Alpha4-integrins play important roles in the trafficking of inflammatory cells that re involved in the pathogenesis of rheumatoid arthritis. This may be because alpha4-regulates cell migration, cytoskeletal organization and gene expression differentially from other integrins. Previous studies have demonstrated that paxillin is involved in the unusual biological responses mediated by the alpha4-integrins and mutations in the alpha4- tail that disrupt paxillin binding have been identified. Functional studies of these mutations indicate that the alpha4-paxillin interaction may play a critical role in integrin-mediated cell adhesion. Studies proposed in this application will introduce mutations in the alpha4 integrin cytoplasmic domain that disrupt paxillin binding into mouse alpha4 gene, and generate and characterize mice that bear these mutations. The phenotype of much mice will be analyzed and their mononuclear ells will be assessed. The functional importance of the alpha4-paxillin in primary lymphocytes and monocytes also will be evaluated. These transgenic mice should provide valuable reagents for investigating potential protective effects of disrupting the alpha4-paxillin interaction in models of human inflammatory diseases.
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