Molecular and Genetic Analysis of Murine Steatohepatitis

小鼠脂肪性肝炎的分子和遗传学分析

• 批准号: 7740160
• 负责人: Richard M Green
• 金额: $ 38.13万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740160
• 关键词: Accounting; Affect; American; Animal Model; Arts; Biological; Candidate Disease Gene; Choline; Complex; Cryptogenic cirrhosis; Development; Diet; Disease; Disease Resistance; Disease susceptibility; Dyslipidemias; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Genes; Genetic; Genetic Techniques; Hepatic; Human Genetics; Inflammatory; Injury; Insulin Resistance; Liver diseases; Metabolic; Metabolic syndrome; Methionine; Modeling; Molecular; Molecular Genetics; Mus; Obesity; Pathogenesis; Polygenic Traits; Predisposition; Quantitative Trait Loci; Signal Pathway; Steatohepatitis; Techniques; United States; choline deficient diet; design; feeding; genetic analysis; non-alcoholic fatty liver; nonalcoholic steatohepatitis; public health relevance; resistant strain

DESCRIPTION (provided by applicant): Non-alcoholic steatohepatitis (NASH) is one of the most common causes of liver disease in the United States, and accounts for the majority of cryptogenic cirrhosis. NASH is associated with the "metabolic syndrome", which includes insulin-resistance, obesity, and dyslipidemia. In addition, recent evidence indicates that there is a strong genetic component for the susceptibility and progression of steatohepatitis. Unfortunately, the genetic factors responsible for the pathogenesis of NASH remain poorly understood. NASH is a polygenic disease, and Quantitative Trait Loci (QTL) analysis is a widely utilized genetic technique that can be applied to murine models in order to determine the chromosomal loci responsible for the expression of complex traits and polygenic diseases. Feeding mice a methionine- choline deficient (MCD) diet serves as an animal model for progressive, fibrosing steatohepatitis. Thus, Specific Aim 1 will employ a methionine-choline deficient (MCD) diet to identify steatohepatitis-susceptible and steatohepatitis-resistant strains of mice; and utilize QTL analysis to identify the genetic loci associated with steatohepatitis. NASH is also associated with the metabolic syndrome, and feeding mice a High Fat, High Calorie (HFHC) diet is a well-characterized model for obesity, the metabolic syndrome, and hepatic steatosis. However, the molecular mechanisms of hepatic injury in mice fed a HFHC diet remain poorly understood. Thus, Specific Aim 2 will employ a High Fat, High Calorie (HFHC) diet to determine the genetic loci and signaling pathways that account for the hepatic disease susceptibility. Candidate genes that are important for the pathogenesis of nonalcoholic fatty liver disorders can be identified from hepatic inflammatory and metabolic signaling pathways; particularly if they are differentially expressed in disease-sensitive and disease-resistant mice. Similarly, genes associated with NASH in human genetic studies can also serve as candidate genes. Therefore, Specific Aim 3 will employ a candidate gene approach to identify causative genes that are important in the pathogenesis of steatohepatitis and steatosis. This application utilizes two complementary models of hepatic steatosis and steatohepatitis, and state-of-the-art genetic and molecular biological techniques, in order to enhance our understanding of the pathogenesis of steatohepatitis. This enhanced understanding of the pathophysiologic mechanisms responsible for steatohepatitis will allow for the design of rational therapies for this hepatic disease that affects millions of Americans. PUBLIC HEALTH RELEVANCE: Non-alcoholic steatohepatitis (NASH) is one of the most common causes of liver disease in the United States, although the pathogenesis remains poorly understood. These specific aims will employ two complementary models of steatosis and steatohepatitis, and utilize state-of-the-art genetic and molecular biological techniques, in order to enhance our understanding of the pathogenesis of steatohepatitis and susceptibility to NASH. An understanding of the pathophysiologic mechanisms responsible for the development and progression of NASH will allow for the design of rational therapies of this common hepatic disease that affects millions of Americans.

描述（由申请人提供）：非酒精性脂肪性肝炎 (NASH) 是美国肝病最常见的原因之一，占隐源性肝硬化的大部分。 NASH 与“代谢综合征”有关，包括胰岛素抵抗、肥胖和血脂异常。此外，最近的证据表明，脂肪性肝炎的易感性和进展具有很强的遗传因素。不幸的是，对于 NASH 发病机制的遗传因素仍然知之甚少。 NASH 是一种多基因疾病，定量性状位点 (QTL) 分析是一种广泛使用的遗传技术，可应用于小鼠模型，以确定负责复杂性状和多基因疾病表达的染色体位点。给小鼠喂食蛋氨酸胆碱缺乏（MCD）饮食可作为进行性纤维化脂肪性肝炎的动物模型。因此，具体目标 1 将采用蛋氨酸胆碱缺乏 (MCD) 饮食来鉴定脂肪性肝炎易感性和脂肪性肝炎抗性小鼠品系；并利用QTL分析来鉴定与脂肪性肝炎相关的遗传位点。 NASH 还与代谢综合征有关，给小鼠喂食高脂肪、高热量 (HFHC) 饮食是肥胖、代谢综合征和肝脂肪变性的良好模型。然而，对于饲喂 HFHC 饮食的小鼠肝损伤的分子机制仍知之甚少。因此，具体目标 2 将采用高脂肪、高热量 (HFHC) 饮食来确定导致肝病易感性的基因位点和信号通路。可以从肝脏炎症和代谢信号通路中鉴定对非酒精性脂肪肝疾病发病机制重要的候选基因；特别是如果它们在疾病敏感和抗病小鼠中差异表达。同样，人类遗传学研究中与NASH相关的基因也可以作为候选基因。因此，具体目标 3 将采用候选基因方法来鉴定在脂肪性肝炎和脂肪变性发病机制中重要的致病基因。该应用利用肝脂肪变性和脂肪性肝炎两种互补的模型，以及最先进的遗传和分子生​​物学技术，以增强我们对脂肪性肝炎发病机制的理解。对脂肪性肝炎病理生理机制的深入了解将有助于为这种影响数百万美国人的肝病设计合理的治疗方法。公共卫生相关性：非酒精性脂肪性肝炎 (NASH) 是美国肝病最常见的原因之一，尽管其发病机制仍知之甚少。这些具体目标将采用脂肪变性和脂肪性肝炎两种互补的模型，并利用最先进的遗传和分子生​​物学技术，以增强我们对脂肪性肝炎发病机制和 NASH 易感性的理解。了解导致 NASH 发生和进展的病理生理机制将有助于为这种影响数百万美国人的常见肝脏疾病设计合理的治疗方法。