Circadian Signatures in Chronic Lung Disease

慢性肺病的昼夜节律特征

• 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
• 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

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.

项目摘要/摘要 昼夜节律是慢性下呼吸道疾病的重要特征但知之甚少的特征。在气道 哮喘和慢性阻塞性肺疾病（COPD）等疾病，夜间恶化是一种 定义疾病的特征，在气道阻力中正常昼夜节律在病理上是病理 放大。昼夜节律是由细胞自主分子时钟产生的，该分子时钟精心策划组织 基因表达的特定节奏，导致包括肺在内的生理学振荡。研究 表明分子时钟在气道上皮细胞中特别起作用，调节先天抗菌剂 回答。这种反应在慢性肺病中至关重要，因为它们可能会确定 与病毒或其他病原体相遇会触发临床加重。目前，没有有关 人类肺中的昼夜节律调节计划，以及慢性病如何将这种调节改写为 驱动发病机理。在这里，我们表明慢性肺疾病改变了昼夜节律基因表达中的节奏 在人支气管上皮细胞（HBEC）中。我们证明了HBECS Express Pixadian 包括数百个基因和疾病特异性模式的转录组可以进一步改变 通过急性病毒感染。因此，我们假设慢性气道疾病重编程昼夜节律基因 气道细胞中的表达，从而影响病毒敏感性。这个项目的总体目标是 通过 缓解或预防病毒触发的临床加重。目标1：识别特定疾病的昼夜节律 基因表达程序调节哮喘和COPD患者的抗病毒反应。使用唯一 由我们的小组开发的HBEC存储库，这些存储库是从人类肺部外植体中隔离的，我们将确定 从哮喘和COPD患者获得的HBEC的昼夜节律转录组，并将其与捐助者进行比较 没有慢性气道疾病。同时，我们将以表型HBEC的敏感性来表型 在存在或不存在昼夜节律破坏的情况下，流感病毒（IAV）感染。 HBEC的观察 将由昼夜节律的单细胞成像和体内气道的首次分析 使用从器官移植供体获得的串行气道刷样品的昼夜节律基因表达 当他们等待器官采购时，脑死亡。目标2：发现进化保守的昼夜节律 在慢性气道疾病中重新编程。我们将使用哮喘/copd-的鼠标模型良好 就像抗病毒反应的已知时钟调节的气道重塑一样。使用此模型，我们将检查肺 慢性气道疾病对基因表达和白细胞运输的昼夜节律重编程并确定 该程序对气道上皮细胞外围时钟的依赖性。这些研究将得到 使用生物发光的记者在小鼠中气道时钟基因表达的体内成像。