SCOR ON THE PATHOGENESIS OF RHEUMATOID ARTHRITIS

我们建议继续我们对类风湿关节炎(RA)的SCOR来研究 类风湿关节炎的发病机制。目前的提案是经过精心设计的 作为对RA的多管齐下的深入调查，特别强调 胶原蛋白自身免疫和关节破坏和修复的机制。 具体而言，将针对以下问题作出努力：(一) II型胶原分子间相互作用的研究进展 涉及的表位(S)、Ia分子和T细胞受体 在小鼠自身免疫性关节炎和耐受性的发展过程中的作用； 人外周血中活化T细胞系克隆性检测 类风湿滑膜；(Iii)信号转导机制 细胞因子介导的滑膜成纤维细胞花生四烯酸代谢 这些代谢物在胶原酶和组织调节中的作用 金属蛋白酶抑制剂；(Iv)结构/功能的深入研究 三种金属蛋白酶(胶原酶、明胶酶和明胶酶)的关系 基质分解素)，可能严重参与联合破坏；及(V) 胶原蛋白基因调控机制的详细研究 在成纤维细胞和转基因小鼠中的表达。支持这些 项目将是两个核心设施(分子资源和 行政)，其设计用于提供必要的样本， 材料、合成寡核苷酸和肽，最新进展 仪器仪表和技术专业知识的最高水平 以最具成本效益的方式对参与项目进行口径调整。 因此，这些方法既是临床的，也是基本的，并将 涵盖分子免疫学、生物化学、细胞 除了风湿学，还有生物学和分子生物学。 这项提案中描述的研究代表了 在本批款期内提出的基本意见，并将 只有通过多学科和协同合作才能实现 这是在这一SCOR的调查人员中发展起来的。体能 结缔组织的资源和智力环境 孟菲斯田纳西大学的研究实验室是独一无二的 有利于临床、动物和实验台的最佳性能 成功执行SCOR项目所需的研究。 鉴于参与者在合作方面的出色记录 调查人员，我们完全有理由期待一个非常成功的SCOR 将保持有利的环境，在这种环境中，快速进步将 继续研究类风湿关节炎的发病机制。

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.