Uncovering the Role of Retinoic Acid Receptor Beta in Alcoholic Liver Diseases

揭示视黄酸受体β在酒精性肝病中的作用

• 批准号: 9896234
• 负责人: LORRAINE J GUDAS
• 金额: $ 24.37万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896234
• 关键词: Agonist; Alcohol abuse; Alcohol consumption; Alcohol-Related Disorders; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Animal Model; Apoptosis; Attenuated; Biology; Biometry; Chronic; Cirrhosis; Data; Dedications; Development; Disease; Down-Regulation; Environment; Ethanol; Ethanol toxicity; Etiology; Gene Expression; Goals; Heavy Drinking; Hepatic; Hepatitis C; Hepatocyte; Hepatology; High Fat Diet; Histology; Homeostasis; Hospitalization; Human; Immunity; Inflammation; Inflammatory; Injury; Interleukin-17; Investigation; Laboratories; Lead; Letters; Ligands; Link; Lipids; Liver; Liver Dysfunction; Liver Failure; Liver diseases; Malignant neoplasm of liver; Measures; Mediator of activation protein; Medical center; Medicine; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Pathogenesis; Pathologist; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Postdoctoral Fellow; Primary carcinoma of the liver cells; Production; RARB gene; RNA analysis; Rattus; Reactive Oxygen Species; Research; Retinoic Acid Receptor; Retinoids; Role; Series; Severities; Signal Pathway; Signal Transduction; Specialist; Steatohepatitis; Stress; TNF gene; Testing; Therapeutic; Time; Transcript; Tretinoin; Universities; base; cell growth; cell injury; chronic liver disease; cytokine; diabetic; experimental study; glucose tolerance; improved; in vitro Model; in vivo; lipid metabolism; liver transplantation; molecular targeted therapies; mortality; mouse model; non-alcoholic fatty liver disease; novel therapeutics; overexpression; prevent; problem drinker; professor; retinoic acid receptor alpha; therapeutic development; tool; transcriptome sequencing; transcriptomics

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the U.S, and together with nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), is becoming the most common cause of hospitalization for liver transplantation. ALD, while initially asymptomatic, is characterized by steatosis and increased inflammation, and over time progresses toward a more serious condition, culminating in cirrhosis and liver failure. The pathogenesis of ALD is not fully understood which hinders the develop- ment of therapeutic options to manage not only alcohol-related disorders but also subsequent, fatal conditions such as liver failure. ALD shares molecular and histopathologic features with NAFLD/NASH, including increased steatosis, overproduction of oxygen reactive species (ROS), inflammation, and notably disruption of a key regulator of lipid metabolism, retinoic acid receptor beta (RARβ). Our research group has recently shown that disruption of RARβ signaling is critical in the development of NAFLD/NASH and the diabetic state in mice, and that treatment with a highly selective RARβ2 agonist, AC261066, resulted in improved glucose tolerance, and decreased steatosis, ROS, and inflammation. These findings underscore the central role of RARβ as a potential target to manage metabolic disorders and demonstrate that AC261066 could be a useful drug for treating these disorders. Based on the encouraging results obtained in NAFLD/NASH mice models, we hypothesize that the disruption of the RARβ signaling pathway is a key factor in the development of ALD and that treatment with AC261066 can prevent or reverse the progression of alcohol-related liver disorders. To test this hypothesis, we will use an in vitro model and an in vivo mouse model of chronic alcohol abuse that mimics ALD. We propose the following specific aims: Specific Aim (1): Determine if AC261066 prevents ethanol toxicity and determine if RARβ2 is essential for this effect. We will treat human hepatocytes with ethanol and measure metabolism and the expression of genes associated with oxidative stress and apoptosis in the presence or absence of AC261066. In a separate series of experiments, we will determine if the effects of AC261066 are dependent on RARβ2. Specific Aim (2): Determine if AC261066 prevents ethanol toxicity and explore the mechanisms of this effect in a murine model. For this aim we will use a mouse model of chronic ethanol intake that mimics ALD. We will measure the metabolic state prior to sacrifice and will follow with transcriptomic analyses using RNA-Seq, histology and pathology approaches.

酒精性肝病（ALD）是美国发病率和死亡率的主要原因，以及 非酒精性脂肪肝病/脂肪性肝炎（NAFLD/NASH）正在成为最常见的原因 肝移植的住院。 ALD虽然最初是渐近线，但其特征是脂肪变性 并增加感染，随着时间的流逝，朝着更严重的状况发展，最终导致 肝硬化和肝衰竭。 ALD的发病机理尚未完全理解，这阻碍了发展 - 理论选择不仅管理与酒精有关的疾病，而且随后的致命 肝衰竭等疾病。 ALD与NAFLD/NASH共享分子病理学特征， 包括增加脂肪变性，氧气活性物种（ROS）的过量生产，炎症，尤其是 脂质代谢，视黄酸受体β（RARβ）的关键调节剂的破坏。我们的研究小组 最近表明，RARβ信号的破坏对于NAFLD/NASH的发展至关重要 小鼠的糖尿病状态，以及高度选择性RARβ2激动剂AC261066的治疗导致 葡萄糖耐受性提高，改善了脂肪变性，ROS和炎症。这些发现强调了 RARβ作为管理代谢疾病的潜在目标的核心作用，并证明了这一点 AC261066可能是治疗这些疾病的有用药物。基于在 NAFLD/NASH小鼠模型，我们假设RARβ信号通路的破坏是关键 ALD发展和AC261066处理的因素可以预防或逆转 与酒精相关的肝脏疾病的进展。为了检验该假设，我们将使用体外模型和 模仿ALD的慢性酒精滥用的体内小鼠模型。我们提出以下具体目标： 特定目的（1）：确定AC261066是否防止乙醇毒性，并确定RARβ2是否必不可少 为此。我们将用乙醇处理人类肝细胞，并测量新陈代谢和表达 在存在或不存在AC261066的情况下与氧化应激和凋亡相关的基因。在 单独的一系列实验，我们将确定AC261066的影响是否取决于RARβ2。 具体目的（2）：确定AC261066是否防止乙醇毒性并探索其机制 在鼠模型中的效果。为此，我们将使用模仿慢性乙醇摄入的鼠标模型 阿尔德。我们将在牺牲前测量代谢状态，并进行转录组分析 使用RNA-seq，组织学和病理学方法。