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

TP-R 在酒精引起的多器官损伤中的作用：肝脏和心脏

• 批准号: 10526258
• 负责人: Saraswathi Viswanathan
• 金额: $ 24.18万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-28 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10526258
• 关键词: Affect; Alcohol consumption; Alcohol-Related Disorders; Alcoholic Cardiomyopathy; Alcoholic Liver Diseases; Alcohols; Attenuated; Autoimmune Diseases; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Chronic; Collecting Cell; Congestive Heart Failure; Data; Development; Diet; Echocardiography; Eicosanoids; Ethanol; Event; Exposure to; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Functional disorder; G-Protein-Coupled Receptors; General Population; Genetic; Habits; Health; Heart; Heart Diseases; Heart Injuries; Heavy Drinking; Hepatic; Hepatocyte; High Fat Diet; Human; Impairment; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Isoprostanes; Knockout Mice; Link; Linoleic Acids; Liver; Liver diseases; Measurement; Measures; Mediating; Metabolic; Mitochondria; Molecular; Mus; Myocardial; Nebraska; Nutritional; Obesity; Organ; Oxidative Stress; Patients; Peripheral Blood Mononuclear Cell; Polyunsaturated Fatty Acids; Prostaglandins; Rattus; Reporting; Research; Role; Therapeutic Agents; Thromboxane A2; Thromboxanes; Tissues; Triglycerides; Wild Type Mouse; antagonist; chronic alcohol ingestion; chronic inflammatory disease; comparison control; conditional knockout; feeding; heart function; hemodynamics; improved; in vivo; lipid metabolism; liver inflammation; liver injury; mitochondrial dysfunction; multiorgan damage; non-alcoholic fatty liver disease; obese patients; organ injury; oxidant stress; receptor; receptor expression; therapeutically effective

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.

众所周知，肝脏是乙醇作用和酒精相关肝脏的主要目标 疾病（AALD）是普通人群的主要健康问题。还应该指出的是， 由于长期饮酒而导致的心脏病发病率持续上升 人类长期饮酒习惯增加。越来越明显的是， 酒精相关性肝损伤（AALD）与酒精性肝损伤之间存在强正相关性 心肌病（ACM）。最近已经明确，肥胖与重度体重的结合 饮酒会加剧乙醇引起的器官损伤。因此，迫切需要定义 肥胖和酒精单独或组合促进肝脏和肝脏的机制 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，在所有细胞中表达 组织，并由血栓素 A2 以及异前列烷、类二十烷酸介导激活 炎症反应和氧化应激。 TP-R 已知在病理生理学中发挥作用 几种慢性炎症性疾病，例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方面的作用知之甚少。 失调。我们在这项提案中提供了令人兴奋的初步数据，即乙醇诱导的肝损伤 TP-R-KO 小鼠的炎症大大减弱。有趣的是，我们的初步数据还显示 TP-R 表达在人外周血单核细胞 (PBMC) 中显着较高 与对照受试者相比，从肥胖或心血管疾病患者中收集，因此，其 参与 AALD 和 ACM 可能很重要，并且提供治疗机会。 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 部分通过对炎症和氧化应激的影响来激活 TP-R。我们将使用 营养、遗传和分子方法来确定 TP-R 在改变 AALD 和 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 调节乙醇和/或肥胖引起的小鼠肝损伤和心肌病。全面的， 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，并为发展奠定基础 对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。