Role of beta 2 integrins in macrophage fusion

β2整合素在巨噬细胞融合中的作用

基本信息

批准号：
9127306
负责人：
Tatiana P Ugarova
金额：
$ 38.63万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9127306
关键词：
Accounting Actins Adhesives Apolipoprotein E Arterial Fatty Streak Atherosclerosis Binding Biochemical Biology Blood Vessels Bone Marrow Transplantation CD18 Antigens CD47 gene Cardiovascular Diseases Cardiovascular Pathology Cathepsins Cell Surface Receptors Cells Cellular biology Cholates Chronic Complex Crossbreeding Data Disease Disease Progression Electron Microscopy Environment Enzymes Event Exhibits Family Fibrinogen Filopodia Fingers Fluorescent Antibody Technique Funding Giant Cells Goals Granuloma Health Hereditary Disease High Fat Diet Host Defense ITGAM gene ITGB2 gene Immunofluorescence Microscopy Immunoglobulins Impairment Inflammation Inflammatory Inflammatory Response Integrins Intercellular adhesion molecule 1 Knowledge Lead Leukocytes Ligand Binding Ligands Macrophage-1 Antigen Mass Spectrum Analysis Mediating Membrane Molecular Mus PTPNS1 gene Pathogenesis Pathology Peptide Hydrolases Peptide Library Play Process Property Proteins RNA Interference Reaction Recombinants Research Resolution Role Serum Specificity Structure Surface Techniques Testing Therapeutic Up-Regulation adhesion receptor base behavioral study combinatorial in vivo Model insight knock-down macrophage member mutant neutrophil novel therapeutic intervention protein protein interaction receptor response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Leukocyte integrin αMβ2 (Mac-1) plays a pivotal role in normal protective inflammatory response and pathological inflammation. It is also a potential therapeutic target in many diseases in which inflammation plays an essential role, including cardiovascular diseases. The diverse functions and activities ascribed to Mac-1 arise from its ability to bind a multitude of ligands. We have recently discovered a new function of Mac-1. In particular, we found that Mac-1 is involved in macrophage fusion, a salient feature of chronic inflammation in many diseases, including atherosclerosis and other vascular pathologies. Macrophage fusion requires a specific proinflammatory environment and leads to the formation of multinucleated giant cells (MGCs). Although MGCs have been first discovered in the middle of the 19th century in tuberculoid granuloma and since then were found in numerous inflammatory diseases, the molecular mechanisms of fusion bringing two membranes together remain unknown. In our preliminary studies we found that ICAM-1, a counter-receptor of Mac-1, also promotes macrophage fusion. However, deficiency of ICAM-1 resulted only in a partial decrease of fusion which could not be accounted for the strong impairment of fusion observed in Mac-1- deficient macrophages. These results suggested than other Mac-1 ligands are involved in fusion. We have found that MFR (macrophage fusion receptor/SIRPα), a receptor upregulated on the surface of fusing macrophage, interacts with Mac-1. Like ICAM-1, MFR is a member of the immunoglobulin superfamily of transmembrane receptors and one of the molecules implicated in macrophage fusion. Based on this discovery and some preliminary data, we hypothesize that Mac-1 is required for macrophage fusion during which it interacts with MFR. Specific Aim 1 is to test this hypothesis. Recombinant techniques, studies of protein-protein interactions, RNA interference, bone marrow transplantations, and combinatorial peptide libraries will be used to elucidate how Mac-1 binds MFR and clarify the role of this interaction in fusion. Specific Aim 2 will test the hypothesis that filopodia and microspikes are fusion intermediates in macrophage fusion and that Mac-1 is required for the formation of these structures. The hypothesis is based on our discovery of these hitherto unknown structures during macrophage fusion. Ultrastructural studies using high-resolution electron microscopy, confocal immunofluorescence microscopy, and TIRF will be used to characterize these fusion intermediates. Specific Aim 3 is to test the hypothesis that MGCs, which secrete potent elastolytic enzymes, contribute to the progression of atherosclerosis. The formation of MGCs in atherosclerotic plaques and the role of Mac-1 will be examined in ApoE-/- and LDLR-/- mice and the mice crossbred with Mac-1. Overall, these studies will lead to an increased understanding of the molecular mechanisms of macrophage fusion, identify previously unconsidered structures involved in the fusion of two membranes, give new insights into the biology of Mac-1, and potentially reveal unsuspected therapeutic targets.

描述（由申请人证明）：白细胞整合蛋白αMβ2（MAC-1）起着炎症的炎症作用，炎症的潜在治疗靶点。绑定的能力。我们最近发现了一个新功能Mac-1。多核细胞（MGC）。这些结果比其他MAC-1配体涉及基础。跨膜受体和巨噬细胞融合中的一个分子的特异性目标是测试这种假设。 MFR并阐明了ii n的作用 f融合。 MAC-1的作用将在APOE - / - 小鼠中进行检查，而S MAC-1的小鼠将导致对巨噬细胞融合的分子机制的理解，在两个膜的融合中进行了新的结构。对Mac-1 y Revel未经引起的治疗靶标的生物学的见解。