Defining the mechanism and functions of RIPK1-induced cell death in anti-bacterial immune defense
明确RIPK1诱导细胞死亡在抗菌免疫防御中的机制和功能
基本信息
- 批准号:10329911
- 负责人:
- 金额:$ 56.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnti-Bacterial AgentsAntibiotic ResistanceBacteriaBacterial InfectionsBiological AssayCASP1 geneCASP8 geneCaspaseCell DeathCell Death InductionCellsCessation of lifeComplexCytolysisDataDiseaseExposure toFoundationsGastroenteritisGranulomaHMGB1 geneHost DefenseImmuneImmune responseImmune signalingImmunityImmunologicsInfectionInfection ControlInflammation MediatorsInflammatoryInjectionsInterleukin-1Interleukin-18Knock-in MouseKnowledgeLeadLesionMAP Kinase GeneMAPK Signaling Pathway PathwayMediatingMicrobiologyModificationMolecularMusPasteurella pseudotuberculosisPathogenicityPathologicPathway interactionsPharmacologyPhenocopyPhosphorylationPhosphotransferasesPlaguePopulationPost-Translational Protein ProcessingProductionProtein KinaseProteinsPublishingRIPK1 geneReceptor SignalingReporterReportingResistanceRodentRoleSerineSignal PathwaySignal TransductionStimulusStructureSystemTNF geneTNFRSF1A geneTestingTherapeuticTimeTissuesToll-like receptorsTumor Necrosis Factor ReceptorVDAC1 geneVirulence FactorsVirulentY baseYersiniaYersinia infectionsYersinia pestiscell typecytokinedefined contributiongenetic regulatory proteinin vivoinsightkinase inhibitormacrophageneutrophilnext generationnovelpathogenpathogenic microbepreventpublic health relevancereceptor functionrecruitresistant strainresponse
项目摘要
Project Summary
Immune defense against bacterial infection requires signaling pathways that activate expression of
inflammatory mediators to control and clear infection. Many pathogens inhibit these signaling pathways in
order to evade host immune defenses. In particular, Yersinia injects a virulence factor, YopJ, which potently
blocks key aspects of NF-ΚB and MAPK signaling pathways. How immune defense is mediated against
pathogens that block immune signaling pathways remains poorly understood. NF-κB blockade in macrophages
exposed to bacterial PAMPs leads to cell death. Importantly, our recently published data demonstrate that
RIPK1 kinase activity is required for Yersinia-induced cell death, and that RIPK1 kinase activity is critical for
resistance to Yersinia infection and innate inflammatory cytokine production in vivo. This suggests that RIPK1-
induced death triggered by Yersinia is a key immune protective mechanism. Our new studies indicate that IKK
phosphorylates RIPK1 to limit induction of cell death by inflammatory stimuli, suggesting that Yersinia blockade
of IKK releases RIPK1 from this inhibitory effect. How RIPK1 kinase activity and cell death promote host
defense against bacterial infection is not known. Our central hypothesis is that RIPK1-mediated cell death
triggered in response to pathogen-mediated NF-κB and MAPK blockade releases pro-inflammatory signals,
such as IL-1 cytokines and intracellular alarmins that enable uninfected bystander cells to produce key
inflammatory mediators such as TNF, which control infection by pathogens that interfere with innate signaling.
This is an important problem as this pathway likely responds to many pathogens that block critical innate
immune signaling pathways and in the context of pathological stimuli that lead to RIPK1-induced cell death.
We propose three Specific Aims to address this important gap in our knowledge. First we will define the
molecular basis for how RIPK1 kinase activation occurs in response to YopJ blockade of IKK signaling, and
test the role of this pathway in anti-bacterial immune defense. Second, we will define immune responses of
infected and bystander cells, and will define the contribution of RIPK1-dependent cell death pathways to anti-
bacterial host defense in vivo. Finally, we will determine the contribution of TNF signaling by bystander cells to
antibacterial immune defense and will define the cell-type specific requirement for RIPK1- and TNFR-
dependent cell death in host immune defense against Yersinia.
项目总结
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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IGOR E BRODSKY其他文献
IGOR E BRODSKY的其他文献
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{{ truncateString('IGOR E BRODSKY', 18)}}的其他基金
Defining mechanisms of Casp1/11-independent death triggered by clinical Salmonella Enteritidis
临床肠炎沙门氏菌触发的 Casp1/11 独立死亡的定义机制
- 批准号:
10452195 - 财政年份:2022
- 资助金额:
$ 56.53万 - 项目类别:
Defining mechanisms of Casp1/11-independent death triggered by clinical Salmonella Enteritidis
临床肠炎沙门氏菌触发的 Casp1/11 独立死亡的定义机制
- 批准号:
10580079 - 财政年份:2022
- 资助金额:
$ 56.53万 - 项目类别:
Defining the mechanism and functions of RIPK1-induced cell death in anti-bacterial immune defense
明确RIPK1诱导细胞死亡在抗菌免疫防御中的机制和功能
- 批准号:
10092916 - 财政年份:2019
- 资助金额:
$ 56.53万 - 项目类别:
Defining the mechanism and functions of RIPK1-induced cell death in anti-bacterial immune defense
明确RIPK1诱导细胞死亡在抗菌免疫防御中的机制和功能
- 批准号:
10557104 - 财政年份:2019
- 资助金额:
$ 56.53万 - 项目类别:
Defining the non-apoptotic role of Caspase-8 activity in anti-bacterial immune defense
定义 Caspase-8 活性在抗菌免疫防御中的非凋亡作用
- 批准号:
9229681 - 财政年份:2017
- 资助金额:
$ 56.53万 - 项目类别:
Dissecting the mechanism of RIPK1 kinase-dependent cell death in control of Yersinia infection
剖析 RIPK1 激酶依赖性细胞死亡控制耶尔森菌感染的机制
- 批准号:
9285729 - 财政年份:2016
- 资助金额:
$ 56.53万 - 项目类别:
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