Molecular Clock REV-ERBα in COPD and its exacerbations

COPD 及其恶化中的分子钟 REV-ERBα

• 批准号: 9457213
• 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 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9457213
• 关键词: Adrenal Cortex Hormones; Agonist; Alveolar; Attenuated; Bacterial Infections; Binding; Bronchodilator Agents; Cell Aging; Cells; Chronic; Chronic Obstructive Airway Disease; Circadian Rhythms; 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; base; cigarette smoke; cigarette smoke-induced; exposure to cigarette smoke; influenzavirus; 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.

摘要 慢性阻塞性肺疾病(COPD)是慢性发病率和死亡率的第四大原因 在美国。随着COPD的进展，患者会出现更频繁和更严重的病情恶化 由病毒和细菌感染引起。我们最近报告说，吸烟(CS)会导致异常 肺部的炎症反应，同时也打乱了肺细胞的昼夜分子时钟。我们的 初步数据表明，CS诱导的细胞衰老和流感病毒诱导的细胞衰退 肺功能与肺上皮细胞的分子时钟功能紊乱有关。Rev-erbα是一个核子 受体和分子时钟的关键组成部分，驱动新陈代谢和免疫的日常节律- 炎症反应。我们已经证明，肺部的呼吸道和肺泡REV-ERBα水平降低 在肺气肿小鼠和慢性阻塞性肺疾病患者的肺部，以及在病情恶化期间。此外，Rev-ERBα 激动剂可降低CS诱导的促炎和促衰老介质水平。这些数据表明， 除了作为分子时钟的一部分，REV-ERBα还作为免疫的关键组件- CS的炎症反应，可能是COPD进展和加重的关键因素。尽管 这些耐人寻味的结果，REV-ERBDNA在CS介导的α损伤/修复和细胞衰老中的作用 它在流感病毒介导的肺部反应中的作用尚不清楚。我们假设CS- REV-ERBα丰度的介导性降低加剧肺细胞衰老和炎症 回应。此外，昼夜节律蛋白的丢失会导致COPD的发生、发展，并产生更多 严重流感病毒引起的病情恶化。我们建议通过确定 壳聚糖致REV-ERBα水平降低、细胞数量增加的机制 衰老、DNA损伤/修复、肺气肿反应和病毒介导的肺功能下降和 以下三个目标的粘液产生：目标1：确定REV-ERBα是否具有细胞保护作用 CS诱导的COPD/肺气肿过程中衰老及衰老相关的炎症反应； 目的2：确定REV-ERBα、RoRα和HDAC3之间相互作用的调节机制 CS诱导的肺细胞衰老和炎症反应；目标3：确定REV-ERBα 对流感病毒介导的小鼠模型肺功能下降和粘液高分泌的保护作用 慢性阻塞性肺疾病的恶化。这项提议将解开核受体和时钟蛋白REV-ERBα在 流感病毒诱导过程中肺细胞衰老和炎症反应的调控 慢性阻塞性肺病/肺气肿加重。反过来，这将对开发具有巨大的翻译潜力 改善慢性阻塞性肺疾病和慢性阻塞性肺疾病肺细胞衰老的新的和潜在有效的药物治疗 它的恶化基于靶向REV-ERB的α功能，使用基于分子时钟的治疗。