PROJECT SUMMARY Marijuana smoking and vaping is on the rise in the United States with the increased legalization of recreational and medical marijuana. The main psychoactive component present in marijuana, and added to vaping preparations, is delta-9-tetrahydrocannabinol (THC). Even though the effect of marijuana smoking on obstructive lung disease can vary between studies, it is recognized that marijuana smoking is associated with increased cough, sputum production, and chronic bronchitis often associated with infections, but the mechanism remains to be determined. Our preliminary data show that chronic exposure of THC alone to primary human bronchial epithelial cells grown at air-liquid interface alters several components of the mucociliary function (i.e. ion channels, cilia beating), resulting in increased susceptibility to infections. Environmental pollutants, such as cigarette smoking, can alter gene expression. Unfortunately, some of the changes can persist despite cessation. The goal of this study is to determine the effects of THC-containing preparations (marijuana and vaping) on bronchial epithelium host defenses. This proposal is submitted in response to NOT-DA-20-031 “Transcriptomic, epigenomic, regulatory RNA or functional genomic research in substance use disorders”. Here, we propose to (1) determine whether chronic exposures to THC through marijuana smoke or vaping differentially alter the bronchial epithelium functions involved in host defense against microbial pathogens; and (2) identify the nature of transcriptomic changes which persist in bronchial epithelium after cessation from exposures to marijuana smoke or vaping. This comprehensive study will reveal the effects of THC in marijuana smoke and vaping preparations on airway homeostasis and identify new molecular targets to prevent infections and development of lung diseases.