The Role of TP-R on Alcohol-Induced Multi-Organ Damage: Liver and Heart

肝脏是酒精作用的主要靶点，酒精相关性肝脏是公认的 疾病（AALD）是普通人群中的主要健康问题。还应指出， 由于长期饮酒导致的心脏病发病率继续上升， 人类慢性饮酒习惯的增加。越来越明显， 酒精相关性肝损伤（AALD）与酒精性肝损伤之间存在较强的正相关性。 心肌病（ACM）。最近已经清楚的是，肥胖与超重的结合 饮酒加剧了乙醇引起的器官损伤。因此，迫切需要界定 肥胖和酒精单独或组合的机制，促进肝脏和 心脏损伤我们假设的核心是血栓素-前列腺素受体（TP-R）是一种 AALD和ACM之间的共同联系。TP-R是一种G蛋白偶联受体，在所有的细胞中表达。 组织，并通过血栓素A2以及异前列腺素、类花生酸介导 炎症反应和氧化应激。已知TP-R在糖尿病的病理生理学中起作用。 一些慢性炎症性疾病，如心血管疾病和某些自身免疫性疾病， 疾病然而，人们对TP-R在调节肥胖和酒精相关性肥胖中的作用知之甚少。 紊乱我们提出了令人兴奋的初步数据，在这一建议，乙醇诱导的肝 炎症在TP-R-KO小鼠中大大减弱。有趣的是，我们的初步数据还显示， TP-R在人外周血单个核细胞（PBMC）中的表达显著高于 与对照组相比，从肥胖或CVD患者中收集，因此， 参与AALD和ACM可能是重要的，并提供治疗的机会。 根据以前的报告和我们的初步数据，我们假设，在肥胖的存在， 慢性酒精消耗促进肝脏和心脏损伤，这种作用至少在 部分，通过激活TP-R通过其对炎症和氧化应激的影响。我们将使用 营养、遗传和分子方法来确定TP-R在改变AALD中的作用， ACM。在目标1中，我们将定义肝细胞-TP-R在调节乙醇和/或肥胖中的作用， 诱导小鼠肝损伤和心肌病。在目标2中，我们将评估心肌细胞的作用- TP-R在调节小鼠乙醇和/或肥胖诱导的肝损伤和心肌病中的作用总的来说， 这项研究将揭示TP-R在调节AALD和ACM中的作用， 或没有肥胖，以确定潜在的机制，并为发展奠定基础， 用于受肥胖代谢并发症影响的人类患者的有效治疗剂 和/或过量的乙醇消耗。

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.