Interrogating the Effects of Aging on Influenza Infections: The Role of Prostaglandin E2

项目摘要 流感对老年人的影响不成比例，所有与流感相关的死亡中约80%发生在65岁以下 年龄人口。随着世界人口的平均年龄继续增加，这一问题越来越令人担忧 成长。因此，迫切需要了解与年龄相关的免疫系统功能障碍。 以开发针对老年人的新型抗流感病毒(IAV)疗法。 我们实验室以前的工作表明，肺泡巨噬细胞(AM)对宿主的反应是必不可少的 针对IAV。此外，我们已经证明，衰老限制了AM的数量和分解中性粒细胞的能力 IAV感染后肺部的炎症。然而，老年肺环境中的因素 造成AM这些损害的原因尚未确定。我们的初步数据显示，老龄化 导致支气管肺泡内前列腺素E2(PGE2)水平升高，PGE2是一种免疫抑制脂质 在IAV感染前和感染期间都要进行灌洗液(BALF)。我们假设与年龄相关的 前列腺素E_2升高会损害呼吸道内肺泡巨噬细胞的功能。我们将对此进行测试 用前列腺素E_2体外培养AM并用受体阻断体内PGE_2信号的假说 对抗者。此外，为了全面了解PGE2对AM的调控，RNA-seq 将对从幼年和老年小鼠分离的AM进行分析，并在培养过程中添加或不添加PGE2。 我们还计划确定与年龄相关的高血压背后的主要细胞来源和机制。 PGE2。我们的初步数据表明，II型肺泡上皮细胞(AECIIs)是 PGE2的分泌量随着寄主年龄的增加而增加。然而，促进经济增长的机制 AECIIs分泌PGE2的增加尚不清楚。我们假设p38，a的增龄信号 AECIIs内的丝裂原活化蛋白激酶(MAPK)促进PGE2的产生。我们将对此进行测试 在原代体外培养和体内小鼠模型中使用p38抑制剂的假说。此外，我们还将 利用转基因小鼠模型，在该模型中，与炎症相关的p38的主要亚型p38α是 特别从AECIIs中删除。 这些研究的结果将进一步加深我们对衰老如何影响先天免疫和 潜在地为抗IAV疗法的发展提供了新的靶点。重要的是，这项研究的结果可以 可能被推断为其他呼吸道病毒感染。该项目也将作为优秀的培训项目 对于申请者朱迪·陈来说，获得对研究和批判性思维至关重要的技能，帮助她成为 一个成功的、独立的科学家。

Project Summary Influenza disproportionally affects older people, with ~80% of all influenza-related deaths occurring in the >65 years of age population. This is of increasing concern as the average age of the World population continues to grow. Therefore, there is a critical need to understand the age-related dysfunctions of the immune system in order to develop novel anti-influenza virus (IAV) therapies targeted for older people. Previous work by our lab has shown that alveolar macrophages (AM) are essential for the host response against IAV. Additionally, we have shown that aging limits AM numbers and ability to resolve neutrophilic inflammation within the lungs following an IAV infection. However, factors within the aged-lung environment that contributes to these impairments of AM have yet to be identified. Our preliminary data shows that aging leads to elevated levels of prostaglandin E2 (PGE2), an immunosuppressive lipid, in the bronchial alveolar lavage fluid (BALF) both prior to and during an IAV infection. We hypothesize that the age-associated elevations of PGE2 impair the functions of alveolar macrophages within the airways. We will test this hypothesis by an ex vivo culture of AMs with PGE2 and by blocking PGE2 signaling in vivo with receptor antagonists. Additionally, to obtain a comprehensive understanding of PGE2 regulation on AMs, RNA-seq analysis will be performed on AMs isolated from young and aged mice and cultured with or without PGE2. We also plan on identifying the main cellular sources and mechanisms behind the age-associated elevation of PGE2. Our preliminary data suggests that type II alveolar epithelial cells (AECIIs) are the primary producers of PGE2 and that their secretion of PGE2 increases with host age. However, the mechanisms contributing to the increased PGE2 secretion by AECIIs are unidentified. We hypothesize that age-enhanced signaling of p38, a mitogen-activated protein kinase (MAPK), within AECIIs promotes PGE2 production. We will test this hypothesis using p38 inhibitors in both primary ex vivo cultures and in vivo murine models. Additionally, we will utilize a transgenic murine model in which p38α, the primary isoform of p38 associated with inflammation, is specifically deleted form AECIIs. The results from these studies will further our understanding of how aging impacts innate immunity and can potentially provide novel targets for the development of anti-IAV therapies. Importantly, results of this study can potentially be extrapolated to other respiratory viral infections. This project will also serve as excellent training for the applicant, Judy Chen, to gain skills that are central for research and critical thinking to help her become a successful, independent scientist.