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

基本信息

批准号：
10643859
负责人：
Isaac Kirubakaran Sundar
金额：
$ 38.78万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10643859
关键词：
ARNTL gene Acute Adrenal Cortex Hormones Affect Agonist Agreement Allergens Asthma Attenuated Binding Biological Biological Clocks Cell physiology Cells Circadian Dysregulation Circadian Rhythms Clinical Combined Modality Therapy Data Dependence 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 response Immunity Immunomodulators In Vitro Inflammation Inflammatory Response Inhalation Interleukin-4 Interleukin-6 Knock-out Knockout Mice Link Liquid substance Lung Measures Mediating Metabolism Metaplasia Molecular Mucins Mucous body substance Mus Nuclear Nuclear Receptors Patients Pharmaceutical Preparations Phenotype Plasma Play Production Proteins Pulmonary Inflammation Pyroglyphidae Reaction Time Repression 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 antagonist asthma exacerbation asthma model asthmatic bronchial epithelium cell type chronic inflammatory disease chronic inflammatory lung disease circadian circadian pacemaker circadian transcriptome cytokine design genetic corepressor immune activation immunoregulation in vivo inhibitor molecular clock mouse model novel pharmacologic prevent promoter pulmonary function recruit response small molecule transcription factor transcriptome sequencing translational potential

项目摘要

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尽管吸入（或全身）皮质类固醇和交感神经抑制剂是临床症状和严重程度的主要影响因素。通常用于缓解哮喘对气道功能的直接影响，这些药物大多是有趣的是，哮喘患者的肺功能和粘液产生出现异常的昼夜节律。 REV-ERBα 是一种核受体，与肺部炎症增加和病情加重有关。转录因子在昼夜节律计时系统中起着至关重要的作用，可维持每日的节律我们的初步数据表明，与免疫、炎症和代谢相关的基因表达减少。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）。研究表明，REV-ERBα 表达在小鼠哮喘模型和人类模型中下调总之，这些数据表明 REV-ERBα 可能有助于哮喘患者的气道细胞。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然而，没有数据描述其分子机制，因此 REV-ERBα 可能有所贡献。我们面对过敏原引起的 REV-ERBα 破坏。表达导致时钟功能不规则并增强免疫炎症反应目标 1：确定 REV-ERBα 在免疫细胞招募至肺部过程中的作用。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（AM 与 PM）在 Rev-erbα 敲除和野生型小鼠中的作用目标 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我们将采用遗传和药理学方法来抑制体内 NFIL3-STAT3 轴。确定 REV-ERBα 的激活是否可以保护和/或减轻过敏性哮喘。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和经或未经选择性 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。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。