Alcohol-mediated Clock genes interfere with lung injury and repair

In the United States, the acute respiratory distress syndrome (ARDS) remains a significant public health problem. Despite substantial efforts to improve the outcome, ~ 80% of ARDS survivors experience reduced health-related quality of life and have fibrotic changes on chest imaging for up to 5 years after diagnosis. Chronic alcohol abuse significantly increases the incidence of, and mortality from, ARDS, without directly causing lung damage. Emerging data show that alcohol interferes with the circadian signaling pathway in the liver and intestine which, in turn, render tissue susceptibility to injury and fibrosis. The circadian pathway consists of multiple transcription factors which mediate various organ physiological functions through its regulatory networks. It is known that some of circadian pathway molecules can regulate non-coding RNAs and vice versa, non-coding RNAs can regulate circadian pathway molecules. In this proposal, we present preliminary data showing that alcohol promotes circadian pathway dysfunction in the lung through alterations of circadian pathway molecules BMAL1 and nuclear factor Retinoid-Related Orphan Receptor-alpha (RORα). We believe these changes lead to alcohol-induced TGFβ1 by suppressing RORα-miR-139 activity. Further, we identified the circ-RORα-miR-155 axis as a novel regulatory mechanism of BMAL1. These results led us to hypothesize that chronic alcohol ingestion disrupts circadian pathway signaling and the circ-RORα-miR-155 axis which, thereby perturbing the RORα-miR-139 axis which, in turn, render lung susceptibility toward fibroproliferative disrepair following acute injury. The experimental approaches are designed to test this hypothesis. These studies will provide a firm scientific basis for the underlying mechanisms by which alcohol interferes with tissue repair following lung injury.