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.

总结 慢性阻塞性肺疾病（COPD）是慢性病发病率和死亡率的第四大原因 在美国随着COPD进展，患者发生更频繁和严重的急性加重， 病毒和细菌感染。我们最近报道称，香烟烟雾（CS）会导致异常 肺中的炎症反应，同时也破坏了肺细胞中的昼夜分子钟。我们 初步数据表明，CS诱导的细胞衰老和流感病毒诱导的细胞凋亡下降， 肺功能与肺上皮细胞中的分子钟功能障碍有关。REV-ERBα是一种核 受体和分子时钟的关键组成部分，驱动日常节奏的新陈代谢和免疫- 炎症反应。我们已经证明，气道和肺泡REV-ERBα水平在肺中降低， 在肺气肿小鼠和COPD患者的肺中，以及在加重期间。此外，REV-ERBα 激动剂降低CS诱导的促炎和促衰老介质的水平。这些数据表明， 除了作为分子时钟的一部分外，REV-ERBα还充当免疫的关键成分- 炎症反应的CS和可能是一个关键的球员在COPD的进展和恶化。尽管 这些有趣的结果，REV-ERBα在CS介导的DNA损伤/修复和细胞衰老中的作用， 并且其参与流感病毒介导的肺应答尚不清楚。我们假设CS- 介导的REV-ERBα丰度降低增强肺细胞衰老和炎性细胞凋亡 应答此外，昼夜节律蛋白的丢失导致COPD的发展、进展，并产生更多的 严重流感病毒诱导的急性加重。我们建议通过确定 CS诱导的REV-ERBα水平降低、细胞增殖和细胞凋亡之间的机制关系 衰老、DNA损伤/修复、肺气肿反应和病毒介导的肺功能下降， 目的1：确定REV-ERBα是否能保护细胞免受 CS诱导的COPD/肺气肿期间的衰老和衰老相关的炎症反应; 目的2：确定REV-ERBα、RORα和HDAC 3相互作用调节细胞凋亡的机制。 CS诱导的肺细胞衰老和炎症反应;目的3：确定REV-ERBα 在流感病毒介导的小鼠模型中保护肺功能下降和粘液分泌过多 COPD加重。这一提议将揭示核受体和时钟蛋白REV-ERBα在细胞凋亡中的作用。 流感病毒诱导的肺细胞衰老和炎症反应的调节 COPD/肺气肿加重。反过来，这将对发展具有巨大的转化潜力， 改善COPD患者肺细胞衰老的新型和潜在有效的药理学疗法， 使用基于分子钟的治疗靶向REV-ERBα在肺部的功能，从而缓解其恶化。