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，并且占大多数隐性肝硬化。 NASH与“代谢综合征”有关，其中包括胰岛素抵抗，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有很强的遗传成分。不幸的是，负责纳什发病机理的遗传因素仍然鲜为人知。 NASH是一种多基因疾病，定量性状基因座（QTL）分析是一种广泛使用的遗传技术，可以应用于鼠模型，以确定负责复杂性状和多基因疾病表达的染色体基因座。喂养小鼠蛋氨酸 - 胆碱缺乏饮食（MCD）饮食是进行性，触觉脂肪性肝炎的动物模型。因此，特定的目标1将采用蛋氨酸 - 胆碱饮食（MCD）饮食来鉴定小鼠的脂肪性肝炎敏感和耐脂肪肝炎的菌株；并利用QTL分析来识别与脂肪性肝炎相关的遗传基因座。 NASH还与代谢综合征有关，喂养小鼠高脂肪，高热量（HFHC）饮食是肥胖，代谢综合征和肝脂肪变性的特征良好的模型。然而，喂养HFHC饮食的小鼠肝损伤的分子机制仍然鲜为人知。因此，特定的目标2将采用高脂肪高热量（HFHC）饮食来确定解释肝病敏感性的遗传基因座和信号通路。可以从肝炎和代谢信号通路中鉴定出对非酒精性脂肪肝疾病的发病机理很重要的候选基因；特别是如果它们在对疾病敏感和耐疾病的小鼠中差异表达。同样，在人类遗传研究中与NASH相关的基因也可以用作候选基因。因此，特定的目标3将采用候选基因方法来鉴定在脂肪性肝炎和脂肪增生的发病机理中很重要的致病基因。该应用利用了肝脂肪变性和脂肪性肝炎的两个互补模型，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理的理解。这种对负责脂肪性肝炎的病理生理机制的增强理解将允许设计这种影响数百万美国人的肝病的理性疗法。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，尽管该发病机理仍然了解不足。这些具体目标将采用两种互补的脂肪变性和脂肪性肝炎模型，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的发病机理以及对NASH易感性的理解。对负责纳什发展和进展的导致病理生理机制的理解将允许设计这种影响数百万美国人的常见肝病的理性疗法。