Role of Ezrin in Macrophages

Ezrin 在巨噬细胞中的作用

• 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
• 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

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。他们 因此，它们是包括肺部在内的组织健康的守门人。肺组织驻留 MΦ (TR-MΦ) 是 间质和肺泡 MΦ，它们具有互补但不同的功能。为了应对感染，肺部 迅速被 Ly6C+ 循环单核细胞波所填充。这些单核细胞与 TR-MΦ 协同作战 感染，然后促进炎症反应的解决。许多慢性肺部炎症 包括囊性纤维化 (CF) 在内的疾病与 MΦ 功能失调有关。我们的长期目标是 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林的特征 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皮质肌动蛋白 响应炎症/感染刺激的组织和信号转导事件。这些细胞 变化使得 MΦ 得以传播、移动、吞噬和生存，从而塑造了 肺部对感染的免疫反应。这些研究的基本原理是发现埃兹蛋白水平较低 来自 CF 患者的 MΦ（我们的工作）。其他研究人员也报告了血细胞中埃兹蛋白水平较低 来自哮喘患者。因此，通过阐明埃兹蛋白塑造肺 MΦ 的分子机制 功能，我们可以确定肺部疾病的潜在治疗靶点。我们的具体目标将测试以下内容 假设：（目标 1）ezrin 是驱动 MΦ 粘附到肺细胞外基质的信号传导所必需的 并根据 LPS 进行区分； （目标 2）埃兹蛋白是葡萄球菌有效吞噬作用所必需的 金黄色葡萄球菌和铜绿假单胞菌，CF 患者未能有效根除体内的两种微生物 肺； （目标 3）获得的“细胞埃兹蛋白低态”失活 CF MΦ 是其不受控制的免疫的核心 信号传导和吞噬作用减少。这项贡献意义重大，因为人们对埃兹林的作用知之甚少。 调节肺 MΦ 激活。我们提出的研究是创新的，因为我们将使用前所未有的 单核细胞和 MΦ 中的埃兹蛋白被敲除的小鼠模型。因此，拟议的研究将调查 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。