Genetic control of hepatic fibrogenesis

描述（由申请人提供）：酒精性和非酒精性脂肪性肝病（NAFLD）是一种慢性肝脏疾病，其中肝脏逐渐从脂肪积累和脂肪性肝炎（NASH）过渡到纤维化和肝硬化。调节这一转变的机制，尽管有很大的兴趣和研究努力，仍然在很大程度上没有解决。我们的具体假设是，在协作杂交重组近交8向杂交菌株中产生的遗传变异性将使调节肝纤维化的遗传因素得以确定。换句话说，我们假设纤维化易感性是由称为“数量性状位点”（QTL）的基因内遗传变异的综合效应引起的。为了解决这一重要假设，新开发的协作交叉菌株将用于建立与四氯化碳诱导的纤维化相关的表型。使用协作杂交菌株的基本原理是，在近100个亚菌株中，超过95%的遗传变异被捕获，超过100,000个遗传重组点被建立，使得表型的超精细QTL定位更加精确和重要。此外，由于亲本多态性均匀地分布在整个合作杂交系中，因此预计在品系中表型反应的均匀和连续分布。因此，与使用单基因转基因、敲除菌株甚至重组近交菌株的传统方法相比，这种连锁方法要优越得多，与人类生物学的相关性也要大得多。主要目标是鉴定纤维化易感菌株，表征所有菌株的几种纤维化基准表型，鉴定与纤维化表型相关的qtl，并在慢性乙醇暴露模型中利用易感菌株。为了突出这些目标，概述了以下目标。特异性目标1的目标是鉴定纤维易感菌株，并表征120株合作杂交中与纤维发生相关的表型性状。然后，在Specific Aim2中，我们将基于CC基因型将与肝纤维化相关的数量性状遗传映射到qtl。最后，在Specific Aim 3中，我们将利用上述在乙醇暴露慢性模型中鉴定的纤维化易感性菌株来确定这些菌株中乙醇诱导的纤维化易感性。这些研究将成为正在进行的研究的跳板，这些研究将允许识别和评估参与肝脂肪积累向肝纤维化过渡的候选基因、途径和系统，这是一个与代谢综合征、肥胖、糖尿病甚至心血管疾病的进化特别相关的领域。

DESCRIPTION (provided by applicant): Alcoholic and non-alcoholic fatty liver disease (NAFLD) are chronic liver disorders in which the liver progressively transitions from fatty accumulation and steatohepatitis (NASH) to fibrosis and cirrhosis. The mechanisms regulating this transition, despite significant interest and research efforts, are still largely unresolved. Our specific hypothesis is that the genetic variability created in the Collaborative Cross recombinant inbred 8-way intercross strains will allow the genetic factors regulating hepatic fibrogenesis to be identified. In other words, we hypothesize that fibrosis susceptibility results from the combined effects of genetic variations within genes termed "quantitative trait loci" (QTL). To address this important hypothesis, the newly developed Collaborative Cross strains will be used to establish phenotypes associated with fibrosis induced by carbon tetrachloride. The rationale for the use of the Collaborative Cross strains is that within nearly 100 substrains over 95% of genetic variability is captured and over 100,000 genetic recombination points are established, making ultra-fine QTL mapping of a phenotype more precise and significant. Also, because parental polymorphisms are uniformly dispersed throughout the Collaborative Cross lines, a uniform and continuous distribution of phenotypic responses is anticipated in the strains. Thus, this approach of linkage is far more superior and much more relevant to human biology than the traditional approaches using single-gene transgenic, knock-out strains or even recombinant inbred strains. The key objectives are to identify fibrosis-susceptible strains, characterize several fibrosis benchmark phenotypes across all strains, identify QTLs associated with the fibrosis phenotypes and exploit susceptible strains in a chronic model of ethanol exposure. The following aims are outlined to highlight these objectives. The goal of Specific Aim 1 is to identify fibrosis-susceptible strains and characterize phenotypic traits associated with fibrogenesis across 120 strains of the Collaborative Cross. Then, in Specific Aim2, we will genetically map quantitative traits associated with liver fibrogenesis to QTLs based on the CC genotypes. Finally, in Specific Aim 3, we will utilize fibrosis-prone strains identified above in a chronic model of ethanol exposure to determine ethanol-induced fibrosis susceptibility in these strains. These studies will be the springboard of ongoing studies which will allow for the identification and evaluation of candidate genes, pathways, and systems involved in the role of hepatic fat accumulation in the transition to liver fibrosis, an area with particular relevance to the evolution of metabolic syndrome, obesity, diabetes, and even cardiovascular disease. PUBLIC HEALTH RELEVANCE: Project Narrative Chronic liver disease is a continuum of pathologies starting with fatty liver disease to steatohepatitis to fibrosis to cirrhosis. The mechanisms governing the transition to fibrosis are not well understood. We will use a novel genetically-defined mouse population derived from an 8-way intercross of common inbred strains called the Collaborative Cross in order to address the complex genetic factors that underlie the mechanisms of liver fibrosis. The outcome of this study is the identification of novel fibrosis-susceptible strains of mice that will be a valuable research tool but also the identification of genetic markers (quantitative trait loci) that are associated with fibrosis.