Role of Ezrin in Macrophages

项目总结 巨噬细胞(MΦS)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，它们是组织健康的守门人，包括肺部。常驻肺组织的MΦS(tr-MΦS)是 间质和肺泡MΦS，功能互补但截然不同。作为对感染的反应，肺部 迅速被Ly6C循环中的单核细胞波所填充。在与TR-MΦS的合作中，这些单核细胞 感染，然后促进炎症反应的消退。许多慢性肺部炎症 囊性纤维化(CF)等疾病与M-Φ功能失调有关。我们的长期目标是 了解不同的肺MΦ群体如何促进肺的高炎症和感染，以及 阐明这些不同细胞群体的生物学特性。这项提议的目的是描述Ezrin的 在单核细胞/M细胞Φ功能中的作用。我们的中心假设是Ezrin控制单核细胞/MΦ皮质肌动蛋白 对炎症/感染性刺激作出反应的组织和信号转导事件。这些细胞 变化允许MΦS传播、移动、吞噬和生存，从而塑造了 肺部对感染的免疫反应。这些研究的理论基础是已经发现了低水平的Ezrin 在MΦ中，S来自CF患者(我们的工作)。其他研究人员也报告了血细胞中低水平的Ezrin 来自哮喘患者。因此，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点。我们的具体目标将检验以下几点 假设：(目的1)Ezrin是驱动MΦS与肺细胞外基质黏附的信号所必需的 (目标2)Ezrin是有效吞噬葡萄球菌所必需的 金黄色葡萄球菌和铜绿假单胞菌是CF患者未能有效清除的两种微生物 肺；(目的3)获得性“细胞ezrin低状态”失活的CFMΦS是其失控免疫的中心 信号传递和减少吞噬作用。这一贡献是巨大的，因为人们对Ezrin在 调节肺M-Φ活性。我们提出的研究具有创新性，因为我们将使用史无前例的 Ezrin在单核细胞中被敲除的小鼠模型和MΦS。因此，拟议的研究将在 深度研究肺部感染和炎症过程中单核细胞和MΦS的Ezrin丢失的后果。

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.