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: 10019450
• 负责人: LORRAINE J GUDAS
• 金额: $ 20.13万
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019450
• 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，并且与 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 住院进行肝移植。 ALD 虽然最初无症状，但其特征是脂肪变性 炎症加剧，随着时间的推移，病情会发展为更严重的情况，最终导致 肝硬化和肝功能衰竭。 ALD 的发病机制尚不完全清楚，这阻碍了其发展 治疗选择不仅可以控制与酒精相关的疾病，还可以控制随后的致命疾病 肝功能衰竭等情况。 ALD 与 NAFLD/NASH 具有相同的分子和组织病理学特征， 包括脂肪变性增加、氧活性物质（ROS）过量产生、炎症，尤其是 破坏脂质代谢的关键调节剂视黄酸受体β (RARβ)。我们的研究小组 最近表明 RARβ 信号传导的破坏对于 NAFLD/NASH 的发展至关重要 小鼠的糖尿病状态，以及用高选择性 RARβ2 激动剂 AC261066 治疗，导致 改善葡萄糖耐量，减少脂肪变性、ROS 和炎症。这些发现强调 RARβ 作为管理代谢紊乱的潜在靶点的核心作用，并证明 AC261066 可能是治疗这些疾病的有用药物。基于取得的令人鼓舞的成果 NAFLD/NASH 小鼠模型，我们假设 RARβ 信号通路的破坏是关键 ALD 发展的因素，AC261066 治疗可以预防或逆转 酒精相关肝脏疾病的进展。为了检验这个假设，我们将使用体外模型和 模拟 ALD 的慢性酒精滥用小鼠体内模型。我们提出以下具体目标： 具体目标 (1)：确定 AC261066 是否可以预防乙醇毒性并确定 RARβ2 是否是必需的 为了这个效果。我们将用乙醇处理人肝细胞并测量代谢和表达 在 AC261066 存在或不存在的情况下与氧化应激和细胞凋亡相关的基因。在一个 通过一系列单独的实验，我们将确定 AC261066 的效果是否依赖于 RARβ2。 具体目标 (2)：确定 AC261066 是否可以预防乙醇毒性并探讨其机制 在小鼠模型中的效果。为此，我们将使用慢性乙醇摄入的小鼠模型来模拟 酒精性肝病。我们将在处死前测量代谢状态，然后进行转录组分析 使用RNA-Seq、组织学和病理学方法。