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

基本信息

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
项目类别：
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

项目摘要

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因肝移植而住院的 ALD 虽然最初无症状，但其特点是脂肪变性。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诸如 ALD 分子共享以及 NAFLD/NASH 的组织病理学特征，包括脂肪变性增加、氧活性物质 (ROS) 过度产生、炎症和显着的我们的研究小组破坏了脂质代谢的关键调节剂视黄酸受体β (RARβ)。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，导致这些发现强调了葡萄糖耐量的改善、脂肪变性、ROS 和炎症的减少。 RARβ 作为管理代谢紊乱的潜在靶点的核心作用，并证明基于 2017 年获得的令人鼓舞的结果，AC261066 可能是治疗这些疾病的有用药物。 NAFLD/NASH小鼠模型中，我们探索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为了检验这一假设，我们将使用体外模型和我们提出了以下具体目标：具体目标 (1)：确定 AC261066 是否可以预防乙醇毒性并确定 RARβ2 是否是必需的为了达到这种效果，我们将用乙醇处理人肝细胞并测量代谢和表达。在存在或不存在 AC261066 的情况下与氧化应激和细胞凋亡相关的基因。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为了实现这一目标，我们将使用模拟慢性乙醇摄入的小鼠模型。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。