alpha4beta1 Intergrin Signaling In Immunity And Arthritis

描述(申请人提供)：A4|31整合素在免疫中发挥关键作用，既通过调节白细胞的运输，也通过它们对细胞激活、增殖和存活的影响。因此，这些整合素参与了几种慢性炎症/自身免疫性疾病的发病机制，如类风湿性关节炎，并成为这些疾病的潜在治疗靶点。我们之前已经描述了A4细胞质结构域与信号转接子分子paxlin的直接相互作用。这种蛋白质-蛋白质的相互作用对A4(31)至关重要，因为这种相互作用的中断会抑制“4(31依赖的细胞迁移”等过程。因此，申请人假设CC4-帕西林相互作用对于有效免疫和炎症性关节炎的发展是必要的。为了测试这一点，我们产生了两个独特的敲入小鼠品系；一个具有oc4基因的选择性突变，导致A4-paxlin相互作用中断(Y991A)，另一个具有突变，导致paxlin与A4整合素亚单位的结构性结合(S988A)。我们将使用从这些小鼠分离的免疫细胞以及通过直接免疫攻击这些小鼠来测试这些突变对适应性免疫的影响。我们还将测试A4-帕西林相互作用是有效地将单核白细胞运送到炎症部位所必需的假设。此外，我们将通过检测这些小鼠的实验性关节炎的发展来检验A4-paxlin相互作用参与关节炎发病机制的假设。综上所述，这项工作将深入了解CT4-paxlin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.