Macrophage Infiltration of Renal Tissue via beta-3 Integrins and Agrin

巨噬细胞通过 β-3 整合素和集聚蛋白浸润肾组织

基本信息

批准号：
7651699
负责人：
SCOTT D BLYSTONE
金额：
$ 37.68万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-16 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7651699
关键词：
Actins Adhesions Agrin Antigen-Antibody Complex Autoimmune Process Basement membrane Biological Assay Cell Adhesion Cell Adhesion Molecules Cells Complement Complex Cytoplasmic Tail Cytoskeletal Modeling Cytoskeleton Defect Disease Progression Drug Delivery Systems Ensure Event Failure Fibrosis Gatekeeping Generations Glomerulonephritis Goals Hyperglycemia Immigration Immune Immunologic Surveillance In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Integrin beta3 Integrins Kidney Kidney Diseases Knockout Mice Laboratories Leukocytes Life Ligands Lupus Mediating Methods Modeling Molecular Nephritis Organ Pathogenesis Pathway interactions Phase Phosphorylation Production Protein Isoforms Proteoglycan Recombinants Recruitment Activity Renal Tissue Renal function Research Proposals Rho-associated kinase Role Signal Transduction Signaling Molecule Site Stress Fibers Testing Therapeutic Intervention Tissues Total Internal Reflection Fluorescent Tyrosine Tyrosine Phosphorylation adhesion receptor in vivo macrophage migration novel prevent public health relevance reconstitution response rho rho GTP-Binding Proteins trafficking

项目摘要

DESCRIPTION (provided by applicant): Glomerulonephritis is most commonly an autoimmune-induced inflammatory event wherein infiltration of the kidney by macrophages results in loss of renal function due to fibrosis. The long-term goal of our laboratory is to identify the molecular switches that govern macrophage adhesion and thus regulate the inflammatory response. We previously identified tyrosine phosphorylation of 23 integrin adhesion receptors as one such switch and have demonstrated that 23 phosphorylation is necessary for macrophage adhesion to some ligands. Blockade of 23 phosphorylation results in loss of adhesion due to a failure of the actin cytoskeleton to organize into stress fibers. In this application we present evidence that this unique mechanism is required for macrophage entry into renal tissues. We hypothesize that macrophage passage through renal basement membrane is mediated by an interaction between the proteoglycan agrin and phosphorylated 23 integrins. In this application we will assess the role of 23 integrins and their phosphorylation in migration to renal tissues during experimental glomerulonephritis. We will determine whether agrin in renal basement membrane regulates macrophage infiltration by in vitro transmigration studies. We will characterize the production of macrophage podosomal adhesions and pseudopods that are required for migration into three-dimensional tissues by TIRF microscopy of living macrophages. We will biochemically determine the signaling from phosphorylated 23 that controls actin cytoskeletal reorganization in the macrophage pseudopod and podosome. Identification of mechanisms used during organ-specific macrophage immune trafficking can provide novel targets for therapeutic intervention and complement global immune-suppressive therapies. PUBLIC HEALTH RELEVANCE: r laboratory has identified a new mechanism of white blood cell adhesion to tissues. This research proposal will determine whether a particular adhesion molecule called 23 integrin, found on a subset of white blood cells, contributes to glomerulonephritis (inflammation of the kidneys). Understanding the mechanism of glomerulonephritis can provide new targets for drugs to reduce the progression of this disease.

描述（由申请人提供）：肾小球肾炎是最常见的自身免疫诱发的炎症事件，其中巨噬细胞对肾脏的浸润导致由于纤维化而导致肾功能丧失。我们实验室的长期目标是确定控制巨噬细胞粘附从而调节炎症反应的分子开关。我们之前将 23 整联蛋白粘附受体的酪氨酸磷酸化确定为此类开关之一，并证明 23 磷酸化对于巨噬细胞粘附到某些配体是必需的。由于肌动蛋白细胞骨架无法组织成应力纤维，23 磷酸化的阻断会导致粘附力丧失。在本申请中，我们提供的证据表明，这种独特的机制是巨噬细胞进入肾组织所必需的。我们假设巨噬细胞通过肾基底膜的通道是由蛋白聚糖集聚蛋白和磷酸化 23 整合素之间的相互作用介导的。在此应用中，我们将评估 23 个整合素及其磷酸化在实验性肾小球肾炎期间迁移至肾组织中的作用。我们将通过体外迁移研究确定肾基底膜中的集聚蛋白是否调节巨噬细胞浸润。我们将通过活体巨噬细胞的 TIRF 显微镜来表征巨噬细胞足体粘连和伪足的产生，这些粘连和伪足是迁移到三维组织中所需的。我们将通过生化方法确定磷酸化 23 的信号传导，该信号控制巨噬细胞伪足和足体中肌动蛋白细胞骨架的重组。识别器官特异性巨噬细胞免疫运输过程中使用的机制可以为治疗干预提供新的靶点并补充整体免疫抑制疗法。公共健康相关性：实验室已确定白细胞粘附到组织的新机制。该研究计划将确定在白细胞子集上发现的一种称为 23 整合素的特殊粘附分子是否会导致肾小球肾炎（肾脏炎症）。了解肾小球肾炎的机制可以为药物提供新的靶点，以减少该疾病的进展。