We propose to continue our SCOR on rheumatoid arthritis (RA) to investigate the pathogenetic mechanisms of RA. The current proposal has been designed as a multipronged, in-depth investigation of RA with special emphasis on collagen autoimmunity and the mechanisms of joint destruction and repair. Specifically, efforts will be directed at the following issues: (i) elucidation of the molecular interactions among the type II collagen epitope(s), the Ia molecule and the T cell receptor (TcR) that are involved in the development of autoimmune arthritis and tolerance in mice; (ii) examination of clonality of the activated T cell repertoire present in the rheumatoid synovium; (iii) the mechanisms of signal transduction via cytokine-mediated arachidonic acid metabolism in synovial fibroblasts and the role of these metabolites in the regulation of collagenase and tissue inhibitor of metalloproteases; (iv) in-depth studies of structure/function relationship of three metalloproteases (collagenase, gelatinase, and stromelysin) which may be critically involved in joint destruction; and (v) detailed studies of the mechanisms involved in regulation of collagen gene expression in fibroblasts and in transgenic mice. Supporting these projects will be two core facilities (Molecular Resources and Administrative) which are designed to provide the necessary samples, materials, synthetic oligonucleotides and peptides, the state-of-the-art instrumentation and technical and professional expertise of the highest caliber to the participating projects in the most cost-effective manner. Thus, the approaches will be both clinical and fundamental, and will encompass the disciplines of molecular immunology, biochemistry, cell biology, and molecular biology, in addition to rheumatology. The research described in this proposal represents a natural extension of the fundamental observations made during the present grant period and will be possible only through the multidisciplinary and synergistic cooperation that has developed among the investigators in this SCOR. The physical resources and the intellectual environment of the Connective Tissue Research Laboratories of the University of Tennessee, Memphis, are uniquely favorable for optimal performance of the clinical, animal and bench research necessary for the successful execution of the SCOR projects. Given the outstanding track record of collaboration by the participating investigators, there is every reason to expect a very successful SCOR that will maintain the conducive environment in which rapid progress will continue in research dealing with the pathogenesis of RA.
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