Molecular Clock REV-ERBα in COPD and its exacerbations

COPD 及其恶化中的分子钟 REV-ERBα

• 批准号: 9891076
• 负责人: IRFAN RAHMAN
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891076
• 关键词: Adrenal Cortex Hormones; Agonist; Alveolar; Attenuated; Bacterial Infections; Binding; Bronchodilator Agents; Cell Aging; Cells; Chronic; Chronic Obstructive Airway Disease; Clock protein; DNA; DNA Repair; Data; Development; Disease Progression; Epithelial Cells; Excision; Exhibits; Functional disorder; Genes; Growth; HDAC3 gene; Hour; Immune; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza A Virus, H1N1 Subtype; Influenza A virus; Knockout Mice; Luciferases; Lung; Lung Compliance; Mediating; Mediator of activation protein; Messenger RNA; Metabolism; Mitochondria; Molecular; Monitor; Morbidity - disease rate; Mucous body substance; Mus; Mutate; Nuclear Receptors; Outcome; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Play; Predisposition; Process; Production; Proteins; Puerto Rico; Pulmonary Emphysema; Reporter; Reporter Genes; Reporting; Respiratory physiology; Response Elements; Role; Stress; Testing; Therapeutic Agents; Time; Tissues; United States; Viral; Virus; Virus Diseases; airway obstruction; base; cigarette smoke; cigarette smoke-induced; cigarette smoke-induced COPD; circadian; exposure to cigarette smoke; genetic corepressor; influenzavirus; molecular clock; mortality; mouse model; mucus hypersecretion; novel; premature; prevent; promoter; receptor; recruit; response; rev Protein; senescence

SUMMARY Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of chronic morbidity and mortality in the United States. As COPD progresses, patients develop more frequent and severe exacerbations induced by viral and bacterial infections. We have recently reported that cigarette smoke (CS) causes abnormal inflammatory responses in the lungs while also disrupting the circadian molecular clock in lung cells. Our preliminary data suggest that CS-induced cellular senescence and the influenza virus-induced decline in lung function are associated with molecular clock dysfunction in lung epithelial cells. REV-ERBα is a nuclear receptor and critical component of the molecular clock that drives daily rhythms of metabolism and immune- inflammatory responses. We have shown that airway and alveolar REV-ERBα levels are reduced in the lungs of mice with emphysema and in the lungs of COPD patients, and during exacerbations. Further, REV-ERBα agonists reduce CS-induced levels of pro-inflammatory and pro-senescent mediators. These data suggest that, besides its function as part of the molecular clock, REV-ERBα also acts as a critical component of the immune- inflammatory response to CS and may be a key player in the progression and exacerbation of COPD. Despite these intriguing results, the role of REV-ERBα in CS-mediated DNA damage/repair and cellular senescence and its involvement in influenza virus-mediated lung responses is not known. We hypothesize that the CS- mediated reduction in REV-ERBα abundance potentiates lung cellular senescence and inflammatory responses. Further, the loss of circadian protein leads to COPD development, progression, and produces more severe influenza virus-induced exacerbations. We propose to test this hypothesis by determining the mechanistic relationship between the CS-induced reduction of REV-ERBα levels, increased cellular senescence, DNA damage/repair, emphysematous responses and virus-mediated decline in lung function and mucus production in the following three Aims: Aim 1: Determine whether REV-ERBα protects against cellular senescence and senescence-associated inflammatory responses during CS-induced COPD/emphysema; Aim 2: Determine the mechanism whereby the interaction between REV-ERBα, RORα and HDAC3 regulates CS-induced lung cellular senescence and inflammatory responses; and Aim 3: Determine whether REV-ERBα protects against lung function decline and mucus hypersecretion in a mouse model of influenza virus-mediated COPD exacerbation. This proposal will unravel the role of the nuclear receptor and clock protein REV-ERBα in regulating lung cellular senescence and inflammatory responses during influenza virus-induced COPD/emphysema exacerbations. In turn, this will have great translational potential for the development of novel and potentially effective pharmacological therapies to ameliorate lung cellular senescence in COPD and its exacerbations based on targeting REV-ERBα function in the lungs using a molecular clock based treatment.

概括 慢性阻塞性肺疾病（COPD）是慢性发病率和死亡率的第四个主要原因 在美国。随着COPD的进展，患者的发展频率更高，诱发了严重的加重 通过病毒和细菌感染。我们最近报告说，香烟烟（CS）会导致异常 肺部的炎症反应也破坏了肺部细胞中的昼夜节律。我们的 初步数据表明，CS诱导的细胞感受和影响病毒诱导的影响下降 肺功能与肺上皮细胞中的分子钟功能障碍有关。 Rev-ERBα是核 分子时钟的受体和关键成分，该成分每天驱动代谢和免疫的节奏 炎症反应。我们已经表明，气道和肺泡Rev-ERBα水平在肺中降低 患有肺气肿的小鼠和COPD患者的肺部以及病情加重。此外，Rev-erbα 激动剂降低了CS诱导的促炎和促介质介体的水平。这些数据表明， 除了作为分子时钟的一部分功能外，Rev-erbα还充当免疫的关键成分 对CS的炎症反应，可能是COPD进展和加剧的关键人物。尽管 这些有趣的结果，Rev-ERBα在CS介导的DNA损伤/修复和细胞感应中的作用 并且它参与了影响扎病毒介导的肺反应的参与尚不清楚。我们假设CS- 介导的Rev-ERBα抽象电势的降低肺细胞感染和炎症 回答。此外，昼夜蛋白的丧失会导致COPD的发展，进展，并产生更多 严重的影响力。我们建议通过确定 CS诱导的Rev-ERBα水平降低之间的机械关系，细胞增加 感应，DNA损伤/修复，杂质反应以及病毒介导的肺功能下降和 以下三个目标中的粘液产生：目标1：确定Rev-ERBα是否可以防止细胞 CS诱导的COPD/肺气肿期间的感应和感应相关的炎症反应； AIM 2：确定Rev-ERBα，RORα和HDAC3之间相互作用的机制调节 CS诱导的肺细胞感应和炎症反应；目标3：确定Rev-erbα是否 防止肺部病毒介导的小鼠模型中的肺功能下降和粘液过度分泌 COPD加剧。该建议将揭示核接收器和时钟蛋白Rev-erbα在 调节流感病毒诱导期间肺细胞衰老和炎症反应 COPD/肺气肿加重。反过来，这将具有巨大的转化潜力 新颖且潜在的有效的药物疗法，可改善COPD和 它基于基于肺中的Rev-ERBα功能使用基于分子时钟的治疗而加剧。