The Role of Alveolar Mononuclear Phagocytes in Acute Respiratory Distress Syndrome

项目摘要/摘要 然而，急性呼吸窘迫综合征(ARDS)相关的28天死亡率高达33% 目前还没有专门针对ARDS发病机制的有效药物干预措施来改善 这些患者的结果。肺泡巨噬细胞(Am)是人体内最丰富的白细胞。 人体肺的动态平衡。它们被认为是炎症和修复的关键调节器。 ARDS的过程具有表型可塑性和功能异质性。这种表型可塑性 赋予AM许多潜在的重新编程靶点，这些靶点可能被用作治疗 阿兹。然而，动物研究发现，急性肺损伤中存在多种AM亚型 关于人类AM亚型在健康和ARDS中的信息非常有限。埃里克·莫雷尔博士研制出 一项研究发现不同的AM表型和转录亚型与 分别为ARDS和ARDS相关结局。 莫雷尔博士的总体目标是描述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 此目标通过以下3个目标实现：1)测试AM亚型与ARDS严重程度之间的关联 2)确定不同AM亚型是否有不同的炎性分泌物 并评估可溶性肺泡炎信号是否介导AM亚型和AM亚型之间的关联 ARDS的严重程度；以及3)用单细胞鉴定ARDS中AM亚型的转录程序 RNA测序。 这项拨款提案的职业发展计划旨在为莫雷尔博士提供人力资源方面的培训 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 他的基础科学背景，并推动了他发展成为一名独立翻译人员的总体目标 能够获得复杂的生物数据并将其整合到流行病学和统计学中的内科科学家 回答面向临床的研究问题的模型。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一样，莫雷尔博士将拥有基础设施和技能 有必要在其拟议的K23资助期结束时提交一份具有竞争力的R01赠款提案。未来 可以基于这一赠款提案的项目包括使用单细胞分析来预测性地丰富 可能对治疗有反应的ARDS亚群，研究修复性AM之间的关系 使用纵向收集的患者样本的亚型和ARDS临床结果 其他ARDS调查人员检查通过该项目的特定目标确定的特定目标。

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.