Pseudomonas-Macrophage IL-1β Interactions in Lung Transplant Recipients
肺移植受者中假单胞菌-巨噬细胞 IL-1β 的相互作用
基本信息
- 批准号:10606768
- 负责人:
- 金额:$ 6.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-02-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAllograftingAlveolarAlveolar MacrophagesBacteriaBioinformaticsBronchoalveolar LavageCASP1 geneCategoriesCell LineCessation of lifeChronicChronic Lung InjuryClinicalCritical ThinkingDataDevelopmentDiagnosisExposure toFellowshipFunctional disorderFutureHumanIL18 geneIL8 geneImmuneImmunophenotypingImpairmentIncidenceIndividualInfectionInflammasomeInflammationInflammatoryInflammatory ResponseInjuryInnate Immune ResponseInterleukin-1 betaInterleukin-6KineticsKnowledgeLaboratoriesLifeLinkLungLung TransplantationLung diseasesMacrophageMeasuresMediatingMediatorMethodsModelingNational Research Service AwardsOutcomePhagocytesPhenocopyPhenotypePlayPopulationPreventiveProductionProteinsPseudomonasPseudomonas aeruginosaPulmonary InflammationResearchRibosomal RNARisk FactorsRoleSamplingScientistTNF geneTestingTransplant RecipientsTransplantationUpper respiratory tractbactericidebiobankcareerclinical diagnosiscytokinegraft failurehost-microbe interactionsimmune activationinhibitorlung allograftlung colonizationlung injurylung microbiomelung microbiotamicrobialmicrobiomemicrobiome alterationmonocytenovelpathogenpharmacologicpreventpulmonary functionresearch and developmentresponsesensorskillstherapeutic target
项目摘要
The objectives of this NRSA individual fellowship are to 1) facilitate the development of research skills necessary
for the applicant to become an effective and independent scientist and 2) investigate the mechanisms behind
Pseudomonas aeruginosa-induced interleukin-1 beta (IL-1β) production in lung transplantation. Lung
transplantation is a life-extending treatment for individuals with end-stage lung diseases; however, long-term
outcomes are limited by allograft injury and chronic lung allograft dysfunction (CLAD). While CLAD is defined as
a clinical diagnosis with median onset several years after transplantation, the antecedent risk factors may occur
months or years prior to diagnosis, supporting a hypothesis that early inflammatory mechanisms could represent
important triggers for lung inflammation and injury. Increased bacterial burden, decreased bacterial diversity,
and prominence of P. aeruginosa are associated with worsening lung function, graft failure, and CLAD through
pathogen-driven inflammatory triggers and impaired innate responses impacting bacterial clearance. The
applicant has preliminary data demonstrating that P. aeruginosa upregulates sustained IL-1β production in lung
transplant recipient-derived alveolar macrophages compared to other common upper respiratory tract bacteria.
Elevated IL-1β has been associated with a decline in lung function and lung inflammation, and chronic lung
injury, but few studies have examined the role of pathogen-driven inflammatory triggers on human activation of
alveolar macrophage innate immune responses in lung transplantation. This proposal focuses on the
mechanisms underlying the interaction between the lung microbiota and its innate sensing by macrophages to
address this knowledge gap. We hypothesized that the lung microbiome, particularly those dominated by P.
aeruginosa, following transplantation mediates sustained alveolar macrophage proinflammatory responses. To
assess the effects of the lung microbiome on macrophages, we used a novel method to isolate lung microbiota
from lung transplant recipients for stimulation of macrophages. This proposal uses two approaches to evaluate
the impact of P. aeruginosa and Pseudomonas-dominant lung microbiota on immune activation and
inflammation: 1) focusing on IL-1β production through activation of the inflammasome using specific canonical
sensor proteins and 2) focusing on macrophage immunophenotype. Rigorous immunophenotyping and
advanced bioinformatic analysis will be used to elucidate the relationship between P. aeruginosa and
inflammasome-activated macrophage IL-1β production in lung transplant recipients. This proposal will add
a novel understanding of cellular mechanisms linking microbial lung populations to aberrant innate immune
activation, which is critical to developing future therapeutic targets and preventing immune-mediated lung injury.
This proposal will provide a rich opportunity for the applicant to establish the laboratory and critical thinking skills
necessary for a successful research career.
NRSA个人奖学金的目标是1)促进必要研究技能的发展
项目成果
期刊论文数量(0)
专著数量(0)
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专利数量(0)
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Rachel Noel Britton其他文献
Rachel Noel Britton的其他文献
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