NRSA Fellowship For Madison Blanton: Uncovering The Functional And Mechanistic Dysregulation Of Monocytes After Abstinence And Post-Abstinence Drinking

1 Over 85% of individuals 18 years and older within the United States (US) consume alcohol. More importantly, a 2 staggering 25.8% and 6.3% are classified by the National Institute on Alcohol Abuse and Alcoholism criteria as 3 binge or heavy drinkers, respectively, making alcohol the 3rd leading cause of preventable death. Chronic heavy 4 drinking (CHD) increases the incidence of heart disease, stroke, cancer, and alcoholic liver disease. CHD is also 5 associated with heightened susceptibility to bacterial/viral pathogens and tissue repair mechanisms, suggesting 6 alcohol negatively impacts the immune system. Indeed, studies from our group and others have reported 7 functional, transcriptional, and epigenetic modifications in peripheral monocytes and tissue-resident 8 macrophages, skewing them toward a hyper-inflammatory phenotype while impairing pathogen defense 9 mechanisms. Despite the significant contribution of aberrant monocyte/macrophage responses to CHD-induced 10 injury, no studies to date have investigated the effects of abstinence and relapse on these critical cells. Organs 11 and organ systems after alcohol consumption (brain, liver, lung) are challenging to interrogate throughout 12 repeated bouts of abstinence and relapse. Since circulating monocytes provide some of the precursors to 13 infiltrating tissue-resident macrophages, investigating the effects of abstinence and relapse on circulating 14 monocytes will provide greater insight into how CHD dysregulates organs and organ systems. To address this 15 knowledge gap, we will leverage a rhesus macaque model of voluntary ethanol self-administration to test the 16 hypothesis that short periods of abstinence are insufficient for fully restoring functional, transcriptional, 17 and epigenetic changes in peripheral monocytes, and repeated bouts of abstinence and relapse will 18 exacerbate these changes. We will interrogate monocyte functional capacity by measuring immune mediator 19 and antimicrobial function, and phagocytic capacity. The functional capacity of monocytes is regulated by 20 transcriptional and metabolic landscapes, we will use scRNAseq and metabolic assays to determine 21 transcriptional changes and metabolic shifts that occur throughout abstinence and relapse episodes. Finally, to 22 gain a better understanding of the underlying mechanisms driving changes after CHD, we will uncover the 23 influence of successive bouts of abstinence and relapse on the epigenetic landscape. These experiments will 24 provide deeper insight into the persistence of CHD-induced immune modifications in complex organs and organ 25 systems. This understanding could identify novel druggable targets that decrease alcohol cravings or organ 26 damage/opportunistic infections that occur after CHD.