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

探究衰老对流感感染的影响：前列腺素 E2 的作用

• 批准号: 10543037
• 负责人: Judy Chen
• 金额: $ 3.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543037
• 关键词: Adoptive Transfer; Affect; Age; Age-Years; Aging; Alveolar Macrophages; Apoptosis; Autophagocytosis; Cell Count; Cells; Cessation of life; Complement; Critical Thinking; Cyclic AMP-Dependent Protein Kinases; Data; Development; Dinoprostone; Elderly; Environment; Epithelial Cells; Exhibits; Goals; Immune; Immune System Diseases; Immune response; Immunity; Impairment; In Vitro; Individual; Inflammation; Influenza; Interferons; Laboratories; Lead; Lipids; Lung; Lung Lavage Fluid; Measures; Mitogen-Activated Protein Kinases; Morbidity - disease rate; Mus; Natural Immunity; Pathologic; Persons; Phagocytosis; Pharmacology; Population; Production; Prostaglandin Production; Prostaglandins; Protein Isoforms; Regulation; Research; Resolution; Role; Scientist; Signal Transduction; Signaling Molecule; Source; Testing; Training; Transgenic Organisms; Viral Respiratory Tract Infection; Vulnerable Populations; WFDC2 gene; Work; age effect; age related; aged; aging population; alveolar epithelium; antagonist; anti-influenza; base; burden of illness; career; flu; in vivo; influenza infection; influenzavirus; inhibitor; insight; mortality; mouse model; negative affect; neutrophil; novel; novel therapeutics; p38 Mitogen Activated Protein Kinase; prevent; promoter; receptor; receptor expression; response; senescence; skills; targeted treatment; transcriptome sequencing

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.

项目摘要 流感不成比例地影响老年人，约80％的所有与影响力相关的死亡发生在> 65中 年龄人口年龄。随着世界平均年龄的人口继续持续 生长。因此，迫切需要了解免疫系统与年龄相关的功能障碍 为了开发针对老年人的新型抗炎性病毒（IAV）疗法。 我们实验室的先前工作表明，肺泡巨噬细胞（AM）对于宿主反应至关重要 反对IAV。此外，我们已经表明，衰老限制AM数量和解决中性粒细胞的能力 IAV感染后肺部的炎症。但是，老年肺环境中的因素 这有助于AM的这些障碍，尚未确定。我们的初步数据表明老化 导致前列腺素E2的水平升高（PGE2），一种免疫抑制脂质，在支气管肺泡中 在IAV感染之前和期间，灌洗液（BALF）。我们假设与年龄相关 PGE2的升高会损害气道内肺泡巨噬细胞的功能。我们将测试这个 通过PGE2的AMS的离体培养和通过接收器阻止PGE2信号传导的假设 对手。此外，要获得对AMS PGE2调节的全面理解，RNA-seq 分析将对从年轻小鼠和老年小鼠分离的AM进行分析，并在有或没有PGE2的情况下进行培养。 我们还计划确定与年龄相关的升高背后的主要细胞源和机制 PGE2。我们的初步数据表明，II型肺泡上皮细胞（AECII）是 PGE2和他们对PGE2的分泌随着寄主时代的增加而增加。但是，有助于 AECIIS分泌的PGE2分泌增加不明。我们假设p38的年龄增强信号，a AECII中的有丝分裂原激活蛋白激酶（MAPK）促进PGE2的产生。我们将测试这个 在原发性培养物和体内鼠模型中使用p38抑制剂的假设。此外，我们会的 利用一个转基因鼠模型，其中p38α是与注射相关的p38的主要同工型 专门删除的形式AECII。 这些研究的结果将进一步理解衰老如何影响先天免疫，并且可以 有可能为抗IAV疗法的发展提供新的靶标。重要的是，这项研究的结果可以 可能被推断到其他呼吸道病毒感染。该项目也将作为出色的培训 对于申请人朱迪·陈（Judy Chen），要获得研究和批判性思维的核心技能，以帮助她成为 成功的独立科学家。