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Circadian Signatures in Chronic Lung Disease

慢性肺病的昼夜节律特征

基本信息

批准号：
10410498
负责人：
Jeffrey Adam Haspel
金额：
$ 61.02万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10410498
关键词：
Acute Airway Disease Airway Resistance Alpha Rhythm Animal Model Antiviral Response Asthma Atlases Back Brain Death Cells Characteristics Chronic Chronic Disease Chronic Obstructive Pulmonary Disease Chronic lung disease Chronotherapy Circadian Rhythms Circadian gene expression Clinical Custom Cytometry Dangerousness Data Dependence Deterioration Disease Donor person Epithelial Cells Exhibits Gene Expression Gene Expression Profile Genes Goals Hospitalization Human Individual Influenza A virus Influenza prevention Knowledge Lead Leukocyte Trafficking Life Lung Modeling Molecular Mus Organ Organ Procurements Organ Transplantation Pathogenesis Pathologic Pathology Patient Care Patients Pattern Periodicity Peripheral Phenotype Physiology Predisposition Public Health Quality of life Regulation Reporter Research Respiratory Disease Risk Sampling Therapeutic Time Tissues Translating Transplantation Viral Virus Virus Diseases airway epithelium airway remodeling antimicrobial asthma model asthmatic base bronchial epithelium cellular imaging chronic respiratory disease circadian circadian biology circadian pacemaker circadian regulation circadian transcriptome fighting improved in vivo in vivo imaging individual patient molecular clock mouse model new therapeutic target novel marker pathogen precision medicine prevent programs repository respiratory virus response trafficking trait user-friendly web-accessible

项目摘要

PROJECT SUMMARY/ABSTRACT Circadian rhythms are an important yet poorly understood feature of chronic lower respiratory disease. In airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), nocturnal exacerbations are a disease-defining characteristic in which normal circadian swings in airway resistance are pathologically amplified. Circadian rhythms are generated by a cell-autonomous molecular clock that orchestrates tissue- specific rhythms in gene expression, leading to oscillations in physiology including in the lung. Research suggests that molecular clock function specifically within airway epithelial cells regulates innate antimicrobial responses. Such responses are critical in chronic lung disease because they may determine whether an encounter with a virus or other pathogen triggers a clinical exacerbation. Currently, there is no information on the circadian regulatory program within the human lung and how chronic disease might rewrite this regulation to drive pathogenesis. Here we show that chronic lung disease alters rhythms in circadian clock gene expression in human bronchial epithelial cells (HBECs) from patients. We demonstrate that HBECs express circadian transcriptomes encompassing hundreds of genes and exhibit disease-specific patterns that can be further altered by acute viral infection. As such, we hypothesize that chronic airway disease reprograms circadian gene expression in airway cells thereby influencing virus susceptibility. The overarching goal of this project is to translate circadian biology into disease-modifying treatments for patients with chronic airway disease by mitigating or preventing virally triggered clinical exacerbations. Aim 1: Identify disease-specific circadian gene expression programs regulating antiviral responses in asthma and COPD patients. Using a unique repository of HBECs developed by our group that were isolated from human lung explants, we will determine the circadian transcriptomes of HBECs obtained from asthma and COPD patients and compare these to donors without chronic airway disease. In parallel, we will phenotype HBECs in terms of their susceptibility to acute influenza A virus (IAV) infection in the presence or absence of circadian clock disruption. Observations in HBECs will be backed by single cell imaging of circadian rhythms and a first-of-its-kind analysis of in vivo human airway circadian gene expression using serial airway brushing samples obtained from organ transplant donors after brain death while they await organ procurement. Aim 2: Discover evolutionarily conserved circadian reprogramming in chronic airway disease. We will use a well characterized mouse model of asthma/COPD- like airway remodeling with known clock regulation of antiviral responses. Using this model, we will examine lung circadian reprogramming of gene expression and leukocyte trafficking by chronic airway disease and determine the dependency of this program on the airway epithelial cell peripheral clock. These studies will be backed by in vivo imaging of airway clock gene expression in mice using bioluminescent reporters.

项目总结/文摘