alpha4beta1 Intergrin Signaling In Immunity And Arthritis

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DESCRIPTION (provided by applicant): a4|31 integrins play key roles in immunity both through regulating leukocyte trafficking and through their effects on cell activation, proliferation and survival. As such, these integrins are involved in the pathogenesis of several chronic inflammatory/ autoimmune diseases such as rheumatoid arthritis, and are potential therapeutic targets for these diseases. We have previously described the direct interaction of the a4 cytoplasmic domain with the signaling adapter molecule, paxillin. This protein-protein interaction is critical for a4 (31 integrin function as disruption of this interaction inhibits such processes as "4(31 dependent cell migration. Thus, the applicant hypothesizes that the cc4-paxillin interaction is necessary for effective immunity and the development of inflammatory arthritis. To test this, we have generated two unique strains of knock-in mice; one with a selective mutation in the oc4 gene resulting in disruption of the a4-paxillin interaction (Y991A), and the second with a mutation that results in constitutive binding of paxillin to the a4 integrin subunit (S988A). We will test the effect of such mutations on adaptive immunity using immune cells isolated from these mice as well as through direct immune challenge of these mice. We will also test the hypothesis that the a4-paxillin interaction is required for effective trafficking of mononuclear leukocytes to sites of inflammation. Furthermore, we will test the hypothesis that the a4-paxillin interaction is involved in arthritis pathogenesis by examining the development of experimental arthritis in these mice. .Collectively, this work will provide insight into the role of the ct4-paxillin interaction in inflammation and immunity, and whether this interaction is a potential bona fide therapeutic target for arthritis.