Systems genetics dissection of non-alcoholic steatohepatitis

非酒精性脂肪性肝炎的系统遗传学解析

• 批准号: 10434833
• 负责人: Aldons Jake Lusis
• 金额: $ 64.57万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434833
• 关键词: Affect; Biological; Biological Models; CETP gene; Candidate Disease Gene; Cell physiology; Cells; Characteristics; Cirrhosis; Clinical; Complex; Computer Models; Data; Development; Diabetes Mellitus; Diagnostic; Diet; Disease; Disease Progression; Dissection; Dyslipidemias; Etiology; Exhibits; Fatty acid glycerol esters; Fibrosis; Gene Expression; Genes; Genetic; Genotype; Goals; Grant; Health; Hepatic; Hepatocyte; Hepatology; High Fat Diet; High Prevalence; Human; Hybrids; Inbred Strains Mice; Inflammation; Inflammatory Infiltrate; Knockout Mice; Laboratories; Lipoproteins; Liver Fibrosis; Longitudinal Studies; Methods; Mitochondria; Modeling; Modernization; Molecular; Mus; Natural History; Obesity; Pathogenesis; Pathway interactions; Phenotype; Play; Population; Population Study; Predisposition; Prevention; Primary carcinoma of the liver cells; Rapid screening; Research; Resistance; Resolution; Resources; Risk; Role; Societies; Statistical Models; Steatohepatitis; Sucrose; Surveys; System; Therapeutic; Tissues; Transgenes; Transgenic Organisms; Validation; Variant; adeno-associated viral vector; apolipoprotein E-3; base; cell type; chronic liver disease; cohort; disease natural history; editorial; end stage liver disease; epidemiology study; gene discovery; genetic approach; genome wide association study; innovation; matrix Gla protein; metabolomics; mouse model; multiple omics; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; population based; prevent; simple steatosis; single cell sequencing; stellate cell; therapeutic target; trait; transcriptomics

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.

项目概要 非酒精性脂肪肝病 (NAFLD) 是最常见的慢性肝病，包括 一系列肝脏异常，从单纯性脂肪变性到脂肪性肝炎 (NASH)，这些异常可能会进展 至肝硬化和肝细胞癌。尽管进行了大量的研究工作，但这种疾病的病因仍不清楚 不太了解；特别是，与脂肪变性进展为 NASH 相关的因素尚不清楚。我们 已经从混合小鼠多样性面板 (HMDP) 开发了小鼠模型，该模型表现出以下谱系： 在人类中观察到 NAFLD。我们提案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 非酒精性脂肪性肝病。使用合并组学（我们开发的一种基于关联的建模方法），我们之前确定了 并验证了一组与喂食高脂肪、高蔗糖的 HMDP 小鼠中的脂肪变性相关的基因 饮食。将相同的策略应用于新型 NASH 转基因 HMDP 小鼠模型，我们现已鉴定出 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研究 对耐药菌株和敏感菌株进行分析以检查 NASH 的进展。我们将识别并验证 使用多组学方法和腺相关病毒 (AAV) 进行 NASH 进展的候选基因 用于在小鼠中快速筛选的载体。我们还将识别基因表达和细胞的细胞特异性变化 与肝纤维化和其他 NAFLD 特征相关的成分。这将使我们能够跟踪功能变化 主要肝细胞类型以及星状细胞和浸润炎症细胞群 NASH 进展。在目标 2 中，我们将检查五个导致肝纤维化的优先基因，包括 我们最近使用基因敲除小鼠验证了一种基因 Mgp。将进行机理研究 研究这些基因如何影响纤维化。将检查目标 1 中确定的其他候选基因 具有类似的策略。这些研究的结果将揭示潜在的遗传机制 NAFLD 并可能确定潜在的治疗靶点。