The Multi-Cellular Basis of Urate-induced Arthropathies

描述(申请人提供)：本申请的长期目标是定义和了解尿酸盐晶体诱导的关节病的细胞基础，特别是确定参与尿酸盐晶体诱导的关节病的急性和慢性表现的不同细胞类型的贡献。 虽然中性粒细胞和单核/巨噬细胞对MSU晶体的反应性得到了很好的评价(尽管它们的分子基础仍有待充分表征)，但其他免疫细胞和骨细胞对尿酸盐晶体的反应性要么被低估，要么直到最近才被认识到。 本应用的具体目的是1/从分子水平确定尿酸盐晶体激活人中性粒细胞的机制和急性痛风发作症状的发生，21研究尿酸盐晶体对免疫反应的调节及其在慢性痛风形成中的作用，3/确定尿酸盐晶体与骨细胞的相互作用，为研究慢性痛风的衰弱和特征性骨损害提供基础。本申请中提出的实验将利用最先进的技术来检测中性粒细胞、T和B淋巴细胞、树突状细胞、成骨细胞和破骨细胞对尿酸盐晶体的反应。这将包括细胞生物学、基因组学、蛋白质组学和免疫学方法等。 这些研究将为合理理解尿酸盐晶体引起的关节病变提供迫切需要和目前缺失的信息。这些结果将进一步加深我们对各种炎症反应的基础的理解，因此也可能为它们的治疗控制提供创新的线索。

DESCRIPTION (provided by applicant): 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/macrophages to 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.