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.
NRSA个人奖学金的目标是:1)促进必要的研究技能的发展 使申请者成为一名有效和独立的科学家,并2)调查背后的机制 铜绿假单胞菌诱导肺移植中IL-1β(β)的产生肺 移植是终末期肺部疾病患者的一种延长生命的治疗方法;然而,长期的 结果受到移植肺损伤和慢性肺移植功能障碍(CLAD)的限制。而CLAD被定义为 移植后中位发病数年的临床诊断,可能出现先天危险因素 在诊断前几个月或几年,支持早期炎症机制可能代表 肺部炎症和损伤的重要诱因。细菌负担增加,细菌多样性减少, 和突出的铜绿假单胞菌与肺功能恶化、移植物衰竭和包裹性 病原体驱动的炎症诱因和受损的先天反应影响细菌清除。这个 申请人有初步数据表明,铜绿假单胞菌上调肺内持续的IL-1β产生 移植受体来源的肺泡巨噬细胞与其他常见上呼吸道细菌的比较。 IL-1β升高与肺功能下降、肺部炎症和慢性肺损伤有关 损伤,但很少有研究检查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。这项提案的重点是 肺微生物区系与巨噬细胞先天感知相互作用的机制 解决这一知识鸿沟。我们推测肺内微生物群,尤其是以P。 移植后的铜绿假单胞菌可介导持续的肺泡巨噬细胞促炎反应。至 评估肺微生物群对巨噬细胞的影响,我们使用了一种新的方法来分离肺微生物区系 来自肺移植受者的刺激巨噬细胞。该提案使用两种方法来评估 铜绿假单胞菌和以假单胞菌为主的肺微生物区系对免疫激活和免疫功能的影响 炎症:1)通过使用特定的规范激活炎症小体,专注于IL-1β的产生 传感器蛋白;2)巨噬细胞免疫表型。严格的免疫表型和 先进的生物信息学分析将用于阐明铜绿假单胞菌和 肺移植受者炎症小体激活的巨噬细胞IL-1β的产生。这项提案将增加 对肺微生物种群与异常先天免疫相关细胞机制的新认识 激活,这对于开发未来的治疗靶点和防止免疫介导的肺损伤至关重要。 这项建议将为申请者提供一个丰富的机会来建立实验室和批判性思维技能 对于一个成功的研究事业来说是必要的。

项目成果

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Rachel Noel Britton的其他文献

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