Systems genetics dissection of non-alcoholic steatohepatitis

非酒精性脂肪性肝炎的系统遗传学解析

基本信息

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
项目类别：
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

项目摘要

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群喂食高脂肪、高蔗糖的 HMDP 小鼠中与脂肪变性相关的几个基因饮食。将相同的策略应用于新型 NASH 转基因 HMDP 小鼠模型，我们现在已经确定几个高置信度 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。我们还将鉴定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。