Nuclear Receptor REV-ERB alpha Role in the Pathophysiology of Allergic Asthma

核受体 REV-ERB α 在过敏性哮喘病理生理学中的作用

• 批准号: 9816410
• 负责人: Isaac Kirubakaran Sundar
• 金额: $ 39.52万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816410
• 关键词: ARNTL gene; Acute; Adrenal Cortex Hormones; Affect; Agonist; Allergens; Asthma; Attenuated; Binding; Biological; Biological Clocks; Cell physiology; Cells; Chronic; Circadian Dysregulation; Circadian Rhythms; Clinical; Combined Modality Therapy; Complex; Data; Dependence; Disease; Epithelial; Epithelial Cells; Epithelium; Etiology; Exposure to; Extrinsic asthma; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Goblet Cells; HDAC3 gene; Hour; House Dust Mite Allergens; Household; Human; Hyperplasia; IgE; Immune; Immune Cell Activation; Immune response; Immunity; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Interleukin-4; Interleukin-6; Knock-out; Knockout Mice; Link; Liquid substance; Lung; Lung Inflammation; Measures; Mediating; Metabolism; Metaplasia; Molecular; Mucins; Mucous body substance; Mus; Nuclear; Nuclear Receptors; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Plasma; Play; Production; Proteins; Pyroglyphidae; Research; Respiratory physiology; Response Elements; Role; STAT3 gene; Serum; Severities; Specificity; Symptoms; System; Testing; Time; Tissues; Variant; Wild Type Mouse; airway epithelium; airway hyperresponsiveness; airway inflammation; allergic airway inflammation; allergic response; asthma exacerbation; asthma model; asthmatic; cell type; circadian; circadian pacemaker; cytokine; design; in vivo; inflammatory lung disease; inhibitor/antagonist; molecular clock; mouse model; novel; prevent; promoter; recruit; response; small molecule; transcription factor; transcriptome; transcriptome sequencing

SUMMARY: Allergic asthma is a chronic inflammatory disease that displays time-of-day dependent variations in clinical symptoms and severity. Though inhaled (or systemic) corticosteroids and sympathetic inhibitors are commonly used to alleviate the immediate impact of asthma on airway function, these drugs are mostly ineffective. Intriguingly, asthmatics show abnormal circadian rhythms of lung function, and mucus production associated with increased lung inflammation and exacerbations. REV-ERBα is a nuclear receptor and transcription factor that plays a critical role in the circadian timing system, acting to maintain daily rhythms of gene expression linked to immunity, inflammation and metabolism. Our preliminary data show that reduced expression of REV-ERBα in the airway epithelium of mouse lungs following exposure to the House Dust Mite (HDM) allergen is associated with augmented asthmatic lung phenotypes (increased airway inflammation, airway hyperresponsiveness, Th2 cytokines, plasma IgE and mucous metaplasia). This data agrees with studies showing that REV-ERBα expression is downregulated in mouse models of asthma and in human airway cells recovered from asthmatics. Together, these data suggests that REV-ERBα may contribute to the pathophysiology of allergic asthma and represent a novel target for alleviating the immune-inflammatory response. However, there is no data describing the molecular mechanism, whereby REV-ERBα may contribute to the pathobiology of allergic asthma. We hypothesize that allergen-induced disruption of REV-ERBα expression leads to irregular clock function and enhanced immune-inflammatory response in the lungs. Aim 1: Determine the role of REV-ERBα in recruitment of immune cells into the lung during allergic asthma. We will measure lung immune-inflammatory response over time and global circadian transcriptome by RNA-sequencing (RNA-seq) following acute HDM exposure at two different times of the day (AM vs. PM) in Rev-erbα knockout and wild-type mice. Aim 2: Determine if small molecule activation of REV-ERBα can prevent and/or attenuate airway inflammation and asthmatic lung phenotypes by repressing NFIL3-STAT3 axis in vivo. We will employ both genetic and pharmacological approaches to determine if activation of REV-ERBα can protect and/or attenuate allergic asthma. Target specificity and cell- type dependency will be determined using RNA-seq analysis. Aim 3: Determine the mechanism how HDM/Th2 cytokines suppress REV-ERBα expression in the epithelium leading to epithelial barrier dysfunction and goblet cell hyperplasia in vitro. We will treat primary human bronchial epithelial cells and EpiAirway tissues (normal and asthmatics) to HDM/Th2 cytokines with or without treatment with selective REV- ERBα agonists/antagonists or a STAT3 inhibitor. This will determine how NFIL3-STAT3 axis represses REV- ERBα function in Th2 cytokine-induced barrier dysfunction and goblet cell hyperplasia. Overall, this study will delineate the novel role of REV-ERBα in the clock-dependent pathophysiological response to allergic asthma.

摘要：过敏性哮喘是一种慢性炎症性疾病，表现出时间依赖性变化 临床症状和严重程度。虽然吸入（或全身）皮质类固醇和交感神经抑制剂， 这些药物通常用于缓解哮喘对气道功能的直接影响， 无效。有趣的是，哮喘患者表现出肺功能和粘液产生的昼夜节律异常 与肺部炎症增加和恶化相关。REV-ERBα是核受体， 一种转录因子，在昼夜节律计时系统中起关键作用，用于维持 与免疫、炎症和新陈代谢相关的基因表达。我们的初步数据显示， REV-ERBα在屋尘螨暴露小鼠气道上皮中的表达 (HDM)过敏原与增强的哮喘肺表型（增加的气道炎症， 气道高反应性、Th 2细胞因子、血浆IgE和粘膜化生）。这些数据与 研究显示REV-ERBα表达在哮喘小鼠模型和人类中下调， 从哮喘病人身上找到的气道细胞总之，这些数据表明，REV-ERBα可能有助于 过敏性哮喘的病理生理学，并代表了减轻免疫炎症的新靶点， 反应然而，没有数据描述REV-ERBα可能参与的分子机制 过敏性哮喘的病理学我们假设过敏原诱导的REV-ERBα的破坏 表达导致不规则的时钟功能和增强的免疫炎症反应， 肺目的1：确定REV-ERBα在免疫细胞募集到肺中的作用， 过敏性哮喘我们将测量随着时间的推移和全球昼夜节律的肺免疫炎症反应 一天中两个不同时间急性HDM暴露后通过RNA测序（RNA-seq）进行的转录组 (AM与PM）。目的2：确定小分子活化是否 REV-ERBα可通过以下途径预防和/或减轻气道炎症和哮喘肺表型： 在体内抑制NFIL 3-STAT 3轴。我们将采用遗传学和药理学方法， 确定REV-ERBα的激活是否可以保护和/或减轻过敏性哮喘。目标特异性和细胞- 将使用RNA-seq分析来确定类型依赖性。目标3：确定机制如何 HDM/Th 2细胞因子抑制REV-ERBα在上皮中的表达导致上皮屏障 功能障碍和杯状细胞增生。我们将处理原代人支气管上皮细胞， 无论是否接受选择性REV治疗，EpiAirway组织（正常和哮喘患者）对HDM/Th 2细胞因子的影响 ERBα激动剂/拮抗剂或STAT 3抑制剂。这将决定NFIL 3-STAT 3轴如何抑制REV-1。 ERBα在Th 2型丝氨酸诱导的屏障功能障碍和杯状细胞增生中的作用总的来说，这项研究将 描述REV-ERBα在过敏性哮喘的时钟依赖性病理生理反应中的新作用。