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 exacerbation, and have an increased rate of emergency room visits and hospitalizations, particularly in the night time and early hours of the day when lung function is lowest and steroids and bronchodilators have their smallest effects. Patients with COPD have abnormal circadian rhythm, reflected in circadian changes in the airway caliber and resistance and respiratory symptoms. However, the cellular and molecular mechanism that underlies altered circadian rhythm in lungs of patients with COPD is not understood. Circadian clock period proteins (Per) and cryptochrome (Cry) and their transcriptional activators core CLOCK and BMAL1 regulate intrinsic daily rhythm, but the role of these molecular oscillators in lung physiology and pathology in response to environmental cues is not known. Our preliminary data show the presence of circadian oscillator in mouse and human lungs and further show that this clock oscillation is disturbed by cigarette smoke (CS) and in patients with COPD. Our preliminary data further show that the acetylation of BMAL1 and Per2 is increased in bronchial epithelial cells, macrophages and lungs of mice exposed to CS, and in sputum and lung cells from COPD patients associated with reduction in the activity/level of deacetylase sirtuin 1 (SIRT1). Genetic ablation of SIRT1 leads to dampening of circadian clock associated with exaggerated lung inflammatory responses and decline in lung function, suggesting that SIRT1 plays a regulatory role in lung circadian physiology. However, the functional consequence of altered circadian rhythmicity in lungs by CS is not known. We, therefore, hypothesize that circadian proteins BMAL1 and Per2 are altered by CS via downregulation of SIRT1 leading to disruption of circadian rhythm, increased lung inflammation and steroid resistance associated with decline in lung function in mouse model of COPD/emphysema and its exacerbations. We propose the three specific aims to test this hypothesis in vitro in bronchial epithelial cells and macrophages and in vivo in mouse lungs exposed to CS. We propose to: (1) determine the molecular mechanisms by which CS exposure results in alteration of circadian proteins BMAL1 and Per 2 in human bronchial epithelial cells, macrophages and in mouse lungs;(2) determine the mechanisms whereby SIRT1 regulates BMAL1, inflammatory response and circadian periodicity by CS;and (3) determine the role of circadian proteins and SIRT1 on CS-mediated alteration in circadian periodicity, inflammation and steroid resistance in a mouse model of COPD and its exacerbations, and in patients with exacerbations of COPD. Overall, this study will understand the cellular and molecular mechanisms of peripheral circadian-coupled lung functions and identify SIRT1 as novel target for strategic chronotherapeutic manipulation of circadian proteins and reversal of steroid resistance.
Impact on public health: COPD is the fourth leading cause of chronic morbidity and mortality in the United States, hence it is a major public health concern. Circadian regulation of COPD exacerbations is associated with worsening and rapid decline in lung function in patients with COPD where current therapies are palliative. Our research will identify the mechanisms of molecular circadian clock in lung cells regulating lung inflammation and augment the therapeutic potentials of steroids and bronchodilators by modulating circadian proteins in COPD.
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