Systems genetics dissection of non-alcoholic steatohepatitis

项目摘要 非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病，其包括： 一系列肝脏异常，从单纯性脂肪变性到脂肪性肝炎（NASH），可进展 肝硬化和肝癌。尽管有大量的研究工作，但这种疾病的病因是 了解甚少;特别是与从脂肪变性进展为NASH相关的因素尚不清楚。我们 已经从杂交小鼠多样性小组（HMDP）中开发出小鼠模型， 在人类中观察到的NAFLD。我们建议的总体目标是在小鼠中使用基于群体的方法 确定有助于发展和进展的途径和高阶生物网络， NAFLD。使用Mergeomics，我们开发的一种基于关联的建模方法，我们以前发现 并验证了几个与脂肪变性相关的基因，这些基因来自一组喂食高脂肪、高蔗糖的HMDP小鼠， 饮食.将相同的策略应用于NASH的新型转基因HMDP小鼠模型，我们现在已经鉴定出 几个高置信度NASH候选基因。在目标1中，我们将进行转录组学和代谢组学 对耐药和敏感菌株进行谱分析以检查NASH的进展。我们会确认 使用多组学方法和腺相关病毒（AAV）的NASH进展的候选基因 用于在小鼠中快速筛选的载体。我们还将确定基因表达和细胞增殖中的细胞特异性变化。 与肝纤维化和其他NAFLD特征相关的组合物。这将使我们能够跟踪功能变化， 主要的肝细胞类型以及星状细胞和浸润的炎性细胞的群体， NASH进展。在目标2中，我们将研究五个优先考虑的基因，包括 一个基因，Mgp，我们最近用敲除小鼠验证了它。将进行机制研究， 研究这些基因如何影响纤维化。目标1中确定的其他候选基因将被检查 采取类似的策略。这些研究的结果将揭示潜在的遗传机制， 并可能确定潜在的治疗靶点。

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder which comprises of a spectrum of hepatic abnormalities ranging from simple steatosis to steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma. Despite significant research efforts, the etiology of this disease is poorly understood; in particular, factors associated with progression from steatosis to NASH are unknown. We have developed mouse models from the Hybrid Mouse Diversity Panel (HMDP) that exhibit the spectrum of NAFLD observed in humans. The overall goal of our proposal is to use population-based approaches in mice to identify pathways and higher order biological networks that contribute to the development and progression of NAFLD. Using Mergeomics, an association-based modeling method we developed, we previously identified and validated several genes associated with steatosis from a cohort of HMDP mice fed a high fat, high sucrose diet. Applying the same strategy to a novel transgenic HMDP mice model of NASH, we have now identified several high confidence NASH candidate genes. In Aim 1, we will perform transcriptomic and metabolomics profiling on resistant and susceptible strains to examine the progression of NASH. We will identify and validate candidate genes for NASH progression using multi-omics approaches and Adeno-Associated Virus (AAV) vectors for rapid screening in mice. We will also identify cell-specific changes in gene expression and cell composition related to liver fibrosis and other NAFLD features. This will allow us to follow functional changes in the major hepatic cell types as well as populations of stellate cells and infiltrated inflammatory cells during NASH progression. In Aim 2, we will examine five prioritized genes contributing to hepatic fibrosis, including one gene, Mgp, that we recently validated using knockout mice. Mechanistic studies will be performed to investigate how these genes affect fibrosis. Additional candidate genes identified in Aim 1 will be examined with a similar strategy. Results from these studies will reveal the underlying genetic mechanisms contributing to NAFLD and may identify potential therapeutic targets.