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：
8440816
负责人：
SCOTT D BLYSTONE
金额：
$ 32.3万
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 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8440816
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 Targeting Ensure Event Failure Fibrosis Gatekeeping Generations Glomerulonephritis Goals Health 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 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.

描述（由申请人提供）：肾小球肾炎最常见的是自身免疫性诱导的炎症事件，其中巨噬细胞通过巨噬细胞浸润肾脏会导致由于纤维化而导致的肾功能丧失。我们实验室的长期目标是确定控制巨噬细胞粘附的分子开关，从而调节炎症反应。我们先前鉴定出23个整联蛋白粘附受体的酪氨酸磷酸化为一种转换，并证明23磷酸化对于巨噬细胞粘附到某些配体是必需的。封闭23磷酸化导致由于肌动蛋白细胞骨架将组织为应激纤维的失败而导致粘附丧失。在此应用中，我们提供了证据，表明这种独特的机制是进入肾脏组织的。我们假设巨噬细胞通过肾脏基底膜是由蛋白聚糖agrin和磷酸化23个整联蛋白之间的相互作用介导的。在此应用中，我们将评估在实验性肾小球肾炎期间，将23个整联蛋白及其在向肾脏组织迁移到肾脏组织中的作用。我们将确定肾脏基底膜中的Agrin是否通过体外转移研究来调节巨噬细胞浸润。我们将表征巨噬细胞上的足体粘附和伪足的产生，这些粘连和伪足，这些粘连是通过生存巨噬细胞的TIRF显微镜迁移到三维组织所必需的。我们将从生化确定磷酸化23的信号传导，该信号传导控制巨噬细胞假脚架和足体中肌动蛋白细胞骨架重组。鉴定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和补充全球免疫抑制疗法提供新的靶标。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The multiplicity of human formins: Expression patterns in cells and tissues.

DOI：
10.1002/cm.21113
发表时间：
2013-08
期刊：
CYTOSKELETON
影响因子：
2.9
作者：
Krainer, Elisabeth C.;Ouderkirk, Jessica L.;Miller, Eric W.;Miller, Matthew R.;Mersich, Akos T.;Blystone, Scott D.
通讯作者：
Blystone, Scott D.

Human Macrophages Utilize the Podosome Formin FMNL1 for Adhesion and Migration.