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。 因此，它们是包括肺部在内的组织健康的守门人。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， 肺中迅速充斥着大量Ly6C+循环单核细胞。与TR-MΦS合作，这些 单核细胞对抗感染，然后促进炎症反应的消退。很多慢性肺病 炎症性疾病，包括囊性纤维化(CF)，与MΦ功能失调有关。我们的长- 学期目标是了解不同的肺MΦ群体如何促进肺高炎症和 感染，并阐明这些不同细胞群体的生物学。这项建议的目的是 研究Ezrin在单核细胞/MΦ功能中的作用。我们的中心假设是Ezrin控制单核细胞/MΦ 炎症/感染性刺激反应中的皮质肌动蛋白组织和信号转导事件。这些 细胞的变化允许MΦS传播、移动、吞噬和存活，从而塑造了 肺部对感染的免疫反应的质量。这些研究的基本原理是，低水平的Ezrin具有 在CF患者的MΦS中发现(我们自己的工作)。其他调查人员也报告了低Ezrin 哮喘患者的血细胞水平。因此，通过阐明Ezrin的分子机制 通过对肺M-Φ功能的研究，我们可以发现肺部疾病的潜在治疗靶点。我们的具体目标 我将检验以下假设：(目标1)埃兹林是单核细胞/MΦ适应炎症肺所必需的 微环境；(目标2)埃兹林是有效吞噬金黄色葡萄球菌和 铜绿假单胞菌，两种CF患者无法有效清除的微生物； (目的3)功能性CFTR是维持正常Ezrin水平所必需的，该基因在突变时会导致CF 在MΦ激活期间。这一贡献是巨大的，因为人们对Ezrin在调节中的作用知之甚少 肺MΦ活化。我们提出的研究是创新的，因为我们将使用一种前所未有的老鼠模型 其中，Ezrin在单核细胞和MΦS中被特异性敲除。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 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.