Role of Ezrin in Macrophages

Ezrin 在巨噬细胞中的作用

• 批准号: 10646199
• 负责人: Emanuela Marina Bruscia
• 金额: $ 61.87万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/10646199
• 关键词: Actin-Binding Protein; Actins; Adhesions; Affect; Alveolar Macrophages; 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; Macrophage; Macrophage Activation; Membrane Proteins; Modeling; Molecular; Morbidity - disease rate; Mucous body substance; Mus; Obstruction; PI3K/AKT; PIK3CG gene; Pathologic; Pathway interactions; Phagocytes; Phagocytosis; Population; Proliferating; 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; cell cortex; chronic inflammatory lung disease; cystic fibrosis mouse; cystic fibrosis patients; ezrin; fighting; immune function; immunoregulation; improved; in vivo Model; innovation; interstitial; member; microorganism; moesin; monocyte; mortality; mouse model; particle; pathogen; radixin protein; recruit; response; targeted treatment; therapeutic target

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.

项目摘要 巨噬细胞（MφS）杀死微生物，吞噬死细胞和碎屑，并调节免疫激发。他们 因此是组织健康的守门人，包括肺部。肺组织居民MφS（TR-Mφ）是 间质和牙槽Mφs，具有互补但不同的功能。响应感染，肺 由LY6C+循环单核细胞的波快速填充。这些单核细胞与TR-MφS结合 感染，然后促进炎症反应的分辨率。许多慢性肺炎症 包括囊性纤维化（CF）在内的疾病与失调的Mφ功能有关。我们的长期目标是 了解不同的肺Mφ种群如何有助于肺部超炎和感染以及 阐明这些不同细胞群体的生物学。该提议的目的是表征Ezrin的 在单核细胞/Mφ函数中的作用。我们的中心假设是，ezrin控制单核细胞/Mφ皮质肌动蛋白 响应炎症/传染性刺激的组织和信号转导事件。这些细胞 变化允许MφS扩散，移动，吞噬并生存，从而塑造了幅度和质量 对感染的肺免疫反应。这些研究的基本原理是发现了低Ezrin水平 在CF患者（我们的工作）的Mφ中。其他研究人员还报告了血细胞中的埃兹林水平较低 来自患有哮喘的人。通过阐明ezrin塑造肺Mφ的分子机制 功能，我们可以确定肺部疾病的潜在治疗靶标。我们的具体目标将测试以下 假设：（ AIM 1）驱动Mφ粘附在肺外基质的信号传导需要Ezrin是必需的 并以响应LP的方式进行区分； （AIM 2）需要Ezrin才能有效地吞噬葡萄球菌 金黄色葡萄球菌和铜绿假单胞菌，两种微生物CF患者无法有效地从他们的 肺； （AIM 3）获得的“细胞Ezrin低状态”灭活的CFMφS是其不受控制的免疫的核心 信号传导和减少吞噬作用。贡献很重要，因为对Ezrin在Ezrin中的作用知之甚少 调节肺Mφ激活。我们提出的研究具有创新性，因为我们将使用前所未有的 小鼠模型在单核细胞和Mφs中被淘汰。这是拟议的研究将在 深度在肺部感染和注射过程中单核细胞和MφS中Ezrin损失的后果。