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: 10188615
• 负责人: Isaac Kirubakaran Sundar
• 金额: $ 38.54万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-20 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188615
• 关键词: ARNTL gene; Acute; Adrenal Cortex Hormones; Affect; Agonist; Allergens; Asthma; Attenuated; Binding; Biological; Biological Clocks; Cell physiology; Cells; Circadian Dysregulation; Circadian Rhythms; Clinical; Combined Modality Therapy; Data; Dependence; Epithelial; Epithelial Cells; 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 response; Immunity; Immunomodulators; In Vitro; Inflammation; 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; Repressor Proteins; Research; 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; bronchial epithelium; cell type; chronic inflammatory disease; chronic inflammatory lung disease; circadian; circadian pacemaker; cytokine; design; genetic corepressor; immune activation; in vivo; inhibitor/antagonist; molecular clock; mouse model; novel; prevent; promoter; pulmonary function; 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，表现出随时间变化的变化 临床症状和严重程度。尽管吸入（或全身）皮质类固醇和交感神经抑制剂是 通常用于缓解哮喘对气道功能的直接影响，这些药物大多是 无效。有趣的是，哮喘患者的肺功能和粘液产生的昼夜节律异常 与肺部炎症增加和病情加重有关。 REV-ERBα 是一种核受体 转录因子在昼夜节律计时系统中起着至关重要的作用，可维持每日的节律 与免疫、炎症和代谢相关的基因表达。我们的初步数据显示，减少 暴露于屋尘螨后小鼠肺部气道上皮中 REV-ERBα 的表达 (HDM) 过敏原与哮喘肺表型增强相关（气道炎症增加、 气道高反应性、Th2 细胞因子、血浆 IgE 和粘液化生）。此数据符合 研究表明 REV-ERBα 表达在小鼠哮喘模型和人类中下调 从哮喘患者身上恢复的气道细胞。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 回复。然而，没有数据描述 REV-ERBα 可能有助于的分子机制 过敏性哮喘的病理学。我们假设过敏原诱导的 REV-ERBα 破坏 表达导致时钟功能不规则并增强免疫炎症反应 肺。目标 1：确定 REV-ERBα 在免疫细胞招募至肺部的过程中的作用 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部免疫炎症反应 一天中两个不同时间急性 HDM 暴露后通过 RNA 测序 (RNA-seq) 进行转录组分析 Rev-erbα 敲除小鼠和野生型小鼠（AM 与 PM）。目标 2：确定小分子是否激活 REV-ERBα 可以通过以下方式预防和/或减轻气道炎症和哮喘肺表型 体内抑制 NFIL3-STAT3 轴。我们将采用遗传和药理学方法 确定 REV-ERBα 的激活是否可以保护和/或减轻过敏性哮喘。靶标特异性和细胞 类型依赖性将使用 RNA-seq 分析来确定。目标 3：确定机制 HDM/Th2细胞因子抑制上皮中REV-ERBα的表达，导致上皮屏障 体外功能障碍和杯状细胞增生。我们将治疗原代人支气管上皮细胞 经或未经选择性 REV- 治疗的外气道组织（正常和哮喘患者）对 HDM/Th2 细胞因子的影响 ERBα 激动剂/拮抗剂或 STAT3 抑制剂。这将决定 NFIL3-STAT3 轴如何抑制 REV- ERBα 在 Th2 细胞因子诱导的屏障功能障碍和杯状细胞增生中发挥作用。总体而言，本研究将 描述了 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。