Molecular and Genetic Mechanisms of Fatty Liver Disease

脂肪肝的分子和遗传机制

• 批准号: 9135051
• 负责人: Richard M Green
• 金额: $ 34.55万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-23 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135051
• 关键词: Animals; Applications Grants; Cardiovascular Diseases; Cell Survival; Cells; Cessation of life; Chemicals; Cirrhosis; Data; Development; Diet; Disease; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Health; Hepatic; Hepatocyte; Human; In Vitro; Inflammatory; Injury; Investigation; Liver; Liver Function Tests; Liver diseases; Luciferases; Medical; Metabolic syndrome; Modeling; Molecular Biology; Molecular Genetics; Mus; Names; Obesity; Pathogenesis; Pathway interactions; Primary Cell Cultures; Primary carcinoma of the liver cells; Proteins; Quantitative Trait Loci; RNA Splicing; Regulatory Element; Reporter Genes; Risk Factors; Role; Signal Pathway; Signal Transduction; Steatohepatitis; Testing; Therapeutic; United States; endoplasmic reticulum stress; feeding; forward genetics; in vivo; lipid metabolism; liver injury; liver transplantation; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; positional cloning; response; reverse genetics; therapy development; transcription factor

 DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver function tests in the United States, and it can progress to cirrhosis, hepatocellular carcinoma, need-for- liver transplantation and death. Fatty liver disorders are polygenic diseases that are associated with obesity and the metabolic syndrome, however, the pathogenesis remains poorly understood. Human studies demonstrate that the Unfolded Protein Response (UPR) is important in the pathogenesis of fatty liver; and dysregulation of the XBP1s pathway of the UPR is associated with the progressive form of NAFLD termed non-alcoholic steatohepatitis (NASH). The overall objectives of this grant proposal are to further determine the role of Xbp1s in the pathogenesis of non-alcoholic fatty liver disease and identify novel regulatory factors and pharmacologic agents that can provide therapies for this common disease. We have recently developed mice with a hepatocyte-specific deletion of Xbp1s and will utilize these mice to determine the role and mechanisms of Xbp1s signaling on hepatic: A) injury in vivo using mice fed High-Fat diets; and lipotoxicity in vitro usng Huh7 cells and primary hepatocytes (Specific Aim 1). We will subsequently employ Quantitative Trait Loci (QTL) analysis and positional cloning of mice fed a High-Fat diet to identify novel genes and gene modifiers that are important in the pathogenesis of fatty liver diseases (Specific Aim 2). Finally, we will perform a high-throughput chemical screen to identify compounds that enhance hepatic XBP1s expression using Huh-7 cells with a XBP1- splicing luciferase reporter gene construct (Specific Aim 3). This proposal combines molecular biology, forward and reverse genetics, and high-throughput approaches to further determine the pathogenesis of steatohepatitis and develop therapies for non-alcoholic fatty liver diseases.

 描述（由适用提供）：非酒精性脂肪肝疾病（NAFLD）是美国肝功能异常测试的最常见原因，它可以发展为肝硬化，肝细胞癌，肝癌的需求，肝移植和死亡。脂肪肝疾病是与肥胖症和代谢综合征相关的多基因疾病，但是，发病机理仍然很少了解。人类研究表明，展开的蛋白质反应（UPR）在脂肪肝的发病机理中很重要。 UPR的XBP1S途径的失调与称为非酒精性脂肪性肝炎（NASH）的NAFLD的进行性形式有关。该赠款提案的总体目标是进一步确定XBP1在非酒精性脂肪肝病发病机理中的作用，并确定可以为这种常见疾病提供疗法的新型调节因素和药理剂。我们最近开发了用XBP1的肝细胞特异性缺失的小鼠，并将利用这些小鼠来确定XBP1S信号传导在肝上的作用和机制：a）使用喂养高脂饮食的小鼠在体内受伤；和脂肪毒性在体外USNG HUH7细胞和原发性肝细胞（特定AIM 1）。随后，我们将采用喂养高脂饮食的小鼠的定量性状基因座（QTL）分析和位置克隆，以鉴定在脂肪肝疾病发病机理中很重要的新型基因和基因修饰剂（特定目标2）。最后，我们将执行一个高通量化学筛选，以鉴定使用具有XBP1刺激性荧光素酶报告基因构建体的HUH-7细胞增强肝XBP1S表达的化合物（特定AIM 3）。该建议结合了分子生物学，前进和反向遗传学，以及进一步确定脂肪性肝炎发病机理并开发非酒精性脂肪肝疾病的疗法的高通量方法。