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

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.
这个NRSA个人奖学金的目标是1)促进必要的研究技能的发展 使申请人成为有效和独立的科学家,2)调查背后的机制 肺移植中铜绿假单胞菌诱导的白细胞介素-1 β(IL-1β)产生。肺 移植是终末期肺病患者延长生命的治疗方法;然而, 结果受到同种异体移植物损伤和慢性肺移植物功能障碍(CLAD)的限制。虽然CLAD被定义为 如果在移植后数年内出现中位临床诊断,可能会出现先前的风险因素 诊断前数月或数年,支持早期炎症机制可能代表 肺部炎症和损伤的重要触发因素。细菌负荷增加,细菌多样性降低, 铜绿假单胞菌和突出与肺功能恶化、移植物衰竭和CLAD相关, 病原体驱动的炎症触发和影响细菌清除的先天性应答受损。的 申请人有初步数据证明铜绿假单胞菌上调肺中持续的IL-1β产生 与其他常见的上呼吸道细菌相比,移植物来源的肺泡巨噬细胞。 IL-1β升高与肺功能下降和肺部炎症有关,慢性肺功能衰竭和慢性肺功能衰竭也与IL-1β升高有关。 损伤,但很少有研究探讨病原体驱动的炎症触发对人类激活的作用, 肺移植中肺泡巨噬细胞的天然免疫应答该提案的重点是 肺微生物群与巨噬细胞的先天感知之间相互作用的潜在机制, 填补这一知识空白。我们假设肺部微生物组,特别是那些以P。 铜绿假单胞菌,移植后介导持续的肺泡巨噬细胞促炎反应。到 为了评估肺部微生物对巨噬细胞的影响,我们使用了一种新的方法来分离肺部微生物 用于刺激巨噬细胞。本提案使用两种方法来评估 铜绿假单胞菌和假单胞菌占优势的肺微生物群对免疫激活和 炎症:1)通过使用特异性经典免疫反应来激活炎性体,关注IL-1β的产生。 传感器蛋白和2)聚焦于巨噬细胞免疫表型。严格的免疫表型分析和 先进的生物信息学分析将用于阐明铜绿假单胞菌和 肺移植受者中炎性小体激活的巨噬细胞IL-1β的产生。该提案将增加 对微生物肺种群与异常先天免疫相关的细胞机制的新认识 激活,这是至关重要的发展未来的治疗目标和预防免疫介导的肺损伤。 这份提案将为申请人提供丰富的机会,以建立实验室和批判性思维能力 这是成功的研究生涯所必需的。

项目成果

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Rachel Noel Britton的其他文献

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