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.

项目概要哮喘是一种常见的肺部疾病，其活动性受时间的影响很大。季节（反映呼吸道病毒感染率），并且它们还随一天中的不同时间而变化，因此许多患者在半夜经历最严重的症状，后者表明生物钟，产生昼夜节律的基因集合与哮喘有关。众所周知，节律都会影响哮喘症状，但疾病的这两个方面从未被研究过。在这里，我们发现一种名为 bmal1 的生物钟基因可能通过以下方式影响哮喘。我们发现时钟基因 bmal1 的破坏可以调节肺部对常见呼吸道病毒的反应。小鼠体内对副流感和甲型流感病毒产生异常的抗病毒反应，导致严重的 bmal1 的抗病毒作用似乎局限于气道上皮细胞，其中我们发现，在急性病毒性疾病消退后，该基因会协调干扰素反应。在小鼠中，bmal1 缺乏会导致病毒后慢性气道疾病恶化，包括以下特征：最后，我们发现气道样本中 bmal1 表达下调。根据这些数据，我们勇敢地承认生物钟调节抗病毒药物。通过 bmal1 调节气道上皮细胞的反应，从而控制急性和慢性病毒的严重程度肺部病理学我们进一步发现，气道上皮细胞的生物钟功能存在缺陷。哮喘患者，导致 bmal1 表达减少，并可能解释哮喘易感性这些患者必须对呼吸道病毒进行检测，以确定 bmal1 介导抗病毒的机制。针对呼吸系统的防御，我们提出以下具体目标： 1) 确定 bmal1 在气道中的作用上皮细胞控制干扰素基因表达和急性呼吸道病毒性疾病的严重程度小鼠；2) 确定 bmal1 缺乏如何促进小鼠病毒后慢性气道疾病；以及确定哮喘气道上皮生物钟功能障碍的性质我们将通过使用气道条件性bmal1基因敲除小鼠和bmal1-体外培养来解决Aim1问题。空小鼠气管上皮细胞，以描绘该基因如何调节呼吸系统的干扰素反应我们将通过使用他莫昔芬诱导的 bmal1 敲除来解决目标 2。小鼠以确定在感染过程中何时需要 bmal1 来调节病毒后肺部疾病。将通过使用荧光素酶报告系统分析生物钟功能和 bmal1 表达来解决目标 3 在来自正常和哮喘受试者的培养的人类气道细胞中。