HEPATOCYTE-DERIVED MIF: A KEY CONTRIBUTOR TO ALCOHOLIC LIVER DISEASE

肝细胞衍生的 MIF：酒精性肝病的关键因素

• 批准号: 10268259
• 负责人: Kyle Poulsen
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10268259
• 关键词: Abstinence; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcoholic steatohepatitis; Alcohols; Animal Model; Animals; Blood Circulation; CCL2 gene; Cell Line; Chronic; Cirrhosis; Communication; Complex; Data; Developed Countries; Development; Diagnostic; Dimensions; Disease; Disease Progression; Encapsulated; Ethanol; Etiology; Fibrosis; Functional disorder; Goals; Half-Life; Heavy Drinking; Hepatic; Hepatocyte; Human; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Internet; Knock-out; Liver; Malignant neoplasm of liver; Mediating; Mediator of activation protein; MicroRNAs; Migration Inhibitory Factor; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Nucleic Acids; Patients; Phase; Phenotype; Plasma; Play; Primary carcinoma of the liver cells; Principal Component Analysis; Proteins; Proteomics; Public Health; ROC Curve; Regulation; Research; Role; Series; Site; Source; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; United States; Work; alcohol abstinence; alcohol exposure; chemokine; combat; cytokine; diagnostic biomarker; drinking; endoplasmic reticulum stress; extracellular vesicles; feeding; human model; inhibitor/antagonist; innovation; insight; interest; liver inflammation; mimetics; monocyte; mortality; non-alcoholic; novel; novel marker; novel therapeutic intervention; prevent; problem drinker; protein expression; receptor; release factor; searchable database; small molecule; socioeconomics; targeted treatment; therapeutic candidate; tool; transcriptomics; vesicular release; welfare

Alcoholic liver disease (ALD) is a significant cause of preventable morbidity and mortality worldwide. Alcohol- related morbidity and mortality has remained constant over the past decades, and drinking rates in developed countries continue to increase. ALD is a spectrum disorder encompassing steatosis, alcoholic hepatitis (AH), cirrhosis and even progressing to liver cancer. Therapies for ALD, and specifically AH, are unchanged for 40 years as well as ineffective for a significant proportion of ALD patients. Identifying novel biomarkers of ALD progression and the development of targeted therapies is of marked interest to public health and welfare. Macrophage Migration Inhibitory Factor (MIF), a ubiquitously expressed regulator of innate immunity with chemokine- and cytokine-like activities, is associated with ALD in humans and in ethanol feeding models in animals. MIF is increased in circulation in AH and cirrhosis patients, MIF protein expression is robustly increased in hepatocytes of AH patients, and MIF is predictive of liver morbidity and patient mortality in AH. In animal models of ethanol feeding, MIF deficiency protects from ethanol-induced liver injury and normalizes ethanol- induced inflammation and hepatocyte ER stress. Taken together, these data identified the hepatocyte as a likely tissue source and site of action for aberrant MIF expression and downstream activity in ALD. The aim of this proposal is to test the hypothesis that that chronic, excessive alcohol increases hepatocyte MIF release that acts as a potent upstream regulator of Alcoholic Liver Disease progression through control of chemokine expression, chemokine packaging, and liver ER stress. The work proposed herein will utilize tissue-specific MIF knockouts, MIF receptor knockouts and a novel small-molecule MIF inhibitor to interrogate the role of hepatocyte-derived MIF in multiple alcohol feeding models in animals, ethanol exposure in primary hepatocyte cultures, and in human ALD patient tissues. Furthermore, the protective phenotype in MIF-deficient mice is associated with profound changes in chemokine expression in the liver and in circulating extracellular vesicles (EV). EVs are pivotal intracellular communication mediators, and the chemokine cargoes in EVs are quite dynamic in both ethanol- and MIF-dependent mechanisms. The other aim of this proposal will then transition to explore what leads to this increased hepatic MIF expression in ALD. A database search of mircoRNAs from ALD patient livers (GEO series GSE59492) revealed that a potent negative regulator of MIF expression, miR-451, is decreased along the spectrum of ALD and was selective to an alcoholic etiology of disease. The project will then expand to study EVs as a novel mechanism of therapeutic transfer in ALD, as the proposed studies will look to normalize MIF expression through restoring miR-451 expression as well as selectively inhibit MIF in the liver.

酒精性肝病（ALD）是全世界可预防的发病率和死亡率的一个重要原因。酒精- 过去几十年来，相关发病率和死亡率一直保持不变，发达国家的饮酒率 国家持续增加。 ALD 是一种谱系疾病，包括脂肪变性、酒精性肝炎 (AH)、 肝硬化，甚至发展为肝癌。 ALD（特别是 AH）的治疗方法在 40 年内保持不变 多年且对相当比例的 ALD 患者无效。鉴定 ALD 的新型生物标志物 靶向治疗的进展和开发对公众健康和福祉具有显着意义。 巨噬细胞迁移抑制因子 (MIF)，一种普遍表达的先天免疫调节因子 趋化因子和细胞因子样活性，与人类和乙醇喂养模型中的 ALD 相关。 动物。 AH 和肝硬化患者循环中 MIF 增加，MIF 蛋白表达大幅增加 AH 患者肝细胞中的 MIF 可以预测 AH 患者的肝脏发病率和患者死亡率。在动物中 在乙醇喂养模型中，MIF 缺乏可防止乙醇引起的肝损伤并使乙醇正常化 诱导炎症和肝细胞 ER 应激。综合起来，这些数据表明肝细胞可能是 ALD 中异常 MIF 表达和下游活性的组织来源和作用位点。此举的目的 该提案旨在检验以下假设：长期过量饮酒会增加肝细胞 MIF 的释放， 通过控制酒精性肝病进展，发挥有效的上游调节作用 趋化因子表达、趋化因子包装和肝脏 ER 应激。本文提出的工作将利用 组织特异性 MIF 敲除、MIF 受体敲除以及新型小分子 MIF 抑制剂的研究 肝细胞源性 MIF 在动物多种酒精喂养模型中的作用，原发性乙醇暴露 肝细胞培养物和人类 ALD 患者组织中。此外，MIF 缺陷的保护表型 小鼠肝脏和循环细胞外趋化因子表达的深刻变化有关 囊泡（EV）。 EV 是关键的细胞内通讯介质，EV 中的趋化因子货物是 乙醇和 MIF 依赖性机制都非常动态。该提案的另一个目标将是 转变以探索导致 ALD 中肝脏 MIF 表达增加的原因。数据库搜索 来自 ALD 患者肝脏的 mircoRNA（GEO 系列 GSE59492）揭示了 MIF 的有效负调节因子 miR-451 的表达在 ALD 谱系中降低，并且对酒精性病因具有选择性 疾病。该项目随后将扩大研究 EVs 作为 ALD 治疗转移的新机制，因为 拟议的研究将寻求通过恢复 miR-451 表达以及 选择性抑制肝脏中的MIF。