Clock Gene Control of Viral Infection and Asthma

病毒感染和哮喘的时钟基因控制

基本信息

批准号：
9402650
负责人：
Jeffrey Adam Haspel
金额：
$ 55.77万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-15 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9402650
关键词：
ARNTL gene Acute Address Affect Age Aging Air Airway Disease Antiviral Agents Antiviral Response Asthma Attenuated Behavior Therapy Biological Canis familiaris Cells Characteristics Child Chronic Circadian Rhythms Collection Complement Data Defect Disease Epithelial Cells Expression Profiling Functional disorder Gene Expression Genes Genetic Transcription Heterogeneity Hospitalization Human In Vitro Incidence Infant Infection Infiltration Influenza A virus Interferons Jet Lag Syndrome Knockout Mice Link Lower Respiratory Tract Infection Luciferases Lung Lung diseases Mediating Mediator of activation protein Modeling Mucous body substance Mus Nature Parainfluenza Pathogenesis Pathology Pathway interactions Patients Predisposition Production Pulmonary Pathology Regulation Reporter Research Resolution Respiratory System Respiratory Tract Infections Risk Role Sampling Seasons Severities Symptoms System Tamoxifen Testing Therapeutic Time United States National Institutes of Health Variant Viral Viral Bronchiolitis Viral Respiratory Tract Infection Virus Virus Diseases Virus Replication Work acute infection advanced disease airway epithelium asthmatic asthmatic patient base circadian pacemaker drug modification experience experimental study human subject in vivo insight macrophage novel pathogen prevent programs public health relevance repository respiratory respiratory virus response

项目摘要

PROJECT SUMMARY Asthma is a common lung disorder whose activity is strongly influenced by time. Asthma symptoms vary with the season (reflecting rates of respiratory viral infection), and they also vary by the time of day, such that many patients experience their worst symptoms in the middle of the night. The latter suggests that the circadian clock, a collection of genes that produce circadian rhythms, is connected to asthma. While viruses and circadian rhythms are both known to affect asthma symptoms, these two aspects of disease have never been mechanistically linked. Here, we discovered that a circadian clock gene called bmal1 may impact asthma by regulating the lung’s response to common respiratory viruses. We show that disruption of the clock gene bmal1 in mice produces an aberrant antiviral response to parainfluenza and influenza A viruses, resulting in severe lower respiratory tract infection. The antiviral actions of bmal1 appear localized to airway epithelial cells, where this gene orchestrates interferon responses during acute viral illness. After the acute infection resolves, we show in mice that bmal1 deficiency exacerbates post-viral chronic airway disease, including features that are characteristic of asthmatic lungs. Finally, we found that bmal1 expression is down-regulated in airway samples from asthma patients. Based on these data, we hypothesize that the circadian clock regulates the antiviral responses of airway epithelial cells through bmal1, and thereby controls the severity of acute and chronic viral lung pathology. We further hypothesize that circadian clock function is defective in the airway epithelial cells of asthmatics, leading to reduced bmal1 expression, and potentially explaining the heightened susceptibility that these patients have to respiratory viruses. To determine the mechanism by which bmal1 mediates antiviral defenses in the respiratory system we propose the following Specific Aims: 1) Determine how bmal1 in airway epithelial cells controls interferon gene expression and the severity of acute respiratory viral illness in mice; 2) Determine how bmal1 deficiency promotes post-viral chronic airway disease in mice; and, 3) Determine the nature of the circadian clock dysfunction in the airway epithelium of asthmatic patients. We will address Aim1 by using airway-conditional bmal1 knockout mice and in vitro culture of bmal1- null mouse tracheal epithelial cells to delineate how this gene regulates the interferon response to respiratory viruses (Sendai and Influenza A viruses). We will address Aim 2 by using tamoxifen-inducible bmal1 knockout mice to define when in the course of infection bmal1 is needed for the regulation of post-viral lung disease. We will address Aim 3 by using a luciferase reporter system to analyze circadian clock function and bmal1 expression in cultured human airway cells, derived from normal and asthmatic subjects.

项目摘要哮喘是一种常见的肺疾病，其活性受时间的强烈影响。哮喘症状因季节（反映呼吸道病毒感染的发生率），它们也随着一天的时间而有所不同，因此许多患者在深夜经历了最严重的症状。后者表明昼夜节律，产生昼夜节律的基因集合与哮喘有关。而病毒和昼夜节律众所周知，节奏都会影响哮喘症状，这两个方面从未有过机械链接。在这里，我们发现一个名为BMAL1的昼夜节律基因可能会影响哮喘调节肺对常见呼吸道病毒的反应。我们证明了时钟基因BMAL1的破坏在小鼠中，对副氟氟扎和影响病毒产生异常的抗病毒反应，导致严重下呼吸道感染。 BMAL1的抗病毒作用似乎位于气道上皮细胞，其中该基因在急性病毒疾病期间策划了干扰素反应。急性感染解决后，我们显示在BMAL1缺乏症的小鼠中，病毒后慢性气道疾病加剧了哮喘肺的特征。最后，我们发现BMAL1表达在气道样品中下调来自哮喘患者。基于这些数据，我们假设昼夜节律调节抗病毒气道上皮细胞通过BMAL1的反应，从而控制急性和慢性病毒的严重程度肺病理学。我们进一步假设，昼夜节律的功能在气道上皮细胞中有缺陷哮喘患者，导致BMAL1表达降低，并有可能解释敏感性的增强这些患者必须呼吸道病毒。确定BMAL1介导抗病毒的机制呼吸系统中的防御措施我们提出以下特定目的：1）确定气道中的BMAL1 上皮细胞控制干扰素基因表达和急性呼吸病毒疾病的严重程度小鼠； 2）确定BMAL1缺乏症如何促进小鼠病毒后慢性气道疾病； 3）确定哮喘的气道上皮中昼夜节律的性质患者。我们将通过使用气道条件BMAL1敲除小鼠和BMAL1-的体外培养来解决AIM1。空小鼠气管上皮细胞以描绘该基因如何调节干扰素对呼吸的反应病毒（仙台和流感病毒）。我们将使用他莫昔芬诱导的BMAL1敲除解决AIM 2 小鼠在感染过程中何时需要BMAL1来调节病毒后肺部疾病。我们将通过使用荧光素酶报告器系统分析昼夜节律函数和BMAL1表达来解决目标3 在培养的人类气道细胞中，源自正常和哮喘受试者。