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Transcriptional Regulation of Migrating Neutrophils during Pneumonia

肺炎期间迁移中性粒细胞的转录调节

基本信息

批准号：
10642707
负责人：
Katrina Traber
金额：
$ 41.25万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10642707
关键词：
Address Affect Air Alveolar Automobile Driving Biology Bone Marrow COVID-19 pandemic Cell Separation Cell membrane Cells Circulation Clinical Cytokine Signaling Data Development Environment Epithelium Equilibrium Exposure to Flow Cytometry Future Gene Expression Regulation Genes Genetic Transcription Goals Heterogeneity Immune System Diseases Immune response Immunologics In Vitro Infection Inflammatory Injury Intervention Knowledge Label Lead Liquid substance Location Lung Maintenance Mediating Metabolism Modeling Morbidity - disease rate Mucous Membrane Mus Outcome Pathway interactions Pneumonia Population Proteins Recording of previous events Site Sorting Stimulus Surface Testing Therapeutic Thinness Tissues Transcriptional Regulation Travel Up-Regulation Work biomarker identification in vivo in vivo Model loss of function migration mortality neutrophil novel novel marker pathogen pneumonia model programs response single-cell RNA sequencing transcription factor transcriptome transcriptome sequencing transcriptomics

项目摘要

Project Summary/Abstract Pneumonia remains a significant cause of morbidity and mortality, which has come into sharp focus recently during the COVID-19 pandemic. The lung is immunologically unique, and neutrophils traversing the lungs must be ready to respond to potential pathogen challenges without causing injury to surrounding tissues. Disruptions of this balance lead to many severe complications of pneumonia, but we lack therapeutics directed toward neutrophil-mediated immune dysfunction. Our preliminary data demonstrate that neutrophils undergo transcriptional remodeling as they travel from the circulation to the alveolar space during pneumonia. A subset of pro-inflammatory genes is upregulated as neutrophils move from the vasculature to the interstitium, while genes related to metabolism and degranulation are upregulated as cells move from interstitium to the alveolar space. Maintenance of appropriate neutrophil function and development requires tight regulation of gene changes, yet the specific pathways underlying such changes constitute a major knowledge gap. The goal of this proposal is to delineate the transcriptional and functional changes neutrophils undergo as they migrate from the circulation to the site of infection during pneumonia. Our central hypothesis is that during pneumonia, appropriate neutrophil function is achieved by proscribed responses to specific environmental stimuli, resulting in a heterogenous population defined by their interaction history. Aim 1: Test the hypothesis that location-specific neutrophil responses in pneumonia are achieved by the tuning of neutrophil transcriptome and function by environmental stimuli. Using complementary in vitro and in vivo models we will determine the contributions of migration, pathogen interaction and cytokine signaling to neutrophil gene programs and function. Outcomes will include transcriptional and functional changes predicted by our preliminary studies. These findings will then be confirmed in an in vivo model of pneumonia, employing exogenously added labeled neutrophils. Aim 2: Test the hypothesis that during transit to the alveolar space, neutrophils differentiate into subpopulations unique to the lung, with transcriptional and functional heterogeneity. Using a combination of in vivo cell labeling, flow cytometry assisted cell sorting, and single cell RNA sequencing, we will track modulations in the neutrophil transcriptome from circulation to alveolar space at a single cell level. Aim 3: NFκB-RelA is a central transcription factor in neutrophils, driving the upregulation of a pro-inflammatory transcriptional program during migration to the alveolar space. Using complementary in vitro and in vivo loss-of function models we will determine the effect of neutrophil NFκB-RelA on pneumonia outcomes neutrophil transcriptome and neutrophil function. The results of these studies will have a positive impact the field of pneumonia biology furthering our knowledge of neutrophil function and laying the groundwork for future development of novel host-directed neutrophil-based pneumonia therapeutics.

项目总结/文摘