PROJECT SUMMARY ABSTRACT This K08 application proposes a 5-year training program to develop the career of Dr. Bashar Staitieh as he studies the mechanisms by which chronic alcohol ingestion causes oxidative stress and impairs innate immune function in the lung. His primary mentor, Dr. David Guidot, is an internationally- recognized expert in the field of alcohol and lung biology who has mentored multiple post-doctoral MD and PhD trainees including four NIH K awardees and two VA Career Development awardees. Outstanding senior investigators at Emory have been recruited to join the mentoring team that will guide Dr. Staitieh’s career development. Together they determined that alcohol depletes the alveolar space of the critical anti-oxidant glutathione, in part through its previously unrecognized inhibition of the transcription factor Nrf2, and impairs the ability of the lung to defend itself against oxidative stress. This renders individuals with alcohol use disorders at increased risk for a variety of lung-related complications including pneumonia and acute lung injury. Dr. Staitieh has identified a novel and provocative connection between Nrf2 and PU.1, another key transcription factor responsible for a wide range of innate immune functions in the alveolar macrophage. His published and new preliminary data suggest that the regulation of PU.1 by Nrf2 may have significant consequences for the phenotype and function of the ‘alcoholic alveolar macrophage’. These results led to the fundamental hypothesis underlying this project that alcohol-mediated inhibition of Nrf2 and the consequent effects on PU.1 are key mediators of innate immune dysfunction in the alveolar macrophages of individuals with alcohol use disorders. Previous work by the Emory Alcohol and Lung Biology Center has established the detrimental effects of chronic alcohol ingestion on both Nrf2 and PU.1, but the connection between these two factors and the implications of their interaction have not been yet been elucidated. This K08 project reflects a novel approach to understanding the fundamental mechanisms by which alveolar macrophage innate immune functions are impaired in individuals living with alcohol use disorders. Further, the training necessary to achieve these aims will provide Dr. Staitieh with the skills to develop into an independent physician-scientist in the important field of alcohol and lung biology. Emory is among the premier sites in the world for alcohol and lung biology research and this nurturing mentoring team has a strong track record of developing the careers of alcohol researchers. Dr. Staitieh recently joined the faculty at Emory following a productive training period with NIH T32 support and is at a critical stage of his career development. The support of a K08 will enable him to meet his goal of becoming an independent physician-scientist focused on improving the health of individuals suffering from alcohol use disorders.