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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

基本信息

批准号：
10643784
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2024-04-30
项目状态：
已结题

项目摘要

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).

项目概要虽然流感和肺炎球菌感染历来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，导致了 2019 年冠状病毒病 (COVID-19) 已被证明会发展为严重疾病，发病率最高以及老年人（> 65 岁）的死亡率。我们相信本次竞赛中的实验修订将扩展我们目前在流感模型中的发现，并将提供更深入的理解研究衰老肺部的分子和细胞途径如何促进冠状病毒的发病机制。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，对线粒体功能障碍和 ROS 产生增加的反应，导致过度促炎响应传染性病毒因子（例如流感或冠状病毒）的信号。通过建立和剖析老年肺细胞反应途径与炎症信号之间的关键机制联系病毒感染，这项研究提案具有很大的潜力来阐明创新的监管途径，扩大我们的研究范围目前对线粒体稳态变化的年龄相关的了解，并设计治疗方法改善针对病原体刺激的发病率和死亡率的策略。我们目前正在请求两个多年的支持来完成竞争性修订版中详述的所有实验：第一年将重点关注具体目标 1 和第二年的完成将重点关注具体目标 2 的完成。总结和影响：提高我们对有益与有害之间平衡的理解炎。众所周知，炎症反应受到严格调节，但是对冠状病毒的有害反应和有益反应之间的平衡尚未完全阐明。需要工作在当前的提案中，将检查炎症细胞浸润的位置和程度的影响和细胞因子的产生对冠状病毒对老年肺部肺炎和急性呼吸窘迫综合征（ARDS）发展的影响。强调流感和冠状病毒之间的异同，重点关注流感和冠状病毒的作用促炎性免疫反应对老年肺疾病发病机制的影响。目前，人们知之甚少关于流感和冠状病毒发病机制的异同。加强亲炎症性宿主免疫反应（而不是病毒毒力）可能导致多器官组织病理学发生在对 CRS 的反应中。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化肺部的反应并确定宿主的异同对流感的反应（有关流感的工作在父 R01 中描述）。