alpha4beta1 Intergrin Signaling In Immunity And Arthritis

描述（申请人提供）：a4|整合素通过调节白细胞运输和通过其对细胞活化、增殖和存活的影响在免疫中起关键作用。因此，这些整联蛋白参与了几种慢性炎症/自身免疫性疾病如类风湿性关节炎的发病机制，并且是这些疾病的潜在治疗靶点。我们先前已经描述了α 4胞质结构域与信号衔接分子桩蛋白的直接相互作用。这种蛋白质-蛋白质相互作用对于α 4 β 1整联蛋白功能是关键的，因为这种相互作用的破坏抑制了诸如α 4 β 1依赖性细胞迁移的过程。因此，申请人假设α 4-桩蛋白相互作用是有效免疫和炎性关节炎发展所必需的。为了测试这一点，我们产生了两种独特的敲入小鼠品系;一种在α 4基因中具有导致α 4-桩蛋白相互作用破坏的选择性突变（Y 991 A），第二种具有导致桩蛋白与α 4整联蛋白亚基组成型结合的突变（S988 A）。我们将使用从这些小鼠中分离的免疫细胞以及通过这些小鼠的直接免疫攻击来测试这些突变对适应性免疫的影响。我们还将检验α 4-桩蛋白相互作用是单核白细胞有效运输到炎症部位所必需的假设。此外，我们将通过检查这些小鼠实验性关节炎的发展来检验α 4-桩蛋白相互作用参与关节炎发病机制的假设。总的来说，这项工作将提供深入了解ct 4-桩蛋白相互作用在炎症和免疫中的作用，以及这种相互作用是否是关节炎的潜在真正治疗靶点。

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.