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Role of Ezrin in Macrophages

Ezrin 在巨噬细胞中的作用

基本信息

批准号：
10427446
负责人：
Emanuela Marina Bruscia
金额：
$ 63.23万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10427446
关键词：
Actin-Binding Protein Actins Adhesions Affect Alveolar Asthma Bacteria Bacterial Infections Binding Biology Blood Cells Calpain Cell Adhesion Cell membrane Cell physiology Cells Chronic Obstructive Pulmonary Disease Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Cytoskeleton Data Disease Event Extracellular Matrix Failure Functional disorder Gatekeeping Goals Health Host Defense IgG Receptors Immune System Diseases Immune response Immune signaling Impairment Individual Infection Inflammation Inflammatory Inflammatory Response Integrins Knock-out Knockout Mice Lipopolysaccharides Lung Lung diseases Lung immune response Lung infections Membrane Proteins Modeling Molecular Morbidity - disease rate Mucous body substance Mus Obstruction PI3K/AKT Pathologic Pathway interactions Phagocytes Phagocytosis Population Protein Family Pseudomonas aeruginosa Publishing Pulmonary Cystic Fibrosis Pulmonary Inflammation Reporting Research Research Personnel Resolution Respiratory Tract Infections Role Severity of illness Shapes Signal Transduction Staphylococcus aureus Stimulus Structure of parenchyma of lung Testing Tissues Work bactericide base cell cortex chronic inflammatory lung disease cystic fibrosis mouse cystic fibrosis patients ezrin fighting immune function immunoregulation improved in vivo Model innovation interstitial macrophage member microorganism moesin monocyte mortality mouse model particle pathogen radixin protein recruit response targeted treatment therapeutic target

项目摘要

PROJECT SUMMARY Macrophages (MΦs) kill microorganisms, engulf dead cells and debris, and regulate the immune response. They are thus gatekeepers of tissue health, including the lungs. The lung-tissue-resident MΦs (TR-MΦs) are the interstitial and alveolar MΦs, which have complementary but distinct functions. In response to infections, lungs are rapidly populated by waves of Ly6C+ circulating monocytes. In concert with TR-MΦs, these monocytes fight the infection, then facilitate the resolution of the inflammatory response. Many chronic lung inflammatory diseases, including cystic fibrosis (CF), are associated with dysregulated MΦ function. Our long- term goal is to understand how different lung MΦ populations contribute to lung hyper-inflammation and infection and to elucidate the biology of these distinct cell populations. The objective of this proposal is to characterize ezrin’s role in monocyte/MΦ function. Our central hypothesis is that ezrin controls monocyte/MΦ cortical actin organization and signal transduction events in response to inflammatory/infectious stimuli. These cellular changes allow the MΦs to spread, move, phagocytize, and survive, thus shaping the magnitude and quality of the lung immune response to infections. The rationale for these studies is that low ezrin levels have been found in MΦs from patients with CF (our work). Other investigators have also reported low ezrin levels in blood cells from individuals with asthma. Thus, by elucidating the molecular mechanism by which ezrin shapes lung MΦ functions, we could identify potential therapeutic targets for lung diseases. Our specific aims will test the following hypotheses: (Aim 1) ezrin is required for the signaling that drives MΦs to adhere to the lung extracellular matrix and to differentiate in response to LPS; (Aim 2) ezrin is needed for efficient phagocytosis of Staphylococcus aureus and Pseudomonas aeruginosa, two microorganisms that CF patients fail to efficiently eradicate from their lungs; (Aim 3) the acquired “cellular ezrin low-state” inactivated CF MΦs is central to their uncontrolled immune signaling and reduced phagocytosis. The contribution is significant since very little is known about ezrin’s role in regulating lung MΦ activation. Our proposed research is innovative because we will use an unprecedented mouse model in which ezrin is knocked out in monocytes and MΦs. Thus, the proposed studies will investigate in depth the consequences of ezrin loss in monocytes and MΦs during lung infection and inflammation.

项目总结