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-ERB? 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-ERB? 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-ERB? expression is downregulated in mouse models of asthma and in human airway cells recovered from asthmatics. Together, these data suggests that REV-ERB? 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-ERB? may contribute to the pathobiology of allergic asthma. We hypothesize that allergen-induced disruption of REV-ERB? expression leads to irregular clock function and enhanced immune-inflammatory response in the lungs.
Aim 1 : Determine the role of REV-ERB? 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-erb? knockout and wild-type mice.
Aim 2 : Determine if small molecule activation of REV-ERB? 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-ERB? 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-ERB? 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- ERB? agonists/antagonists or a STAT3 inhibitor. This will determine how NFIL3-STAT3 axis represses REV- ERB? function in Th2 cytokine-induced barrier dysfunction and goblet cell hyperplasia. Overall, this study will delineate the novel role of REV-ERB? in the clock-dependent pathophysiological response to allergic asthma.
Allergic asthma is a chronic lung inflammatory disease with a strong circadian signature and patients with allergic asthma develop worse symptoms during the night and early in the mornings. It is likely that circadian variation plays a crucial role during the pathophysiology of allergic asthma. Our research will unravel key molecular mechanisms that link circadian clock targets and asthmatic lung phenotypes and may identify new treatment options through novel pharmacological and chronotherapeutic agents (e.g., selective REV-ERB? agonists) to ameliorate the intensity of exacerbations and the overall impact of allergens in severe asthmatics.
