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.
