在粘连的作用 疾病发病机制中的分子。这些分子介导相互作用 对炎症过程至关重要而类风湿性滑膜显示 一些粘附分子水平的增加，它们的功能作用， 时间表达的模式是未知的，虽然这一信息 是抗粘连疗法发展的关键为了进一步描绘 粘附分子在启动和维持 类风湿性滑膜炎，我们提出了一个详细的分析表达 选择素和整合素分子在小鼠关节炎模型中的作用。在 此外，我们计划使用新的淘汰模型来评估对 粘附分子表达缺陷性疾病。四个具体目标 计划：i）通过组织学和免疫染色粘附评估 MRL-lpr/lpr小鼠自发性滑膜炎中的分子表达 作为DBA/1小鼠中胶原诱导的关节炎; 2）表征缺陷 在MRL-lpr/lpr小鼠淋巴细胞迁移中， 背景基因和lpr，并可能有助于倾向于 炎性疾病表现; 3）回交MRL-lpr/lpr， DBA/1小鼠与基因敲除品系的小鼠，以开发其中表达 L-选择素、E-选择素、P-选择素或α 4 β 7整联蛋白已被研究。 淘汰这些粘附分子表达不足的影响 将确定分子对滑膜炎症参数的影响 通过组织学和免疫染色;以及4）评估 抗黏附分子单克隆抗体对MRL-lpr/lpr滑膜炎的研究 小鼠和胶原诱导的关节炎。这些实验将 有助于阐明粘附分子在滑膜炎症中的作用 并确定潜在的治疗目标。

The goal of these investigations is to elucidate the mechanisms of inflammation in rheumatoid arthritis, focusing on the role of adhesion molecules in disease pathogenesis. These molecules mediate interactions critical to the inflammatory process. While rheumatoid synovium shows increased levels of some adhesion molecules, their functional role and pattern of temporal expression are not known, although this information is key to the development of anti-adhesive therapy. To delineate further the role of adhesion molecules in the initiation and perpetuation of rheumatoid synovitis, we propose a detailed analysis of the expression of selectin and integrin molecules in murine models of arthritis. In addition, we plan to use new knockout models to assess the impact on disease of deficient adhesion molecule expression. Four specific aims are planned: i) to assess by histology and immunostaining adhesion molecule expression in spontaneous synovitis in MRL-lpr/lpr mice as well as collagen-induced arthritis in DBA/1 mice; 2) to characterize a defect in lymphocyte migration in MRL-lpr/lpr mice that may reflect both background genes and lpr and may contribute to the propensity for inflammatory disease manifestations; 3) to backcross MRL-lpr/lpr and DBA/1 mice with knockout strains to develop mice in which expression of L-selectin, E-selectin, P-selectin or alpha4beta7 integrin has been eliminated. The influence of deficient expression of these adhesion molecules on parameters of inflammation in synovium will be determined by histology and immunostaining; and 4) to assess the influence of monoclonal antibodies to adhesion molecules on synovitis in MRL-lpr/lpr mice and collagen-induced arthritis. Together, these experiments will help elucidate the role of adhesion molecules in synovial inflammation and identify potential targets for therapy.