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 虽然流感和肺炎球菌感染在历史上是造成重大发病率和死亡率的原因， 新型冠状病毒（SARS-CoV-2）引起的呼吸道疾病大流行，导致 2019冠状病毒病（COVID-19）已被证明在严重疾病中发展，发病率最高 和老年人（> 65岁）的死亡率。我们相信，在这个竞争性的实验， 修订将扩大我们目前在流感模型中的发现， 研究老年肺部的分子和细胞途径如何影响冠状病毒的发病机制。基于 我们从亲本R 01获得的初步发现，我们假设免疫激活失调， 对线粒体功能障碍和ROS产生增加的反应，导致过度的促炎性反应。 在一些实施方案中，所述方法包括响应于感染性病毒因子（例如流感或冠状病毒）的信号传导。通过建立和解剖 老年肺中细胞反应途径和炎症信号传导之间的关键机制联系 病毒感染，这项研究提案具有很高的潜力，以阐明创新的调控途径，扩大我们的 目前的理解年龄相关的变化，线粒体稳态，并制定治疗 提高发病率和死亡率的战略，以应对致病刺激。我们现在需要两个 年的支持，以完成竞争修订版中详细说明的所有实验：第1年将重点关注 完成具体目标1和第2年将侧重于完成具体目标2。 总结和影响：提高我们对有益和有害之间平衡的理解 炎症已经确定炎症反应受到严格调控，然而， 对冠状病毒的有害和有益反应之间的平衡尚未完全阐明。工作量 在目前的提案中，将检查炎症细胞浸润的位置和程度的影响， 细胞因子的产生对冠状病毒感染老年人肺炎和ARDS的影响 强调流感和冠状病毒之间的相似性和差异，重点是a 促炎性免疫反应在老年肺疾病发病机制中的作用目前，人们所知甚少 关于流感和冠状病毒发病机制的异同。更高的亲- 炎症性宿主免疫应答，而不是病毒毒力，可导致多器官组织病理学 这是对CRS的回应。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 对流感的反应性（关于流感的工作描述见父R 01）。