Impact of Heightened UPR Activation on Inflammasome Responses to Influenza and Secondary Streptococcus pneumoniae Infection in Aged Lung

UPR 激活增强对老年肺中流感和继发性肺炎链球菌感染炎症反应的影响

• 批准号: 10161896
• 负责人: Heather Winona Stout Delgado
• 金额: $ 37.29万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161896
• 关键词: Adult; Adult Respiratory Distress Syndrome; Age; Age-Months; Age-Years; Alveolar; COVID-19; Cell Death; Cell Survival; Cell physiology; Cells; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Clinical; Complex; Coronavirus; Coronavirus Infections; Critical Care; Development; Diffuse; Disease; Disease Progression; Elderly; Epithelial Cells; Equilibrium; Fatty Acids; Histology; Homeostasis; IL7 gene; Immune; Immune response; Immunomodulators; Impairment; Inbred BALB C Mice; Infection; Infiltration; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Influenza; Injury; Innate Immune Response; Interstitial Pneumonia; Knowledge; Link; Lipids; Lipoproteins; Liquid substance; Location; Lung; Lung diseases; Medical; Metabolic; Mitochondria; Modeling; Molecular; Mononuclear; Morbidity - disease rate; Organelles; Outcome; Oxidative Stress; Parents; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Phospholipids; Play; Pneumococcal Infections; Pneumonia; Predisposition; Production; Pulmonary Inflammation; Pulmonary Surfactants; Recommendation; Reducing Agents; Regulatory Pathway; Research Proposals; Role; Signal Transduction; Stimulus; Stress; Structure of parenchyma of lung; Surface; Surface Tension; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; Viral; Virulence; Virus Diseases; Work; aged; alveolar epithelium; base; cell type; coronavirus disease; cytokine; design; endoplasmic reticulum stress; experimental study; human old age (65+); immune activation; immunopathology; immunoregulation; improved; influenza infection; innovation; lipid metabolism; lung development; lung injury; macrophage; mitochondrial dysfunction; mortality; mouse model; novel coronavirus; pandemic disease; prevent; recruit; repaired; response; self-renewal; stem cells; tauroursodeoxycholic acid; therapy design; tissue injury; young adult

Project Summary While influenza and pneumococcal infections are historically responsible for significant morbidity and mortality, a pandemic of respiratory disease by a novel coronavirus (SARS-CoV-2), resulting in the development of coronavirus disease 2019 (COVID-19), has been shown to develop in severe illness, with the highest morbidity and mortality occurring in older persons (> 65 years of age). We believe that the experiments in this Competitive Revision will expand upon our current findings in the influenza model and will provide a deeper understanding into how molecular and cellular pathways in the aged lung contribute to coronavirus pathogenesis. Based upon our preliminary findings gained by our parent R01, we hypothesize that dysregulated immune activation, in response to increased mitochondrial dysfunction and ROS production, results in overzealous pro-inflammatory signaling in response to an infectious viral agent, such as influenza or coronavirus. By establishing and dissecting a pivotal mechanistic link between cellular response pathways and inflammatory signaling in aged lung during viral infection, this research proposal has high potential to elucidate innovative regulatory pathways, expand our current understanding of age associated changes in mitochondrial homeostasis, and devise therapeutic strategies to improve morbidity and mortality in response to pathogenic stimuli. We are currently requesting two years of support to complete all of the experiments detailed in the Competitive Revision: Year 1 will focus on completion of Specific Aim 1 and Year 2 will focus on completion of Specific Aim 2. Summary and impact: Improve our understanding the balance between beneficial and harmful inflammation. It has been well established that inflammatory responses are tightly regulated, however the balance between harmful and beneficial responses to coronavirus has not been fully elucidated. Work entailed in the current proposal will examine the impact of location and magnitude of inflammatory cell infiltration and cytokine production on the development of pneumonia and ARDS in aged lung in response to coronavirus. Highlight similarities and differences between influenza and coronavirus, with a focus on the role of a pro-inflammatory immune response on disease pathogenesis in aged lung. At present, very little is known regarding the similarities and differences in pathogenesis of influenza and coronavirus. Heightened pro- inflammatory host immune responses, rather than viral virulence, can contribute to multi-organ tissue pathologies occurring in response to CRS. This work will allow us to examine the initiation and progression of immune responses in the aged lung during coronavirus infection and identify similarities and differences in host responsiveness to influenza (work on influenza is described in the Parent R01).

项目摘要 尽管流感和肺炎球菌感染历史上是显着发病率和死亡率的原因，但 新型冠状病毒（SARS-COV-2）大流行，导致发展 冠状病毒疾病2019（Covid-19）已显示出在严重疾病中发育，发病率最高 老年人（> 65岁）发生死亡率。我们相信这种竞争性的实验 修订将扩大我们当前在流感模型中的发现，并将提供更深入的理解 进入年龄肺中的分子和细胞途径如何有助于冠状病毒发病机理。基于 我们的父母R01获得的初步发现，我们假设免疫激活失调，在 对线粒体功能障碍和ROS产生的响应，导致过度热心炎症性 响应感染性病毒剂的信号，例如流感或冠状病毒。通过建立和解剖 细胞反应途径与年龄肺的炎症信号传导之间的关键机理联系 病毒感染，该研究提案具有阐明创新的监管途径的高潜力，扩大了我们的 当前对年龄相关的线粒体稳态变化的理解，并设计治疗 响应致病性刺激的发病率和死亡率的策略。我们目前正在要求两个 多年的支持以完成竞争性修订中详细列出的所有实验：第一年将重点关注 完成特定目标1和2年的完成将集中于完成特定目标2。 摘要和影响：提高我们的理解有益与有害之间的平衡 炎。已经很好地确定炎症反应受到严格调节，但是 对冠状病毒的有害和有益反应之间的平衡尚未完全阐明。工作需要 在当前的建议中，将检查炎症细胞浸润的位置和大小的影响 对冠状病毒的肺炎发育和ARDS发育的细胞因子产生。 突出了流感和冠状病毒之间的相似性和差异，重点是 老年肺疾病发病机理的促炎性免疫反应。目前，很少知道 关于流感和冠状病毒的发病机理的相似性和差异。提高支持 炎症宿主免疫反应，而不是病毒毒力，可能有助于多器官组织病理 响应CRS。这项工作将使我们能够检查免疫的启动和进展 冠状病毒感染期间老年肺的反应，并确定宿主的相似性和差异 对流感的反应（在父r01中描述了流感的作品）。