Circadian Signatures in Chronic Lung Disease

慢性肺病的昼夜节律特征

基本信息

批准号：
10665013
负责人：
Jeffrey Adam Haspel
金额：
$ 60.36万
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10665013
关键词：
Acute Airway Disease Airway Resistance Antiviral Response Asthma Atlases 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 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 Tissues Translating Transplantation Viral Virus Virus Diseases Writing airway epithelium airway remodeling antimicrobial asthma model asthmatic 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 model organism molecular clock mouse model new therapeutic target novel marker pathogen precision medicine prevent programs repository respiratory imaging 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.

项目概要/摘要昼夜节律是慢性下呼吸道疾病的一个重要但人们知之甚少的特征。在气道中哮喘和慢性阻塞性肺病（COPD）等疾病，夜间病情加重是疾病定义特征，其中气道阻力的正常昼夜波动是病理性的放大。昼夜节律是由细胞自主分子钟产生的，该分子钟协调组织基因表达的特定节律，导致包括肺部在内的生理学振荡。研究表明气道上皮细胞内的分子钟功能特别调节先天抗菌能力回应。这种反应对于慢性肺病至关重要，因为它们可能决定是否遇到病毒或其他病原体会引发临床恶化。目前，尚无相关信息人肺内的昼夜节律调节程序以及慢性疾病如何将这种调节改写为驱动发病机制。在这里，我们发现慢性肺部疾病改变了生物钟基因表达的节律来自患者的人支气管上皮细胞（HBEC）。我们证明 HBEC 表达昼夜节律转录组包含数百个基因，并表现出可以进一步改变的疾病特异性模式由急性病毒感染引起。因此，我们假设慢性气道疾病会重新编程昼夜节律基因气道细胞中的表达，从而影响病毒的易感性。该项目的总体目标是将昼夜节律生物学转化为慢性气道疾病患者的疾病缓解疗法减轻或预防病毒引发的临床恶化。目标 1：确定特定疾病的昼夜节律调节哮喘和慢性阻塞性肺病患者抗病毒反应的基因表达程序。使用独特的我们小组开发了从人肺外植体中分离出来的 HBEC 存储库，我们将确定从哮喘和慢性阻塞性肺病患者获得的 HBEC 的昼夜节律转录组，并将其与捐赠者进行比较无慢性气道疾病。与此同时，我们将根据 HBEC 对急性的易感性进行表型分析。在生物钟存在或不存在的情况下甲型流感病毒 (IAV) 感染。 HBEC 中的观察结果将得到昼夜节律的单细胞成像和对人体气道体内的首次分析的支持使用从器官移植捐赠者获得的连续气道刷洗样本进行昼夜节律基因表达他们在等待器官获取时脑死亡。目标 2：发现进化上保守的昼夜节律慢性气道疾病的重编程。我们将使用一个特征明确的哮喘/慢性阻塞性肺病小鼠模型例如利用已知的抗病毒反应时钟调节进行气道重塑。使用这个模型，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重新编程并确定该程序对气道上皮细胞外周时钟的依赖性。这些研究将得到以下机构的支持使用生物发光记者对小鼠气道时钟基因表达进行体内成像。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Circadian immunity from bench to bedside: a practical guide.

DOI：
10.1172/jci175706
发表时间：
2024-02-01
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
Mok H;Ostendorf E;Ganninger A;Adler AJ;Hazan G;Haspel JA
通讯作者：
Haspel JA

Biological rhythms in COVID-19 vaccine effectiveness in an observational cohort study of 1.5 million patients.

DOI：
10.1172/jci167339
发表时间：
2023-06-01
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
通讯作者：

Age-Dependent Reduction in Asthmatic Pathology through Reprogramming of Postviral Inflammatory Responses.

DOI：
10.4049/jimmunol.2101094
发表时间：
2022-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Hazan G;Eubanks A;Gierasch C;Atkinson J;Fox C;Hernandez-Leyva A;Rosen AL;Kau AL;Agapov E;Alexander-Brett J;Steinberg D;Kelley D;White M;Byers D;Wu K;Keeler SP;Zhang Y;Koenitzer JR;Eiden E;Anderson N;Holtzman MJ;Haspel J
通讯作者：
Haspel J

Age-dependent rebound in asthma exacerbations after COVID-19 lockdown.

DOI：
10.1016/j.jacig.2022.06.001
发表时间：
2022-11
期刊：
The journal of allergy and clinical immunology. Global
影响因子：
0
作者：
Hazan, Guy;Fox, Carolyn;Mok, Huram;Haspel, Jeffrey
通讯作者：
Haspel, Jeffrey

Effect of the COVID-19 Lockdown on Asthma Biological Rhythms.

DOI：
10.1177/07487304221081730
发表时间：
2022-04
期刊：
JOURNAL OF BIOLOGICAL RHYTHMS
影响因子：
3.5
作者：
Hazan, Guy;Fox, Carolyn;Eiden, Elise;Anderson, Neil;Friger, Michael;Haspel, Jeffrey
通讯作者：
Haspel, Jeffrey