Genomic and genetic determinants of the susceptibility to non-alcoholic fatty liver disease (NAFLD) and NAFLD-related liver cancer

非酒精性脂肪性肝病 (NAFLD) 和 NAFLD 相关肝癌易感性的基因组和遗传决定因素

• 批准号: 10951483
• 金额: $ 8万
• 依托单位: NATIONAL CANCER INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10951483
• 关键词: Genomic; genetic; determinants; susceptibility; non

Investigating the molecular basis of how epigenomic and genomic factors influence susceptibility to Nonalcoholic fatty liver disease (NAFLD) in humans using human NAFLD samples is desirable but frequently impractical. In contrast, using relevant animal models that resemble human NAFLD development may substantially overcome the many limitations of human studies and provide important clues regarding the molecular consequences of etiological factors linked to NAFLD susceptibility and severity. This Inter-Agency Agreement (IAA) will investigate the extent of molecular changes indicative of NAFLD-associated liver injury (including nonalcoholic steatohepatitis (NASH), a progressive form of NAFLD) to assist in identifying putative molecular markers and/or targets. We hypothesize that (a) the status of individual epigenomic hepatic phenotypes is a fundamental factor that predetermines susceptibility to NAFLD; and (b) an evaluation of epigenomic hepatic phenotypes in a genetically heterogeneous mouse population will assist in identifying molecular susceptibility to NAFLD. To test the hypothesis, we plan to use a well-established dietary- (“Western Diet”) induced model of NASH in Collaborative Cross (CC) mice, a genetically diverse population of mice. We will identify individual mice exhibiting the greatest susceptibility to NAFLD-associated liver injury in the genetically diverse population of mice and define the role of epigenetic alterations in the pathogenesis of NAFLD. We also plan to investigate the key molecular mechanisms associated with the development of NASH and NASH-associated HCC. To achieve this goal, we will feed male and female CC mouse strains (2 sensitive and 2 resistant) a high-fat diet for a prolonged time (60 weeks) to investigate the underlying pathophysiological processes associated with the development of NASH-derived HCC. We anticipate being able to define the underlying molecular mechanisms and identify pathways associated with differential sensitivity to NAFLD and its progression to advance NASH and NASH-fibrosis stages. These studies will utilize next generation sequencing, chromatin immunoprecipitation with DNA microarray methodology (Chip-on-chip) and quantitative RT-PCR to assess whole genome-scale epigenomic changes and expression of protein-coding and non-coding RNAs, especially microRNAs, in plasma, white blood cells, and livers of treated and control mice. Analysis of the relationship between fecal microbiota and fatty liver susceptibility is also being conducted.

使用人类非酒精性脂肪性肝病(NAFLD)样本研究表观基因组和基因组因素如何影响人类对NAFLD易感性的分子基础是可取的，但通常是不现实的。相反，使用类似于人类NAFLD发展的相关动物模型可能实质上克服人类研究的许多局限性，并提供与NAFLD易感性和严重程度相关的病因因素的分子后果的重要线索。这项机构间协议(IAA)将调查NAFLD相关性肝损伤的分子变化程度(包括NAFLD的进展型非酒精性脂肪性肝炎(NASH))，以帮助确定假定的分子标志物和/或靶点。我们假设(A)单个表观基因组肝脏表型的状态是预测NAFLD易感性的一个基本因素；以及(B)对遗传异质性小鼠群体中表观基因组肝脏表型的评估将有助于确定NAFLD的分子易感性。为了验证这一假设，我们计划在合作杂交(CC)小鼠中使用一种公认的饮食(“西方饮食”)诱导的NASH模型，这是一种遗传多样性的小鼠群体。我们将确定在遗传多样性的小鼠群体中表现出对NAFLD相关肝损伤最敏感的单个小鼠，并确定表观遗传学改变在NAFLD发病机制中的作用。我们还计划研究与NASH和NASH相关的肝细胞癌发生发展相关的关键分子机制。为了实现这一目标，我们将长期(60周)喂饲雄性和雌性CC小鼠品系(2个敏感品系和2个抗性品系)，以研究与NASH来源的肝细胞癌发展相关的潜在病理生理过程。我们期待能够定义潜在的分子机制，并确定与NAFLD及其进展到NASH和NASH纤维化阶段的差异敏感性相关的途径。这些研究将利用下一代测序、采用DNA微阵列方法的染色质免疫沉淀(芯片上芯片)和定量RT-PCR来评估全基因组规模的表观基因组变化以及治疗组和对照组小鼠血浆、白细胞和肝脏中蛋白质编码和非编码RNA的表达，特别是microRNAs。还在分析粪便微生物区系与脂肪肝易感性之间的关系。