We propose to establish a SCOR on rheumatoid arthritis in order to investigate the pathogenesis of RA in depth with special emphasis on collagen autoimmunity and the mechanisms of joint destruction and repair. Specifically, efforts will be directed at the following issues: a) the nature of collagen autoimmunity responsible for inducing arthritis and tolerance in mice, b) the degree of autoimmunity to a variety of different joint collagens in rheumatoid arthritis, c) in depth studies of the structure function relationships of interleukin l alpha and beta to target cells in the rheumatoid joint, d) the role of matrix degrading metalloproteinases and metalloproteinase inhibitors in rheumatoid arthritis, e) an assessment of the role of IL-1, metalloproteinases and inhibitors of metalloproteinases in vivo in experimental collagen induced arthritic, and f) a detailed study of the mechanisms involved in regulation of collagen gene expression in connective tissue fibroblasts. Supporting these projects will be three core facilities (Hybridoma, Protein Chemistry and Administrative) which are designed to provide the necessary samples, materials, state-of-the-art instrumentation and technical and professional expertise of the highest caliber to the participating projects in a most cost-effective manner. Thus, the approach to be taken will be both clinical and fundamental and will encompass the disciplines of cellular and humoral immunology, biochemistry, cell biology, morphology and molecular biology in addition to rheumatology. The research described in this proposal is possible only through the interdisciplinary and synergistic cooperation that would continue to develop among the investigators in this SCOR application. The physical resources and intellectual environment of the University of Tennessee, Memphis, are uniquely favorable for optimal performance of the necessary clinical, animal and bench research necessary for the successful completion of the SCOR projects. Given the substantial past track record of collaboration by many of the participating investigators, there is every reason to predict a very successful SCOR that will further bring this group together to create a conducive environment in which to make rapid progress in research dealing with the pathogenesis of rheumatoid arthritis.
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