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.
Acute respiratory distress syndrome (ARDS) is present in 10.4% of all patients admitted to an intensive care unit worldwide and is associated with a mortality rate as high as 33%. To date, there are no pharmacotherapies specifically directed toward the underlying mechanisms of ARDS that have been shown to improve patient outcomes. Alveolar macrophages (AMs) are the most abundant primary immune cell-type in the homeostatic human lung, and the identification of associations between AM subtypes and ARDS outcomes could lead to the discovery of novel therapies to improve patient outcomes in ARDS.