Systems genetics dissection of non-alcoholic steatohepatitis

项目总结 非酒精性脂肪性肝病(NAFLD)是最常见的慢性肝病，包括 肝脏异常的范围从单纯性脂肪变性到脂肪性肝炎(NASH)，可以进展 到肝硬变和肝细胞癌。尽管进行了大量的研究工作，但这种疾病的病因是 了解甚少；尤其是与从脂肪变性进展到NASH相关的因素尚不清楚。我们 我从杂交小鼠多样性小组(HMDP)开发了小鼠模型，展示了 非酒精性脂肪肝在人类身上观察到。我们提案的总体目标是在老鼠身上使用基于种群的方法 确定有助于发展和进展的途径和更高层次的生物网络 NAFLD。使用我们开发的基于关联的建模方法--合并组学，我们之前发现 并验证了喂食高脂肪、高蔗糖的HMDP小鼠队列中与脂肪变性有关的几个基因 节食。将同样的策略应用于新的NASH转基因HMDP小鼠模型，我们现在已经确定 几个高自信的纳什候选基因。在目标1中，我们将执行转录和代谢组学 对耐药和敏感菌株进行图谱分析以检查NASH的进展。我们将识别并验证 应用多组学方法和腺相关病毒(AAV)研究NASH进展的候选基因 用于小鼠快速筛选的载体。我们还将确定特定于细胞的基因表达和细胞变化 与肝纤维化和其他NAFLD特征相关的成分。这将使我们能够在 肝星状细胞和浸润性炎症细胞的主要类型和数量 纳什进展。在目标2中，我们将研究与肝纤维化有关的五个优先基因，包括 我们最近用基因敲除小鼠验证了一种名为Mgp的基因。将进行机械研究，以 研究这些基因是如何影响纤维化的。将检查在AIM 1中确定的其他候选基因 有着类似的策略。这些研究的结果将揭示潜在的遗传机制 对非酒精性脂肪肝，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.