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: 10228859
• 负责人: Judy Chen
• 金额: $ 3.82万
• 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/10228859
• 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; 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; 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; anti-influenza; base; burden of illness; career; flu; in vivo; influenza infection; influenzavirus; inhibitor/antagonist; 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.

项目总结