Identification of Protein-Protein Interactions and Processing Events That Traffic and Activate the Bactericidal Pore-Forming Protein Perforin-2
Identification of Protein-Protein Interactions and Processing Events That Traffic and Activate the Bactericidal Pore-Forming Protein Perforin-2
批准号:
10195288
负责人:
GEORGE Patrick MUNSON
金额:
$19.19万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-02-18 至 2023-01-31
关键词:
AcidsAnimalsAreaBacteriaBiological AssayCellsClinicalCollaborationsCommunicable DiseasesDataDepositionDoseEGF geneEventGenetic PolymorphismHost DefenseHumanIn VitroIndividualInfectionInnate Immune SystemIntegral Membrane ProteinInvadedInvestigationKnockout MiceMediatingMedicineMembraneMicrobeMissense MutationModelingMolecularMusMycobacterium InfectionsOrangesOrganPathogenesisPatientsPatternPeptide HydrolasesPhagocytesPhagocytosisPhagolysosomePhagosomesPharmaceutical PreparationsPolymersPredispositionProcessProliferatingProteinsProteolytic ProcessingPublicationsPublishingRoleRosaniline DyesRotationSalmonellaScienceSideSiteStimulusStructural BiologistStructureTissuesTransmembrane DomainUncertaintyVDAC1 geneantimicrobialbactericidebasechronic infectionclinically significantimmune functioninfancyinnovationinsightmacrophagemicroorganismnon-tuberculosis mycobacteriapathogenpathogenic bacteriaperforin 2periplasmpolymerizationprotein protein interactionresponsetrafficking
中文摘要
吞噬溶酶体内微生物的破坏是机体的基本免疫功能
英文摘要
The destruction of microorganisms within phagolysosomes is an essential immunological function of
macrophages and other phagocytes that protects us from invading pathogens. Over the past several
years we have established that Perforin-2 (PRF2), a recently described effector of the innate immune
system, is pivotal for the destruction of phagocytosed bacteria. For example, we have published
studies demonstrating that PRF2 knockout mice succumb to infectious doses that the majority of their
wild-type littermates survive when challenged with bacterial pathogens. This is accompanied by
replication and dissemination of bacteria to deeper tissues. With cell based studies we established
bacteria that would normally be destroyed are able to replicate and persist within macrophages that
lack PRF2. It has also recently been shown that polymorphisms within human PRF2 increase an
individual's susceptibility to persistent nontuberculous mycobacterial infections. Most recently the
results of our collaboration with structural biologists were published demonstrating that PRF2
polymerizes to form rings of 16 subunits. This study also revealed that the transition from pre-pore to
pore is dependent upon low pH; such as would be encountered within acidifying phagosomes. Thus,
our investigations spanning from the atomic to experimental mice have established that PRF2
underpins an essential function of macrophages as a pore-forming protein that permeabilizes the
envelope of phagocytosed bacteria. Our working HYPOTHESIS is that PRF2-dependent killing of
bacteria is a multistep process that begins with the intracellular trafficking of PRF2 as an inactive
transmembrane (TM) protein in response to exogenous stimuli such as infection or pathogen-
associated molecular patterns. Subsequent cleavage of PRF2 from its TM domain releases it to
polymerize as a pre-pore structure on the membrane of phagocytosed bacteria. Acidification of the
maturing phagosome triggers a dramatic reorganization of PRF2 that culminates in membrane
penetrating pores through which other antimicrobials pass. Within this overall hypothesis are two
areas of uncertainty –trafficking and proteolytic processing– that are appropriate for exploratory
investigations. To redress these gaps Aim 1 will identify the protein-protein interactions that drive the
intracellular trafficking of PRF2. Aim 2 will characterize the proteolytic processing events that regulate
the activation of PRF2 within phagocytes. Significant impacts of this study will include a more
complete understanding of macrophage mediated killing of phagocytosed bacteria and the molecular
events that govern bactericidal pore formation.
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Identification of Protein-Protein Interactions and Processing Events That Traffic and Activate the Bactericidal Pore-Forming Protein Perforin-2
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批准号:10356159
-
项目类别:
-
资助金额:$23.03万
-
财政年份:2021
-
负责人:GEORGE Patrick MUNSON
-
依托单位:
Analyzing the expression and activation of Perforin-2 -a bactericidal pore-forming protein- with single domain antibodies
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批准号:10320041
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项目类别:
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资助金额:$19.19万
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财政年份:2020
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负责人:GEORGE Patrick MUNSON
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依托单位:
Killing of intracellular bacteria by Perforin-2
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批准号:8968229
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项目类别:
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资助金额:$38.38万
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财政年份:2014
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负责人:GEORGE Patrick MUNSON
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依托单位:
Killing of intracellular bacteria by Perforin-2
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批准号:9193612
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项目类别:
-
资助金额:$38.38万
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财政年份:2014
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负责人:GEORGE Patrick MUNSON
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依托单位:
Characterization of the ETEC Virulence Regulator Rns
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批准号:7011169
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项目类别:
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资助金额:$33.05万
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财政年份:2005
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负责人:GEORGE Patrick MUNSON
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依托单位:
Characterization of the ETEC Virulence Regulator Rns
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批准号:7344773
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项目类别:
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资助金额:$31.48万
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财政年份:2005
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负责人:GEORGE Patrick MUNSON
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依托单位:
Characterization of the ETEC Virulence Regulator Rns
-
批准号:7578244
-
项目类别:
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资助金额:$40.48万
-
财政年份:2005
-
负责人:GEORGE Patrick MUNSON
-
依托单位:
Characterization of the ETEC Virulence Regulator Rns
-
批准号:6924167
-
项目类别:
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资助金额:$33.85万
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财政年份:2005
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负责人:GEORGE Patrick MUNSON
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依托单位:
Characterization of the ETEC Virulence Regulator Rns
-
批准号:7169876
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项目类别:
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资助金额:$32.09万
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财政年份:2005
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负责人:GEORGE Patrick MUNSON
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依托单位:
FUNCTIONAL ANALYSIS OF RNS, A VIRULENCE REGULATOR
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批准号:6169411
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项目类别:
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资助金额:$3.92万
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财政年份:2000
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负责人:GEORGE Patrick MUNSON
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依托单位:
FUNCTIONAL ANALYSIS OF RNS, A VIRULENCE REGULATOR
-
批准号:2708392
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项目类别:
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资助金额:$2.5万
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财政年份:1999
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负责人:GEORGE Patrick MUNSON
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依托单位:
FUNCTIONAL ANALYSIS OF RNS, A VIRULENCE REGULATOR
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批准号:6077840
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资助金额:$3.67万
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财政年份:1999
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依托单位:
海外基金