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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：
Rachel Noel Britton
金额：
$ 6.95万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
https://reporter.nih.gov/project-details/10606768
关键词：
Address Allografting Alveolar Alveolar Macrophages Bacteria Bioinformatics Bronchoalveolar Lavage CASP1 gene Categories Cell Line Cessation of life Chronic Chronic Lung Injury Clinical Critical Thinking Data Development Diagnosis Exposure to Fellowship Functional disorder Future Human IL18 gene IL8 gene Immune Immunophenotyping Impairment Incidence Individual Infection Inflammasome Inflammation Inflammatory Inflammatory Response Injury Innate Immune Response Interleukin-1 beta Interleukin-6 Kinetics Knowledge Laboratories Life Link Lung Lung Transplantation Lung diseases Macrophage Measures Mediating Mediator Methods Modeling National Research Service Awards Outcome Phagocytes Phenocopy Phenotype Play Population Preventive Production Proteins Pseudomonas Pseudomonas aeruginosa Pulmonary Inflammation Research Ribosomal RNA Risk Factors Role Sampling Scientist TNF gene Testing Transplant Recipients Transplantation Upper respiratory tract bactericide biobank career clinical diagnosis cytokine graft failure host-microbe interactions immune activation inhibitor lung allograft lung colonization lung injury lung microbiome lung microbiota microbial microbiome microbiome alteration monocyte novel pathogen pharmacologic prevent pulmonary function research and development response sensor skills therapeutic 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。