Project summary: Alcohol remains one of the most frequently used intoxicant in the United States especially among young individuals (1). There is ample evidence that binge alcohol consumption can lead to life-threatening adverse cardiovascular events (2,3). We have recently shown that binge alcohol drinking in a mouse model is associated with the activation of cannabinoid receptor type-1 (CB1) signaling by endocannabinoids, which plays a critical role in the development of binge alcohol intoxication-induced cardiovascular dysfunction. (Paloczi et al., accepted for publication, J Am Coll Cardiol Basic Trans Science). Activation of CB1 receptors by endocannabinoids or their plant-derived or synthetic analogs has a robust impact on cardiovascular functions, as reflected in abnormalities in cardiac inotropy, chronotropy, conduction and vascular tone (reviewed in 4,5). Therefore, elaborating the role of the gut-heart axis in the activation of the endocannabinoid system by acute alcohol intoxication may hold great translational value. The overarching aim of this proposal is to identify the cellular source of endocannabinoids and the cellular mechanisms of CB1 receptor activation in the heart and vasculature following binge alcohol drinking. To this end, I propose three specific aims: Specific aim 1: To determine the cellular source of endocannabinoids in the myocardium following alcohol exposure in vitro and potential changes in CB1 expression in various myocardial cell types. Specific aim 2: To uncover the role of gut-heart axis in binge alcohol drinking in vivo and characterize if acute alcohol-induced gut injury is involved in cardiac anandamide production that ultimately leads to alterations in left ventricular function. Specific aim 3: To investigate the impact of binge alcohol drinking-induced gut injury on vascular endocannabinoid production in vivo and the consequent vascular dysfunction. The anandamide-driven vasodilatation in different types of vessels will also be characterized ex vivo. I have been interested in the cardiovascular physiology and pathophysiology for many years. As I continue my training, I’m sure my mentor, Dr. Pal Pacher will challenge me to continuously improve as a scientist. To further facilitate the achievement of the outlined goals, Drs. Kunos, Cinar and Ungvari, three researchers with expertise in the field of my studies have agreed to be members of my advisory committee. Therefore, I am confident that with the support of my mentor, my intra-, and extramural advisory committee, and the institutional support of the NIAAA, I will be able to execute the proposed experiments, and succeed as an independent scientist in the field of cardiovascular alcohol research.