alpha4beta1 Intergrin Signaling In Immunity And Arthritis

免疫和关节炎中的 alpha4beta1 整合素信号传导

基本信息

批准号：
7211958
负责人：
David M. Rose
金额：
$ 24.01万
依托单位：
VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7211958
关键词：
A Mouse Adhesions Adoptive Transfer Antibodies Antigens Arthritis Autoimmune Diseases B-Lymphocytes Binding Blood Circulation Bone Marrow Bypass Cells Chronic Colitis Collagen Collagen Type II Condition Cytoplasmic Tail Defect Development Disease Disruption Event Experimental Arthritis Family Generations Genes Humoral Immunities Immune Immune response Immunity Immunization Immunoglobulin A Immunoglobulin G Impairment In Vitro Inbred DBA Mice Inflammation Inflammatory Integrin alpha4beta1 Integrins Knock-in Mouse Leukocyte Trafficking Leukocytes Life Lymphocyte Lymphoid Lymphoid Tissue Mediating Modeling Molecular Target Mononuclear Leukocytes Mouse Strains Mus Mutation Numbers Pathogenesis Peripheral Peritoneum Peritonitis Plasma Cells Play Population Process RPS19 gene Research Personnel Rheumatoid Arthritis Role Rosa Serum Signal Transduction Signaling Molecule Site Spleen Structure Structure of aggregated lymphoid follicle of small intestine T-Lymphocyte Techniques Testing Thioglycolates Tissues Upper arm Vascular Cell Adhesion Molecule-1 Work arthropathies base cell motility immune function in vivo insight lymph nodes migration mucosal addressin cell adhesion molecule-1 novel paxillin programs protein protein interaction research study response therapeutic target trafficking

A Mouse Adhesions Adoptive Transfer Antibodies Antigens Arthritis Autoimmune Diseases B-Lymphocytes Binding Blood Circulation Bone Marrow Bypass Cells Chronic Colitis Collagen Collagen Type II Condition Cytoplasmic Tail Defect Development Disease Disruption Event Experimental Arthritis Family Generations Genes Humoral Immunities Immune Immune response Immunity Immunization Immunoglobulin A Immunoglobulin G Impairment In Vitro Inbred DBA Mice Inflammation Inflammatory Integrin alpha4beta1 Integrins Knock-in Mouse Leukocyte Trafficking Leukocytes Life Lymphocyte Lymphoid Lymphoid Tissue Mediating Modeling Molecular Target Mononuclear Leukocytes Mouse Strains Mus Mutation Numbers Pathogenesis Peripheral Peritoneum Peritonitis Plasma Cells Play Population Process RPS19 gene Research Personnel Rheumatoid Arthritis Role Rosa Serum Signal Transduction Signaling Molecule Site Spleen Structure Structure of aggregated lymphoid follicle of small intestine T-Lymphocyte Techniques Testing Thioglycolates Tissues Upper arm Vascular Cell Adhesion Molecule-1 Work arthropathies base cell motility immune function in vivo insight lymph nodes migration mucosal addressin cell adhesion molecule-1 novel paxillin programs protein protein interaction research study response therapeutic target trafficking

展开

项目摘要

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.

描述（由申请人提供）：A4 | 31整联蛋白通过调节白细胞运输及其对细胞激活，增殖和生存的影响，在免疫中起关键作用。因此，这些整合素参与了几种慢性炎症/自身免疫性疾病（如类风湿关节炎）的发病机理，并且是这些疾病的潜在治疗靶标。我们先前已经描述了A4细胞质结构域与信号衔接子分子Paxillin的直接相互作用。这种蛋白质 - 蛋白质相互作用对于A4至关重要（31个整合蛋白起作用这种相互作用抑制了诸如“ 4（31个依赖性细胞迁移）之类的过程。因此，申请人假设CC4 - 帕西林相互作用对于有效的免疫性是必要的，对于炎症性关节炎和爆炸型造成了两种独特的群体，我们对此产生了两种独特的群体，即一种独特的突变。 A4-帕西林相互作用（Y991a），第二个与A4整联蛋白亚基的组成型结合（S988A），我们将使用这些小鼠的免疫群体以及对这些小鼠的直接挑战进行自适应。将单核白细胞运输到炎症部位。综合性，这项工作将提供有关CT4-保杉蛋白相互作用在炎症和免疫力中的作用的洞察力，以及这种相互作用是否是关节炎潜在的善意治疗靶标。