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

众所周知，肝脏是酒精作用的主要靶点，而与酒精相关的肝脏 疾病(AALD)是普通人群的主要健康问题。还应该指出的是， 长期饮酒导致的心脏病发病率继续上升，原因是 人类长期饮酒习惯增加。越来越明显的是， 酒精性肝损伤与酒精性肝损伤呈显著正相关 心肌病(ACM)。最近有一点很清楚，肥胖和肥胖的结合 饮酒会加剧酒精引起的器官损伤。因此，迫切需要界定 肥胖和酒精单独或联合作用促进肝脏和 心脏损伤。我们假设的核心是血栓素A-前列腺素受体(TP-R)是一种 AALD和ACM之间的共同链接。TP-R是一种G蛋白偶联受体，在急性淋巴细胞白血病中表达 组织，并被血栓素A2和异前列腺素激活，二十烷类化合物介导 炎症反应和氧化应激。已知TP-R在高血压的病理生理学中起作用。 几种慢性炎症性疾病，如心血管疾病和某些自身免疫疾病 疾病。然而，关于TP-R在调节肥胖和与酒精相关的过程中的作用，人们知之甚少 精神错乱。在这项建议中，我们提供了令人兴奋的初步数据，乙醇诱导的肝脏 TP-R-KO小鼠的炎症反应明显减轻。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)中的表达显著升高 从肥胖或心血管疾病患者收集的数据与对照组进行比较，因此，其 同时参与急性酒精性肝病和急性心肌梗死可能很重要，并为治疗提供了机会。 根据之前的报告和我们的初步数据，我们假设在肥胖的情况下， 长期饮酒会促进肝脏和心脏损伤，这种影响至少在 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 确定TP-R在改变AALD和AALD中的作用的营养、遗传和分子方法 ACM.在目标1中，我们将确定肝细胞-TP-R在调节酒精和/或肥胖- 致小鼠肝损伤和心肌病。在目标2中，我们将评估心肌细胞- TP-R在调节酒精和/或肥胖诱导的小鼠肝损伤和心肌病中的作用。总的来说， 这项拟议的研究将揭示TP-R在调节AALD和ACM中的作用 或不存在肥胖，以确定潜在的机制，并为发展 肥胖症代谢并发症患者的有效治疗药物 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.