SCOR ON THE PATHOGENESIS OF RHEUMATOID ARTHRITIS

我们建议继续我们的类风湿性关节炎（RA）的SCOR调查 RA的发病机制。 目前的提案是为了 作为一个多管齐下，深入调查RA，特别强调 胶原自身免疫和关节破坏和修复的机制。 具体而言，将努力解决以下问题： 阐明II型胶原蛋白之间的分子相互作用 表位、Ia分子和T细胞受体（TcR） 在小鼠自身免疫性关节炎和耐受性的发展中;（ii） 检查存在于细胞中的活化T细胞库的克隆性， 类风湿性滑膜;（iii）信号转导机制，通过 滑膜成纤维细胞中马槟榔碱介导的花生四烯酸代谢， 这些代谢物在调节胶原酶和组织中的作用 金属蛋白酶抑制剂;（iv）结构/功能深入研究 三种金属蛋白酶（胶原酶，明胶酶， 基质溶解素），其可能关键地参与关节破坏;和（v） 胶原基因调控机制的详细研究 在成纤维细胞和转基因小鼠中表达。 支持这些 项目将是两个核心设施（分子资源和 行政），旨在提供必要的样本， 材料，合成寡核苷酸和肽，最先进的 仪器仪表和最高的技术和专业知识 以最具成本效益的方式为参与项目提供优质服务。 因此，这些方法将是临床和基础的，并且将 涵盖分子免疫学、生物化学、细胞免疫学等学科。 生物学和分子生物学，以及流变学。 本提案中所述的研究代表了 在目前的赠款期间提出的基本意见，并将 只有通过多学科和协同合作， 在这次SCOR的调查人员中发展起来的。 物理 结缔组织的资源和智力环境 位于孟菲斯的田纳西大学的研究实验室是独一无二的 有利于临床、动物和实验室的最佳性能 为成功执行SCOR项目进行必要的研究。 鉴于参与方在合作方面的出色记录， 调查人员，有充分的理由期待一个非常成功的SCOR， 将维持有利的环境，使迅速取得进展， 继续研究RA的发病机制。

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.