The treatment of Alcohol Liver Disease with Retinoid Beta Agonists

类维生素Aβ激动剂治疗酒精性肝病

• 批准号: 9896840
• 负责人: Steven Trasino
• 金额: $ 15.6万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896840
• 关键词: Acute; Affect; Agonist; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; Alcoholic steatohepatitis; Alcoholism; Alcohols; All-Trans-Retinol; Animal Model; Biochemistry; Biological; Biomedical Research; Catabolism; Cells; Cessation of life; Chronic; Cicatrix; Cirrhosis; Clinical; Coupled; Data; Development; Diet; Dimensions; Disease; Disease Progression; Early Intervention; Effectiveness; Ethanol; Etiology; FDA approved; Face; Faculty; Fatty Liver; Gene Expression; Genes; Goals; Grant; Health; Hepatic; Hepatic Stellate Cell; Human; Human Development; Individual; Inflammation; Lead; Learning; Liver; Liver Fibrosis; Liver diseases; Malignant Neoplasms; Mammals; Mediating; Medical; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Micronutrients; Modeling; Molecular; National Institute on Alcohol Abuse and Alcoholism; Oxidative Stress; Pathogenicity; Pathway interactions; Pharmaceutical Preparations; Physicians; Population; Preventive; Production; Property; Proteins; Reactive Oxygen Species; Research; Research Personnel; Research Project Grants; Research Proposals; Retinoic Acid Receptor; Retinoids; Retinol Metabolism Pathway; Role; Scheme; Scholarship; Serous; Severities; Signal Pathway; Signal Transduction; Steatohepatitis; Testing; Therapeutic; Toxin; Training; Treatment Efficacy; Tretinoin; United States; United States National Institutes of Health; Vitamin A; alcohol abstinence; alcohol abuse therapy; alcohol craving; alcohol risk; analog; behavioral pharmacology; chronic liver disease; college; disorder control; disorder prevention; drug development; experience; fatty acid oxidation; high risk; innovation; interest; lipid metabolism; liver injury; mouse model; non-alcoholic fatty liver disease; novel; novel strategies; novel therapeutics; prevent; retinoic acid receptor alpha; social; underserved minority

Project Summary/Abstract Alcoholic liver disease (ALD) is responsible for more than half of all liver-related deaths in the United States. ALD and defined as a spectrum of disorders that begins with steatosis (fatty liver), that can progress to steatohepatitis, cirrhosis, and fibrotic end stage liver disease (ESLD). Current treatment options are focused on behavioral and pharmacological approaches for eliminating alcohol consumption and cravings. Individuals that struggle with alcohol abstinence face a higher risk of developing ALD cirrhosis, thus there is an urgent need for novel anti-ALD therapies. There is convincing evidence that the progression of ALD is driven by reductions and dysregulation of hepatic vitamin A (VA, retinol) metabolism and pathways. VA and related molecules are collectively called retinoids, which, acting through the VA metabolite retinoic acid (RA), and RA receptors (RAR α, β and γ), regulate the expression of genes involved in lipid metabolism, inflammation and anti- fibrotic pathways implicated in the development of ALD. I hypothesize that synthetic agonists for specific RARs, some of which are FDA approved for the treatment of some cancers, can activate and restore hepatic VA signaling pathways and have high therapeutic potential. I have generated preliminary data demonstrating that the specific RARβ2 agonist; AC261066, can significantly reduce hepatic steatosis, production of reactive oxygen species (ROS), and activation of scar forming hepatic stellate cells (HSCs) in a model of dietary induced non-alcoholic fatty liver disease (NAFLD). ALD and NAFLD share several clinical and molecular features, therefore this project will propose to determine i) the effectiveness of RARβ2 agonists on preventing HSC and liver fibrosis in a short- term, murine model of moderate alcohol intake, and ii) the therapeutic efficacy of RARβ2 agonists on reversing the clinical hallmarks of chronic alcohol abuse using the National Institute on Alcohol Abuse and Alcoholism (NIAAA) murine model of chronic, binge alcohol liver injury. This project proposes an innovative approach to the development of ALD therapies by using agonists for RARβ which possesses similar anti-fibrotic properties of RA but, unlike RA, are not susceptible to ethanol-driven catabolism in ALD. Data from this proposal could lead to the development of RARβ agonists as therapies for ALD and other fibrotic liver disorders in humans.

项目摘要/摘要 酒精性肝病（ALD）负责统一的所有与生命有关的死亡中的一半以上 国家。 ALD和定义为从脂肪变性（脂肪肝）开始的疾病范围，可以 进展到脂肪性肝炎，肝硬化和纤维化末期肝病（ESLD）。当前治疗 选择的重点是消除酒精的行为和药物方法 消费和渴望。与戒酒斗争的人面临更高的风险 发展ALD肝硬化，因此迫切需要新型的抗ALD疗法。有 令人信服的证据表明，ALD的进展是由减少和失调驱动的 Hepati维生素A（VA，视黄醇）代谢和途径。 VA和相关分子集体 称为类视黄素，通过VA代谢物视网膜酸（RA）和RA受体作用（RAR） α，β和γ）调节与脂质代谢，注射和抗脂质代谢有关的基因的表达 ALD开发实施的纤维化途径。我假设这种合成激动剂 具体的稀有，其中一些是FDA批准用于治疗某些癌症的，可以激活和 恢复肝VA信号通路，具有高治疗潜力。我已经生成了 初步数据表明特定的RARβ2激动剂； AC261066，可以显着降低 肝脂肪变性，活性氧（ROS）的产生以及疤痕形成肝的激活 饮食中诱导的非酒精性脂肪肝病（NAFLD）模型中的星状细胞（HSC）。阿尔德 NAFLD具有几个临床和分子特征，因此该项目将提出 确定i）RARβ2激动剂对预防短期HSC和肝纤维化的有效性 术语，中度酒精摄入的鼠模型和ii）RARβ2激动剂在 使用国家酒精滥用研究所的持续慢性酒精滥用的临床标志 和酒精中毒（NIAAA）慢性酒精肝损伤的鼠模型。这个项目建议 通过使用激动剂进行RARβ来开发ALD疗法的创新方法，该方法 RA具有相似的抗纤维化特性，但与RA不同，它不容易受到乙醇驱动的影响 ALD中的分解代谢。该提案的数据可能导致RARβ激动剂的发展 人类ALD和其他纤维化肝疾病的疗法。

项目成果

Retinoic Acid Receptor β Loss in Hepatocytes Increases Steatosis and Elevates the Integrated Stress Response in Alcohol-Associated Liver Disease.

• DOI: 10.3390/ijms241512035
• 发表时间: 2023-07-27
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Melis, Marta;Trasino, Steven E.;Tang, Xiao-Han;Rappa, Andrew;Zhang, Tuo;Qin, Lihui;Gudas, Lorraine J.
• 通讯作者: Gudas, Lorraine J.

Success and failures of telehealth during COVID-19 should inform digital applications to combat obesity.

• DOI: 10.1002/osp4.551
• 发表时间: 2022-04
• 期刊: Obesity science & practice
• 影响因子: 2.2
• 作者: Vasselli JR;Juray S;Trasino SE
• 通讯作者: Trasino SE

Fenretinide Reduces Intestinal Mucin-2-Positive Goblet Cells in Chronic Alcohol Abuse.

• DOI: 10.1159/000524386
• 发表时间: 2022
• 期刊: PHARMACOLOGY
• 影响因子: 3.1
• 作者: Melis, Marta;Tang, Xiao-Han;Mai, Karen;Gudas, Lorraine J.;Trasino, Steven E.
• 通讯作者: Trasino, Steven E.