Impact of Heightened ER Stress on NLRP3 Activation in Aged Lung during Infection
感染期间内质网应激升高对老化肺 NLRP3 激活的影响
基本信息
- 批准号:10207384
- 负责人:
- 金额:$ 42.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Project Summary
With an aging population and pulmonary infections becoming an increasingly significant cause of morbidity and
mortality, there is an urgent need to investigate molecular pathways underlying these impairments and devise
new therapeutics that can stimulate innate immune responses within this population. Our results demonstrate
aged hosts have impaired inflammasome activation, decreased gene expression of several key components of
the NLRP3 signaling pathway, reduced caspase-1 activity, and diminished IL1β production in response to in
vitro and in vivo infection with S. pneumoniae. Using in vitro and in vivo aging murine models of S. pneumoniae
infection, we will employ cellular and molecular techniques to test our overall hypothesis that the NLRP3
inflammasome is necessary for protection against S. pneumoniae and age associated decreases in ER and
mitochondrial Ca2+ homeostasis results in impaired activation of the NLRP3 inflammasome in aged lung;
thereby, resulting in increased bacterial pathogenesis, tissue injury, and pneumonic edema in the elderly lung.
To test this hypothesis, we will examine the impact of heightened ER stress and the unfolded protein response
(UPR) on inflammasome activity (Aim 1) and the impact of aging on the maintenance of ER Ca2+ homeostasis
and subsequent modulation of inflammasome activity (Aim 2) in aged lung during S. pneumoniae infection.
Summary and impact: As pulmonary pneumococcal infections remain a substantial cause of morbidity and
mortality in the elderly, even in an era of routine adult vaccination, there is a pressing need to identify
mechanistic pathways that regulate innate immune responses and investigate novel therapeutics and
treatment strategies that reduce serious disease and improve clinical outcomes. Despite the identification of
factors that modulate the inflammasome, the impact of aging and age-enhanced levels of ER stress on the
regulation of NLRP3 responses, specifically in response to pathogenic stimuli, has not been extensively
studied. By establishing and dissecting a pivotal mechanistic link between ER stress regulation and
inflammasome signaling in aged lung during S. pneumoniae infection, this research proposal has high potential
to elucidate innovative regulatory pathways, expand current understanding of age associated changes in ER
homeostasis. Therapeutic strategies designed to target defects in innate signaling in the aged host will aid in
circumventing emergent strains of antibiotic resistant bacteria that continue to develop and may be utilized for
treatment against a wide variety of pathogenic stimuli. Completion of the aims proposed in this R01 will further
define the role of the NLRP3 inflammasome as an important innate signaling pathway during S. pneumoniae
infections as well as yield new therapeutics that can be readily tested in primary human cells and evaluated in
additional model systems.
项目摘要
随着人群和肺部感染的老龄化成为发病率和
死亡率,迫切需要研究这些障碍的基础分子途径并设计
可以刺激该人群中先天免疫反应的新理论。我们的结果证明了
老年宿主的炎性体激活受损,几个关键成分的基因表达降低
NLRP3信号通路,降低caspase-1活性并减少了IL1β的产生
体外和体内感染肺炎链球菌。使用体外和体内衰老的肺炎菌模型
感染,我们将采用细胞和分子技术来检验我们的总体假设,即NLRP3
炎症小体对于防御肺炎链球菌和与年龄相关的ER和年龄下降是必要的
线粒体Ca2+稳态导致老年肺NLRP3炎症体的激活受损;
因此,导致细菌的发病机理,组织损伤和肺炎的肺炎中的增加。
为了检验这一假设,我们将研究ER应力增强和展开的蛋白质反应的影响
(UPR)关于炎性体活动(AIM 1)和衰老对维持ER CA2+体内稳态的影响
并随后在肺炎链球菌感染期间对炎症活性的调节(AIM 2)。
摘要和影响:随着肺肺炎球菌感染仍然是发病率和
在古老的死亡率中,即使在常规成人疫苗接种时代,也有迫切需要识别
调节先天免疫调查并研究新疗法的机械途径
减少严重疾病并改善临床结果的治疗策略。尽管确定了
调节炎性体,衰老的影响以及ER应力水平对炎症的影响的因素
NLRP3响应的调节,特别是针对致病性刺激的响应,尚未广泛
Studiod。通过建立和剖析ER应力调节和
肺炎链球菌感染期间老年肺的炎性体信号传导,该研究提案具有很高的潜力
为了阐明创新的监管途径,扩展了当前对ER年龄相关变化的理解
稳态。旨在针对老年宿主先天信号的缺陷的治疗策略将有助于
规避继续发展并可能用于
针对多种致病性刺激的治疗。在此R01中提出的目标的完成将进一步
将NLRP3炎性体的作用定义为肺炎链球菌期间重要的先天信号通路
感染和产生新疗法,可以在原代人细胞中进行测试,并在
其他模型系统。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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数据更新时间:2024-06-01
Heather Winona Sto...的其他基金
Impact of Aging on Oxysterol Regulation of Alveolar Macrophage Function during S. pneumoniae
衰老对肺炎链球菌期间肺泡巨噬细胞功能的氧甾醇调节的影响
- 批准号:1073701510737015
- 财政年份:2023
- 资助金额:$ 42.38万$ 42.38万
- 项目类别:
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:1064378410643784
- 财政年份:2018
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- 项目类别:
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:1040190110401901
- 财政年份:2018
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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
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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
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Detection & Use of Novel Therapeutics to Stimulate NLRP3 Activity in the Elderly
检测
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- 财政年份:2013
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Detection & Use of Novel Therapeutics to Stimulate NLRP3 Activity in the Elderly
检测
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Aging with Chronic Viral Infections and the Impact on Innate Immune Responses
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Aging with Chronic Viral Infections and the Impact on Innate Immune Responses
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- 批准号:83090758309075
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- 资助金额:$ 42.38万$ 42.38万
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Aging with Chronic Viral Infections and the Impact on Innate Immune Responses
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