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和
死亡率,迫切需要研究这些损伤背后的分子途径,并设计
可以刺激这一人群的先天免疫反应的新疗法。我们的结果表明
老年宿主炎性小体激活受损,几个关键成分基因表达减少
NLRP3信号通路,降低caspase-1活性,减少IL-1β的产生
肺炎链球菌的体外和体内感染。利用肺炎链球菌体外和体内衰老小鼠模型
感染,我们将使用细胞和分子技术来测试我们的总体假设,即NLRP3
炎性小体是预防肺炎链球菌和年龄相关性ER和
线粒体钙稳态导致老年肺组织NLRP3炎症体活化受损;
从而导致老年肺部细菌致病、组织损伤和肺水肿增加。
为了验证这一假设,我们将检验内质网压力增加和未折叠蛋白质反应的影响
(UPR)对炎症体活性的影响(目标1)及衰老对维持ER钙稳态的影响
肺炎链球菌感染时老年肺组织炎性小体活性的调节(目标2)。
摘要和影响:由于肺部肺炎球菌感染仍然是发病率和死亡率的主要原因
老年人的死亡率,即使在成人常规接种疫苗的时代,也迫切需要确定
调节先天免疫反应和研究新疗法和
减少严重疾病和改善临床结果的治疗策略。尽管被确认为
调节炎症小体的因素,衰老和增龄内质网应激水平的影响
对NLRP3反应的调节,特别是对致病刺激的反应,还没有得到广泛的研究
学习。通过建立和解剖内质网应激调节和内质网应激之间的关键机制联系
肺炎链球菌感染时老年肺炎性小体信号的研究
为了阐明创新的调控途径,扩大目前对内质网年龄相关变化的理解
动态平衡。针对老年宿主先天信号缺陷的治疗策略将有助于
绕过新出现的抗药性细菌菌株,这些细菌正在继续发展,并可能被用于
针对各种致病刺激的治疗。完成本R01中提出的目标将进一步
确定NLRP3炎症体在肺炎链球菌中作为一条重要的先天信号通路的作用
感染以及产生新的治疗方法,可以很容易地在原代人类细胞中进行测试和评估
其他模型系统。
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
Impact of Aging on Oxysterol Regulation of Alveolar Macrophage Function during S. pneumoniae
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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
-
财政年份:2023
-
负责人:Heather Winona Stout Delgado
-
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:10643784
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项目类别:
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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:
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:10401901
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项目类别:
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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:
Impact of Heightened UPR Activation on Inflammasome Responses to Influenza and Secondary Streptococcus pneumoniae Infection in Aged Lung
-
批准号:10207433
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项目类别:
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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:
Impact of Heightened UPR Activation on Inflammasome Responses to Influenza and Secondary Streptococcus pneumoniae Infection in Aged Lung
-
批准号:10161896
-
项目类别:
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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:
Detection & Use of Novel Therapeutics to Stimulate NLRP3 Activity in the Elderly
-
批准号:8637399
-
项目类别:
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资助金额:$29.5万
-
财政年份:2013
-
负责人:Heather Winona Stout Delgado
-
依托单位:
Detection & Use of Novel Therapeutics to Stimulate NLRP3 Activity in the Elderly
-
批准号:8741915
-
项目类别:
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资助金额:$21.19万
-
财政年份:2013
-
负责人:Heather Winona Stout Delgado
-
依托单位:
Aging with Chronic Viral Infections and the Impact on Innate Immune Responses
-
批准号:8510540
-
项目类别:
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资助金额:$8.87万
-
财政年份:2011
-
负责人:Heather Winona Stout Delgado
-
依托单位:
Aging with Chronic Viral Infections and the Impact on Innate Immune Responses
-
批准号:8309075
-
项目类别:
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资助金额:$13.74万
-
财政年份:2011
-
负责人:Heather Winona Stout Delgado
-
依托单位:
Aging with Chronic Viral Infections and the Impact on Innate Immune Responses
-
批准号:8897929
-
项目类别:
-
资助金额:$13.74万
-
财政年份:2011
-
负责人:Heather Winona Stout Delgado
-
依托单位:
Aging with Chronic Viral Infections and the Impact on Innate Immune Responses
-
批准号:8841935
-
项目类别:
-
资助金额:$4.88万
-
财政年份:2011
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负责人:Heather Winona Stout Delgado
-
依托单位:
Aging with Chronic Viral Infections and the Impact on Innate Immune Responses
-
批准号:8699107
-
项目类别:
-
资助金额:$13.74万
-
财政年份:2011
-
负责人:Heather Winona Stout Delgado
-
依托单位:
Aging with Chronic Viral Infections and the Impact on Innate Immune Responses
-
批准号:7989516
-
项目类别:
-
资助金额:$13.74万
-
财政年份:2011
-
负责人:Heather Winona Stout Delgado
-
依托单位:
海外基金