It is well-established that liver is the primary target of ethanol action and alcohol-associated liver disease (AALD) is a major health concern in general population. It should also be noted that the incidence of heart disease due to chronic alcohol consumption continues to rise owing to the increased chronic alcohol drinking habits among humans. It is becoming increasingly evident that a strong positive correlation exists between alcohol-associated liver injury (AALD) and alcoholic cardiomyopathy (ACM). It has recently become clear that the combination of obesity with heavy drinking exacerbates ethanol-induced organ injury. Thus, there is an urgent need to define mechanisms by which obesity and alcohol either individually or in combination, promote liver and cardiac injury. Central to our hypothesis is that thromboxane-prostanoid receptor (TP-R) is a common link between AALD and ACM. TP-R is a G-protein coupled receptor, expressed in all tissues, and is activated by thromboxane A2 as well as isoprostanes, eicosanoids mediating inflammatory response and oxidative stress. TP-R is known to play a role in the pathophysiology of several chronic inflammatory diseases, such as cardiovascular disease and certain autoimmune diseases. Little is known, however about a role for TP-R in modulating obesity and alcohol-related disorders. We present exciting preliminary data in this proposal that ethanol-induced hepatic inflammation is greatly attenuated in TP-R-KO mice. Interestingly, our preliminary data also show that TP-R expression is significantly higher in human peripheral blood mononuclear cells (PBMCs) collected from patients with obesity or CVD compared to control subjects and therefore, its involvement in both AALD and ACM might be important, and present opportunities for treatment. Based on previous reports and our preliminary data, we hypothesize that in the presence of obesity, chronic alcohol consumption promotes liver and cardiac injury and this effect is mediated at least in part, via activation of TP-R through its effects on inflammation and oxidative stress. We will use nutritional, genetic, and molecular approaches to determine the role of TP-R in altering AALD and ACM. In Aim 1, we will define the role of hepatocyte-TP-R in modulating ethanol- and/or obesity- induced liver injury and cardiomyopathy in mice. In Aim 2, we will assess the role of cardiomyocyte- TP-R in modulating ethanol- and/or obesity-induced liver injury and cardiomyopathy in mice. Overall, the proposed research will uncover the role of TP-R in modulating AALD and ACM in the presence or absence of obesity, to identify potential mechanisms, and to set the stage for the development of effective therapeutic agents for human patients affected by the metabolic complications of obesity and/or excess ethanol consumption.