SUMMARY 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 exacerbations induced by viral and bacterial infections. We have recently reported that cigarette smoke (CS) causes abnormal inflammatory responses in the lungs while also disrupting the circadian molecular clock in lung cells. Our preliminary data suggest that CS-induced cellular senescence and the influenza virus-induced decline in lung function are associated with molecular clock dysfunction in lung epithelial cells. REV-ERBα is a nuclear receptor and critical component of the molecular clock that drives daily rhythms of metabolism and immune- inflammatory responses. We have shown that airway and alveolar REV-ERBα levels are reduced in the lungs of mice with emphysema and in the lungs of COPD patients, and during exacerbations. Further, REV-ERBα agonists reduce CS-induced levels of pro-inflammatory and pro-senescent mediators. These data suggest that, besides its function as part of the molecular clock, REV-ERBα also acts as a critical component of the immune- inflammatory response to CS and may be a key player in the progression and exacerbation of COPD. Despite these intriguing results, the role of REV-ERBα in CS-mediated DNA damage/repair and cellular senescence and its involvement in influenza virus-mediated lung responses is not known. We hypothesize that the CS- mediated reduction in REV-ERBα abundance potentiates lung cellular senescence and inflammatory responses. Further, the loss of circadian protein leads to COPD development, progression, and produces more severe influenza virus-induced exacerbations. We propose to test this hypothesis by determining the mechanistic relationship between the CS-induced reduction of REV-ERBα levels, increased cellular senescence, DNA damage/repair, emphysematous responses and virus-mediated decline in lung function and mucus production in the following three Aims: Aim 1: Determine whether REV-ERBα protects against cellular senescence and senescence-associated inflammatory responses during CS-induced COPD/emphysema; Aim 2: Determine the mechanism whereby the interaction between REV-ERBα, RORα and HDAC3 regulates CS-induced lung cellular senescence and inflammatory responses; and Aim 3: Determine whether REV-ERBα protects against lung function decline and mucus hypersecretion in a mouse model of influenza virus-mediated COPD exacerbation. This proposal will unravel the role of the nuclear receptor and clock protein REV-ERBα in regulating lung cellular senescence and inflammatory responses during influenza virus-induced COPD/emphysema exacerbations. In turn, this will have great translational potential for the development of novel and potentially effective pharmacological therapies to ameliorate lung cellular senescence in COPD and its exacerbations based on targeting REV-ERBα function in the lungs using a m...