Impact of Heightened ER Stress on NLRP3 Activation in Aged Lung during Infection
Impact of Heightened ER Stress on NLRP3 Activation in Aged Lung during Infection
批准号:
10207384
负责人:
Heather Winona Stout Delgado
金额:
$42.38万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-09-01 至 2023-05-31
关键词:
ATF6 geneAdultAgeAgingAnimal ModelBacterial Antibiotic ResistanceBiological ModelsCASP1 geneCell Culture TechniquesCellsClinicalComplexCytoprotectionDataDefectDiseaseEdemaElderlyEndoplasmic ReticulumGPRC6A geneGene ExpressionGenetic TranscriptionHomeostasisHumanIL18 geneITPR1 geneImmune responseImpairmentIn VitroInfectionInflammasomeInnate Immune ResponseInterleukin-1 betaKnowledgeLinkLungLung infectionsMaintenanceMediatingMediator of activation proteinMitochondriaMolecularMorbidity - disease rateOrganellesOutcomePathogenesisPathogenicityPathway interactionsPneumococcal InfectionsPopulationProcessProductionProtein BiosynthesisProteinsRegulationRegulatory PathwayResearch ProposalsRoleSTIM1 geneSignal PathwaySignal TransductionStimulusStreptococcus pneumoniaeStressTechniquesTestingTherapeuticTherapeutic InterventionTimeTranslationsVaccinationadaptive immune responseagedaging populationdesignendoplasmic reticulum stressimprovedin vivoinfection rateinnovationmitochondrial dysfunctionmortalitymouse modelnovel therapeuticsprogramsprotein expressionprotein functionresponsesensortherapeutic evaluationtissue injurytreatment strategy
中文摘要
项目摘要
随着人口老龄化和肺部感染成为发病率的日益重要的原因,
死亡率,迫切需要调查这些损伤的分子途径,并设计
新的疗法可以刺激这一人群的先天免疫反应。我们的研究结果表明
老年宿主炎性小体活化受损,
NLRP 3信号通路,降低caspase-1活性,减少IL-1 β的产生。
体外和体内感染S.肺炎。本研究采用体外和体内S.肺炎
感染,我们将采用细胞和分子技术来测试我们的整体假设,即NLRP 3
炎性小体是抵抗S.肺炎和年龄相关的ER减少,
线粒体Ca 2+稳态导致老年肺中NLRP 3炎性体的活化受损;
从而导致老年人肺中细菌致病性增加、组织损伤和肺水肿。
为了验证这一假设,我们将研究增强ER应激和未折叠蛋白反应的影响。
(UPR)炎症体活性(目的1)和衰老对维持ER Ca 2+稳态的影响
以及随后在S.肺炎感染。
摘要和影响:由于肺部肺炎球菌感染仍然是发病的主要原因,
老年人的死亡率,即使在常规成人疫苗接种的时代,也迫切需要确定
调节先天免疫反应的机制途径,并研究新的治疗方法,
减少严重疾病和改善临床结果的治疗策略。尽管鉴定出
调节炎性体的因素,衰老和年龄增强的ER应激水平对炎症的影响,
NLRP 3反应的调节,特别是对致病性刺激的反应,还没有被广泛研究。
研究了通过建立和解剖内质网应激调节与细胞凋亡之间的关键机制联系,
在S.肺炎感染,这项研究建议具有很高的潜力
阐明创新的调节途径,扩大目前对ER年龄相关变化的理解
体内平衡针对老年宿主先天信号传导缺陷设计的治疗策略将有助于
避免抗生素耐药细菌的出现菌株,这些菌株继续发展并可用于
针对各种致病刺激的治疗。完成本R 01中提出的目标将进一步
定义NLRP 3炎性体作为S.肺炎
感染,并产生新的治疗方法,可以很容易地在原代人类细胞中进行测试,并在
更多模型系统
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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批准号:10737015
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项目类别:
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资助金额:$65.99万
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财政年份:2023
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负责人:Heather Winona Stout Delgado
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依托单位:
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Impact of Heightened UPR Activation on Inflammasome Responses to Influenza and Secondary Streptococcus pneumoniae Infection in Aged Lung
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Impact of Heightened UPR Activation on Inflammasome Responses to Influenza and Secondary Streptococcus pneumoniae Infection in Aged Lung
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批准号:10161896
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资助金额:$37.29万
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财政年份:2018
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依托单位:
Impact of Heightened UPR Activation on Inflammasome Responses to Influenza and Secondary Streptococcus pneumoniae Infection in Aged Lung
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批准号:10207433
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资助金额:$37.29万
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财政年份:2018
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负责人:Heather Winona Stout Delgado
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依托单位:
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批准号:8637399
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项目类别:
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资助金额:$29.5万
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依托单位:
Detection & Use of Novel Therapeutics to Stimulate NLRP3 Activity in the Elderly
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资助金额:$21.19万
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财政年份:2013
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负责人:Heather Winona Stout Delgado
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依托单位:
Aging with Chronic Viral Infections and the Impact on Innate Immune Responses
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批准号:8510540
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项目类别:
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资助金额:$8.87万
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负责人:Heather Winona Stout Delgado
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依托单位:
Aging with Chronic Viral Infections and the Impact on Innate Immune Responses
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批准号:8309075
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资助金额:$13.74万
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财政年份:2011
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负责人:Heather Winona Stout Delgado
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依托单位:
Aging with Chronic Viral Infections and the Impact on Innate Immune Responses
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批准号:8897929
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项目类别:
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资助金额:$13.74万
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财政年份:2011
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负责人:Heather Winona Stout Delgado
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依托单位:
Aging with Chronic Viral Infections and the Impact on Innate Immune Responses
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资助金额:$4.88万
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依托单位:
Aging with Chronic Viral Infections and the Impact on Innate Immune Responses
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资助金额:$13.74万
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负责人:Heather Winona Stout Delgado
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依托单位:
Aging with Chronic Viral Infections and the Impact on Innate Immune Responses
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资助金额:$13.74万
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负责人:Heather Winona Stout Delgado
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依托单位:
海外基金