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.
该 NRSA 个人奖学金的目标是 1) 促进必要的研究技能的发展
使申请人成为一名有效且独立的科学家,并2)调查背后的机制
肺移植中铜绿假单胞菌诱导白细胞介素 1 β (IL-1β) 的产生。肺
移植是对终末期肺病患者的一种延长生命的治疗方法;然而,长期
结果受到同种异体移植损伤和慢性肺同种异体移植功能障碍(CLAD)的限制。虽然 CLAD 定义为
临床诊断的中位发病时间为移植后数年,先前的危险因素可能会发生
诊断前数月或数年,支持早期炎症机制可能代表的假设
肺部炎症和损伤的重要触发因素。细菌负担增加,细菌多样性减少,
铜绿假单胞菌的突出与肺功能恶化、移植失败和 CLAD 相关
病原体驱动的炎症触发因素和先天反应受损影响细菌清除。这
申请人拥有初步数据证明铜绿假单胞菌上调肺中持续的 IL-1β 产生
与其他常见上呼吸道细菌相比,移植受者来源的肺泡巨噬细胞。
IL-1β升高与肺功能下降和肺部炎症以及慢性肺病有关
损伤,但很少有研究探讨病原体驱动的炎症触发因素对人类激活
肺移植中肺泡巨噬细胞的先天免疫反应。该提案的重点是
肺微生物群与巨噬细胞固有感知之间相互作用的机制
解决这一知识差距。我们假设肺部微生物组,特别是那些以假单胞菌为主的微生物组。
铜绿假单胞菌,移植后介导持续的肺泡巨噬细胞促炎症反应。到
为了评估肺微生物组对巨噬细胞的影响,我们使用了一种新方法来分离肺微生物组
来自肺移植受者用于刺激巨噬细胞。该提案使用两种方法来评估
铜绿假单胞菌和假单胞菌为主的肺部微生物群对免疫激活和
炎症:1) 通过使用特定的规范激活炎症小体来关注 IL-1β 的产生
传感器蛋白;2) 关注巨噬细胞免疫表型。严格的免疫表型分析和
将使用先进的生物信息分析来阐明铜绿假单胞菌和
肺移植受者中炎症小体激活的巨噬细胞 IL-1β 的产生。该提案将添加
对将微生物肺群与异常先天免疫联系起来的细胞机制的新理解
激活,这对于开发未来的治疗靶点和预防免疫介导的肺损伤至关重要。
该提案将为申请人提供丰富的机会来建立实验室和批判性思维技能
成功的研究生涯所必需的。
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)
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