ADHESION MOLECULES IN THE PATHOGENESIS OF MURINE RHEUMATIOD ARTHRITIS

这些调查的目的是为了阐明 炎症在类风湿关节炎中的作用，重点在于粘连 疾病发病机制中的分子。这些分子调节相互作用。 对炎症过程至关重要。类风湿滑膜显示 一些黏附分子的水平增加，它们的功能作用和 时间表达模式是未知的，尽管该信息 是抗粘连疗法发展的关键。为了进一步描绘 黏附分子在血管紧张素转换酶的启动和持续中的作用 我们建议对类风湿滑膜炎的表达进行详细的分析 小鼠关节炎模型中选择素和整合素分子的研究。在……里面 此外，我们计划使用新的击倒模型来评估对 黏附分子表达不足的疾病。四个具体目标 计划：i)通过组织学和免疫染色评估粘连 MRL-LPR/LPR小鼠自发性滑膜炎中的分子表达 作为胶原诱导的DBA/1小鼠关节炎；2)描述缺陷 在MRL-LPR/LPR小鼠的淋巴细胞迁移中，这可能反映了两者 背景基因和LPR，并可能有助于 炎症性疾病表现；3)回交MRL-LPR/LPR和 用基因敲除株DBA/1小鼠发育小鼠，在其中表达 L-选择素、E-选择素、P-选择素或α4β7整合素已被 被淘汰了。这些黏附分子表达不足对其影响的研究 滑膜炎症参数上的分子将被确定 通过组织学和免疫组织化学染色；以及4)评估 抗MRL-LPR/LPR滑膜炎表面黏附分子的单抗 小鼠和胶原蛋白诱导的关节炎。总而言之，这些实验将 有助于阐明黏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.