The theme of this grant is identification and therapeutic modulation of pathogenic mechanisms in rheumatoid arthritis (RA). This proposal is a competitive renewal of application AR39162, Specialized Center of Research in Rheumatoid Arthritis at Duke University. Project 1 will be led by Dr. Barton Haynes, and focuses on the study of mechanisms of leukocyte homing and cell activation in the rheumatoid synovial microenvironment. This work centers on studies of the function of the transmembrane hyaluronate receptor (CD44) family of molecules, that mediate diverse functions, such as immune cell adhesion, motility and immune cell cytokine release. Using deletion mutants of forms of the CD44 gene transfected into CD44- cells, using a model of human RA synovium grown in vivo in SCID mice, and by developing monoclonal antibodies and oligonucleotide probes that will selectively identify isoforms of CD44, Project 1 will define the roles that the CD44 family of molecules play in inflammation in RA, and seek novel ways to interrupt the inflammatory cascade by inhibition of CD44 function. Project 2 is led by Drs. J. Brice Weinberg and Charles Greenberg. Extravascular coagulation/fibrinolysis represents a target for therapeutic intervention in RA, and is the focus of Project 2. Studies will determine if purified components of the coagulation system such as thrombin, fibrin split products, transglutaminases, and proteinase inhibitors modulate monocyte and macrophage adhesion molecule expression and effector function to determine novel sites of inhibition of the inflammatory response in RA. Project 3 is led by Dr. Michael Krangel. Dr. Krangel has described a new member of the intercrine-beta family of cytokines, called I-309. Studies proposed will determine the roles that intercrine-alpha and intercrine-beta cytokines play in the pathogenesis of RA and other types of inflammatory synovitis. Project 4 will be led by Drs. Michael F. Seldin and David S. Pisetsky. Using MRL-lpr X B6-lpr F1 backcrosses, they have found that the inheritance of the development of arthritis in MRL mice is semi-dominant. In order to identify the number of genes involved, determine the chromosomal location of the arthritis susceptibility gene(s), and determine the relationship between synovitis and functional and serologic abnormalities in MRL mice, studies will analyze backcross and/or F2 intercrosses utilizing MRL-Ipr and BY-Ipr parental strains. As part of Project 4, DNA from human families with RA will be collected and studied to determine whether RA segregates with candidate genetic loci including those suggested by MRL studies. Two core facilities are proposed, Core Facility 1, the Tissue Culture and Monoclonal Antibody Core, led by Dr. Stephen M. Denning, and the Administrative Core Facility 2, headed by Dr. Barton Haynes. Thus, this SCOR in RA proposal brings together workers studying adhesion molecules, clotting factors, cytokines and genetic factors that are central to the pathogenesis of joint inflammation in RA. Work is proposed in in vitro systems and in animal models to study new therapeutic strategies for RA based on work in Projects 1-3.
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