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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

基本信息

批准号：
10470157
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
项目类别：
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/10470157
关键词：
Acute Lung Injury Acute 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

项目摘要

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/文摘