PROJECT SUMMARY/ABSTRACT: The primary goal of this mentored career development K99 phase is to develop the knowledge, skills and experience required to progress to an independent investigator R00 phase. The proposed career development plan includes the participation in seminars and scientific meetings to gain knowledge on the current alcohol addiction research, improving laboratory research skills, and mentored learning to ensure a successful transition to independence. This will create a solid platform of knowledge and skills. The mentored proposal under the mentorship of Dr. Madhavan Nair will encourage hypothesis driven research and independent investigation. In the United States, 18 million Americans suffer from alcohol use disorders (AUD). Only 7.1% of these individuals received any treatment in the past year; and alcohol abuse (AA) contributes to 5% of death annually. AA can contribute to a higher risk of infectious diseases and other undesirable medical conditions involving complex interactions between the direct effects of alcohol and its toxic metabolites on various immune cells, induction of oxidative stress, and upregulation of the inflammatory cascade and inflammation- related genes such as cannabinoid genes (CBRs) and histone deacetylases (HDACs). The proposed work is relevant to the mission and research interests of NIAAA since it will elucidate mechanisms underlying the biomedical effects of alcohol in human immune cells and also combines alcohol with innovative research areas including CBRs and epigenetics. The proposed research that leads to the independent R00 phase of the award is aimed to dissect the role of alcohol-associated epigenetic mechanisms in immune modulation of cannabinoid genes. In recent years, chromatin remodeling has emerged as an important regulatory mechanism for drug addiction and also in development of neurodegenerative disorders. Further, HDAC inhibitors (HDACi) have been known to modulate genes involved in drug addiction such as the ? opioid receptor gene (MOR), and decrease cocaine self administration. However, the role HDACs play in AUDs has not been elucidated yet, particularly their ability to modulate drug and alcohol addiction associated genes in human dendritic cells. Accordingly, we hypothesize that alcohol modulates CBRs expressed in human monocyte-derived dendritic cells (MDDCs), and the mechanisms may be mediated by HDACs and oxidative stress. The specific goals are to determine: 1. the levels of HDAC2, CB2, and GPR55 in MDDCs from alcohol abusers, normal donors, and alcohol treated cells. 2. the epigenetic mechanisms involved in alcohol- modulation of CB2 and GPR55 genes in normal MDDCs treated with alcohol. 3. the potential of HDAC inhibitors and cannabinoid agonists to reduce inflammation and restore oxidative stress damage in MDDCs from alcohol users and normal MDDCs treated with alcohol.Thus, an understanding of the alcohol-associated epigenetic changes and its implications in immune modulation will have translational significance for therapeutic targeting and control of AUDs.