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 流感对老年人的影响很大，约80%的流感相关死亡发生在>65岁的人群中。 年人口。随着世界人口的平均年龄继续上升， 成长因此，迫切需要了解年龄相关的免疫系统功能障碍， 目的是开发针对老年人的新型抗流感病毒（IAV）疗法。 本实验室以前的工作表明，肺泡巨噬细胞（AM）对宿主反应至关重要 对抗IAV此外，我们已经表明，老化限制了AM数量和解决嗜酸性粒细胞的能力， IAV感染后肺部的炎症。然而，老年肺环境中的因素 导致这些AM损伤的因素还有待确定。我们的初步数据显示， 导致支气管肺泡中前列腺素E2（PGE 2）（一种免疫抑制脂质）水平升高 在IAV感染之前和期间，灌洗液（BALF）。我们假设与年龄相关的 PGE 2的升高损害气道内肺泡巨噬细胞的功能。我们将测试这个 通过用PGE 2离体培养AM和通过用受体阻断体内PGE 2信号传导来假设 对手。此外，为了全面了解PGE 2对AM的调控，RNA-seq 分析将在分离自年轻和年老小鼠并与或不与PGE 2一起培养的AM上进行。 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。 前列腺素E2。我们的初步数据表明，II型肺泡上皮细胞（AECII）是主要的生产者， PGE 2的分泌量随着宿主年龄的增长而增加。然而，有助于实现这一目标的机制 AECII引起的PGE 2分泌增加还没有确定。我们假设年龄增强的p38信号， AECII内的丝裂原活化蛋白激酶（MAPK）促进PGE 2产生。我们将测试这个 假设在原代离体培养物和体内鼠模型中使用p38抑制剂。此外，我们将 利用转基因小鼠模型，其中p38α，与炎症相关的p38的主要亚型， 特别删除了AECII表格。 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的理解， 潜在地为抗IAV疗法的开发提供新的靶点。重要的是，这项研究的结果可以 可能会外推到其他呼吸道病毒感染。该项目也将作为优秀的培训 申请人，朱迪陈，获得技能是研究和批判性思维的核心，以帮助她成为 一位成功的独立科学家