The Role of Alveolar Mononuclear Phagocytes in Acute Respiratory Distress Syndrome

肺泡单核吞噬细胞在急性呼吸窘迫综合征中的作用

• 批准号: 10231127
• 负责人: Eric Douglas Morrell
• 金额: $ 19.02万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231127
• 关键词: Acute Lung Injury; Adult Respiratory Distress Syndrome; Alveolar; Alveolar Macrophages; Animal Model; Animals; Applications Grants; Award; Basic Science; Biological; Bronchoalveolar Lavage Fluid; CD86 gene; Cells; Cellular Assay; Clinical; Clinical Trials; Cluster Analysis; Collaborations; Complex; Critical Care; Critical Illness; Cytometry; Data; Development; Development Plans; Enrollment; Epidemiology; Failure; Funding; Future; Gases; Gene Expression Profile; Genetic Transcription; Goals; Health; Heterogeneity; Human; Human Characteristics; IL8 gene; Immune; Impairment; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Infrastructure; Intensive Care Units; Interleukin-6; Intervention; Knowledge; Lead; Leukocytes; Link; Liquid substance; Lung; Measures; Mediating; Mediator of activation protein; Modeling; Mononuclear; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Permeability; Phagocytes; Pharmacology; Pharmacotherapy; Phase; Phenotype; Play; Research; Research Design; Research Personnel; Research Training; Role; STAT1 gene; Sampling; Scientist; Severities; Signal Transduction; Stains; Statistical Methods; Statistical Models; Testing; Time; Training; Ventilator; Work; analytical method; biomarker panel; career development; cell type; cohort; design; differential expression; epidemiological model; human subject; improved; improved outcome; indexing; lung injury; monocyte; mortality; novel; novel therapeutics; peripheral blood; power analysis; programmed cell death ligand 1; programs; prospective; protein biomarkers; pulmonary function; recruit; reparative process; response; single-cell RNA sequencing; skills; transcriptome sequencing; translational physician; translational research program; treatment strategy

Project Summary/Abstract Acute respiratory distress syndrome (ARDS) has an associated 28-day mortality as high as 33%, however there are no effective pharmacologic interventions specifically targeted at ARDS pathogenesis that improve outcomes for these patients. Alveolar macrophages (AMs) are the most abundant leukocyte in the homeostatic human lung. They are presumed to be a key regulator of both the inflammatory and reparative processes of ARDS given their phenotypic plasticity and functional heterogeneity. This phenotypic plasticity endows AMs with many potential reprogramming targets which might be used as treatment strategies for ARDS. Animal studies have found multiple AM subtypes that are present in acute lung injury, however information regarding human AM subtypes in health and ARDS is very limited. Dr. Eric Morrell has developed a research program that has found different AM phenotypic and transcriptional subtypes are associated with ARDS and ARDS-related outcomes, respectively. Dr. Morrell’s overall goal is to characterize the functional and transcriptional differences between AM subtypes in ARDS and to determine whether AM subtypes influence ARDS severity. He will specifically work to achieve this goal through the following 3 Aims: 1) Test for associations between AM subtypes and ARDS severity using mass cytometry (CyTOF); 2) Determine whether different AM subtypes differentially secrete inflammatory mediators, and assess if soluble alveolar inflammatory signals mediate associations between AM subtypes and ARDS severity; and 3) Characterize the transcriptional programs of AM subtypes in ARDS using single-cell RNA sequencing. The Career Development Plan for this grant proposal is designed to provide training for Dr. Morrell in human cohort management, epidemiology, “omics” analytics, and statistical methods. These new skills will augment his basic science background and facilitate his overall goal of developing into an independent translational physician-scientist who can obtain and integrate complex biologic data into epidemiologic and statistical models to answer clinically-oriented research questions. Armed with the data generated by this project as well as the training outlined in the Career Development Plan, Dr. Morrell will have the infrastructure and skills necessary to submit a competitive R01 grant proposal at the end of his proposed K23 funding period. Future projects that could build upon this grant proposal include using single-cell assays to predictively enrich for ARDS subpopulations that might respond to therapies, studying the relationship between reparative AM subtypes and ARDS clinical outcomes using longitudinally-collected patient samples, and collaborating with other ARDS investigators to examine specific targets that are identified through the project’s specific Aims.

项目总结/摘要 急性呼吸窘迫综合征（ARDS）的相关28天死亡率高达33%，然而， 目前还没有针对ARDS发病机制的有效药物干预措施， 这些患者的结果。肺泡巨噬细胞（AM）是肺泡巨噬细胞中最丰富的白细胞。 自我平衡的人类肺它们被认为是炎症和修复性炎症的关键调节因子。 ARDS的过程中给予他们的表型可塑性和功能的异质性。这种表型可塑性 赋予AM许多潜在的重编程靶点，这些靶点可用作治疗策略， ARDS。然而，动物研究发现，急性肺损伤中存在多种AM亚型， 关于健康和ARDS中人AM亚型的信息非常有限。埃里克·莫雷尔博士 一个研究项目发现，不同的AM表型和转录亚型与 ARDS和ARDS相关结局。 博士Morrell的总体目标是描述AM亚型之间的功能和转录差异 并确定AM亚型是否影响ARDS的严重程度。他将专门致力于实现 通过以下3个目的来实现这一目标：1）使用 2）确定不同AM亚型是否差异性地分泌炎性细胞因子; 介质，并评估可溶性肺泡炎症信号是否介导AM亚型和 ARDS严重程度; 3）使用单细胞免疫印迹技术表征ARDS中AM亚型的转录程序。 RNA测序。 本赠款提案的职业发展计划旨在为Morrell博士提供人类 队列管理、流行病学、“组学”分析和统计方法。这些新技能将增强 他的基本科学背景，并促进他的总体目标，发展成为一个独立的翻译 能够获得复杂生物数据并将其整合到流行病学和统计学中的医生兼科学家 模型来回答临床研究问题。也有了这个项目产生的数据 正如职业发展计划中概述的培训，莫雷尔博士将拥有基础设施和技能， 有必要在他提议的K23资助期结束时提交一份有竞争力的R 01赠款提案。未来 可以建立在这一赠款提案基础上的项目包括使用单细胞测定来预测性地富集 可能对治疗有反应的ARDS亚群，研究修复性AM 亚型和ARDS临床结果，使用经尿道收集的患者样本，并与 其他ARDS研究人员检查通过项目的具体目标确定的具体目标。