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.
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.
