The Multi-Cellular Basis of Urate-induced Arthropathies

这一应用的长期目标是定义和理解尿酸盐晶体诱导的细胞基础。 关节病，特别是确定参与这两种疾病的不同细胞类型的贡献 尿酸盐结晶所致关节病的急慢性表现。 而中性粒细胞和单核/巨噬细胞对MSU晶体的反应性也得到了很好的评价 (尽管它们的分子基础仍有待充分表征)，其他免疫细胞和 从骨细胞到尿酸盐晶体的研究要么被低估了，要么直到最近才被 被认可了。 本申请的具体目的是用分子术语定义激活的机制 尿酸盐结晶引起的人中性粒细胞与急性痛风发作症状的发生 研究尿酸盐晶体对免疫应答的调节及其在建立免疫系统中的作用 和3/定义尿酸盐晶体与骨细胞的相互作用，以提供基础 慢性痛风时出现的衰弱的、特征性的骨损害。 这项申请中提出的实验将利用最先进的技术来检查 中性粒细胞、T、B淋巴细胞、树突状细胞、成骨细胞和破骨细胞对尿酸盐的反应 水晶。这将包括细胞生物学、基因组学、蛋白质组学和免疫学等。 接近了。 这些研究将提供迫切需要的、目前缺失的信息，用于制定 理性认识尿酸盐结晶所致关节病变。研究结果将进一步加深我们对 各种炎症反应的基础，因此也潜在地提供了关于其 治疗性对照。

The long term aims of this application are to define and understand the cellular basis of urate crystal-induced arthropathy and, in particular, to determine the contributions of the different cell types that participate in both the acute and the chronic manifestations of urate crystal-induced arthropathy. While the responsiveness of neutrophils and monocyte/macrophagesto MSU crystals are well-appreciated (even though their molecular basis remains to be adequately characterized), that of other immune cells and of bone cells to urate crystals have been either under-appreciated or have only very recently been recognized. The specific aims of this application are 1/to define in molecular terms the mechanisms of activation of human neutrophils by urate crystals and the generation of the symptoms of acute gout attacks, 21 to investigate the modulation of the immune responses by urate crystals and its role in the establishment of chronic gout, and 3/ to define the interactions of urate crystals with bone cells in order to provide a basis for the debilitating and characteristic bone lesions occuring in chronic gout. The experiments proposed in this application will take advantage of state-of-the-art technologies to examine the responses of neutrophils, T and B lymphocytes, dendritic cells, osteoblasts and osteoclasts to urate crystals. This will include, among others, cell-biological, genomics, proteomics and immunological approaches. These studies will provide critically required, and presently missing, information for the development of a rational understanding of urate crystal-induced arthropathies. The results will further our understanding of the basis of various inflammatory reactions, and therefore also potentially provide innovative clues as to their therapeutic control.