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.
Showing the most recent 10 out of 152 publications
