Role of Ezrin in Macrophages

Ezrin 在巨噬细胞中的作用

基本信息

批准号：
10202271
负责人：
Emanuela Marina Bruscia
金额：
$ 41.23万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-24 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202271
关键词：
Actin-Binding Protein Actins Adhesions Affect Alveolar Apoptosis Asthma Bacteria Binding Biology Blood Cells Cause of Death Cell Shape Cell membrane Cell physiology Cells Chlorides Chronic Clinical Complex Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Disease Event Extracellular Matrix F-Actin Filopodia Flow Cytometry Gatekeeping Gene Mutation Goals Health Human Image Immune response Impairment In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Inhalation Investigation Knock-out Knockout Mice Laboratories Lipopolysaccharides Lung Lung Inflammation Lung diseases Lung infections Macromolecular Complexes Membrane Proteins Microscopy Molecular Mus Mutate Mutation Nebulizer PI3K/AKT Phagocytes Phagocytosis Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phosphorylation Physical shape Population Production Protein Family Proteins Pseudomonas aeruginosa Publishing Pulmonary Cystic Fibrosis Regulation Regulator Genes Reporting Research Research Personnel Resolution Role Shapes Signal Transduction Spatial Distribution Staphylococcus aureus Stimulus Structure Structure of parenchyma of lung TLR4 gene Techniques Testing Tissues Work bactericide base chemical property cystic fibrosis patients cytokine ezrin fighting genetic approach immunoregulation in vitro testing in vivo in vivo evaluation inflammatory lung disease innovation interstitial macrophage member microorganism migration moesin monocyte mouse model preservation protein degradation radixin protein response small molecule targeted treatment therapeutic target three dimensional cell culture trafficking

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 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 own 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 necessary for monocyte/MΦ adaptation to the inflamed lung microenvironment; (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) functional CFTR, the gene that causes CF when mutated, is needed to preserve normal ezrin levels during MΦ activation. 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 specifically 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.

项目概要巨噬细胞 (MΦ) 杀死微生物、吞噬死亡细胞和碎片并调节免疫反应。因此，它们是组织健康（包括肺部）的看门人。肺组织驻留 MΦ（TR-MΦ）是。间质和肺泡 MΦ 在应对感染方面具有互补但不同的功能。肺部迅速充满了 Ly6C+ 循环单核细胞，这些与 TR-MΦ 相一致。单核细胞抵抗感染，然后促进许多慢性肺部炎症反应的解决。炎症性疾病，包括囊性纤维化 (CF)，与 MΦ 功能失调有关。术语目标是了解不同的肺 MΦ 群体如何导致肺部过度炎症和感染，并阐明这些不同细胞群的生物学。该提案的目的是描述埃兹蛋白在单核细胞/MΦ 功能中的作用我们的中心假设是埃兹蛋白控制单核细胞/MΦ 功能。皮质肌动蛋白组织和信号转导事件响应炎症/感染刺激。细胞变化使 MΦ 能够扩散、移动、吞噬和存活，从而塑造其大小和这些研究的基本原理是低埃兹蛋白水平影响了肺部对感染的免疫反应。在 CF 患者的 MΦ 中发现（我们自己的工作）。因此，通过阐明埃兹蛋白的分子机制。肺部形状 MΦ 功能，我们可以确定肺部疾病的潜在治疗靶点。将测试以下假设：（目标 1）ezrin 对于单核细胞/MΦ 适应发炎的肺部是必需的微环境；（目标 2）埃兹蛋白是金黄色葡萄球菌有效吞噬作用所必需的铜绿假单胞菌，CF 患者无法有效地从肺部根除的两种微生物；（目标 3）需要功能性 CFTR（突变时导致 CF 的基因）来保持正常的埃兹蛋白水平在 MΦ 激活过程中，这一贡献非常重要，因为人们对 ezrin 的调节作用知之甚少。我们提出的研究具有创新性，因为我们将使用前所未有的小鼠模型。其中 ezrin 在单核细胞和 MΦ 中被特异性敲除，因此，拟议的研究将在以下方面进行研究。深入了解肺部感染和炎症期间单核细胞和 MΦ 中埃兹蛋白丢失的后果。