LUNG CELLULAR SENESCENCE AND MOLECULAR CLOCK REV-ERBalpha BY ENVIRONMENTAL TOBACCO SMOKE

About This Grant

SUMMARY Tobacco/cigarette smoke (CS) including environmental tobacco smoke (ETS) exposure leads toxicological effects on the lungs associated with injury and inflammation in airway disorders, such as Chronic Obstructive Pulmonary Disease (COPD). COPD is the third leading cause of chronic morbidity and mortality, both in the United States and globally. Recently, my research has shown that ETS/tobacco smoke- mediated molecular clock disruption is associated with cellular senescence in lung cells. REV-ERBα is a critical component of the molecular clock, which regulates the expression of core clock genes, pro- inflammatory and pro-senescent mediators. We show that ETS-mediated cellular senescence is mediated by alterations in clock gene nuclear receptor REV-ERB in the lungs. I will leverage the ongoing program with my seminal contributions on ‘molecular clock senescence theme’, and continue the upward trajectory of the same high caliber science in the field of inhalation toxicology for improving the environmental human health. There is a gap in understanding the cellular characterization and interactions of senescence and molecular clock in human lungs over the lifespan, particularly in non-smokers, smokers, and COPD with and without smokers. Further, the role of molecular clock REV-ERBα dysfunction in chronic ETS-mediated toxicological lung effects remains unknown. In addition, there is a critical gap on restoration of molecular clock and cellular senescence by using targeted agonists (REV-ERBα) and/or senolytics/senomorphics (senescence inhibitors) in lung cells exposed to ETS. We hypothesize that ETS disrupts molecular clock function, specifically REV- ERBα abundance, resulting in cellular senescence via disruption of nuclear co-repressor complex (NCoR/Sin3A-HDACs) in pulmonary toxicity. Using a combination of cellular, molecular, and toxicological approaches, I propose the three overarching long-term goals on this R35 RIVER application to advance the field of inhalation toxicology and lung molecular clock-inflammaging in chronic environmental lung diseases. 1: Characterization of human molecular clock and lung cellular senescence over the lifespan in COPD (with and without smokers), 2: Determine the role of lung molecular clock REV-ERB in cellular senescence programming via nuclear corepressor complex and airway disease responses, and 3) Attenuation of REV- ERB and senescence and SASP/secretome by pharmacological agents/agonists in lung cells and EpiAirway 3D cells. This will characterize cellular molecular clock and senescent cells at an unprecedented spatial resolution in lungs. This transformative research with a compelling and broad vision will advance the field of environmental lung science, collaborations, and training. The outcome of this proposal will unravel the mechanisms, characterization, and programming of lung molecular clock and senescence based on cellular phenotypes and molecular signatures in the pathogenesis of airways disorder. In turn, this will have a great translational potential for the development of pharmacological therapies in environmental pulmonary diseases.