The proposed continuation of the Specialized Center of Research in Rheumatoid Arthritis at the University of Texas Southwestern Medical Center at Dallas will expand upon the initial goals of the SCOR and focus on new initiatives to understand the genetic and immunologic basis of rheumatoid arthritis. The first four years of the SCOR generated 45 publications in peer-reviewed journals and a comparable number of published abstracts of work presented at national meetings. Moreover, the information generated as part of the SCOR activities provided the ground work for the proposed projects in the continuation of the SCOR. The initial SCOR contained 6 projects of which 4 are continued in the proposed continuation. One of the original proposals generated two separate lines of work, each of which is included as a separate project in the proposed continuation. In addition, 3 new projects with principal investigators who are new to the SCOR are included in the proposed continuation. The SCOR thus will contain seven interrelated projects examining various aspects of the immunologic and genetic basis of rheumatoid arthritis. The proposed continuation of the SCOR includes work of 14 investigators who will study various aspects of the immunologic or genetic basis of rheumatoid arthritis. In project 1, Drs. J.D. Taurog and R.E. Hammer will generate transgenic rats and mice expressing the human HLA-DRw4 molecule and determine its capacity to predispose to the development of experimental arthritis. Project 2 will examine mechanisms regulating the transendothelial migration of T cells into inflammatory sites such as the rheumatoid synovium. Dr. Nancy Oppenheimer-Marks is the principal investigator of this project. In Project 3, Drs. M.C. Wacholtz, T.D. Geppert, and L.S. Davis will examine the mechanisms regulating differentiation of T cells within the rheumatoid synovium and their role in perpetuating chronic inflammation. In Project 4, Drs. Jenkins and Meek will use the polymerase chain reaction technology to examine T cell receptor variable gene usage in rheumatoid arthritis. In Project 5, Dr. Lipsky will study the clinical efficacy and mechanism of action of an extract of a Chinese herbal remedy useful in the treatment of rheumatoid arthritis and its potential to inhibit IL-2 production. In Project 6, Drs. Mueller and Karp will generate a transgenic mouse expressing T cell receptors specific for type II collagen and investigate the influence of peripheral anergy on the induction of a model of collagen induced arthritis in the mouse. Finally, in Project 7, Dr. Ward will generate soluble T cell receptors and examine their potential to compete with pathogenic T cells and mitigate collagen-induced arthritis or their usefulness as immunogens to prevent or ameliorate this model of rheumatoid arthritis. These projects should provide a comprehensive evaluation of the genetic and immunologic basis of rheumatoid arthritis and critically test many hypotheses regarding disease pathogenesis. Each of their projects is linked together intellectually and by the numerous collaborations among the various investigators of the SCOR. It is anticipated that these projects should provide considerable new insight into the immunopathogenesis of rheumatoid arthritis.
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