Modulators of hepatic response to TGF-ß mediated cellular injury in inbred
mice: Identification of modifiers of fibrosis susceptibility
Hepatic fibrosis is a non-specific response to chronic liver injury, the two most
common causes being viral hepatitis or alcohol abuse. Twin studies and ethnic
differences indicate that genetic factors play a role in predisposition to and
progression of both types. In contrast to viral hepatitis, no firm associations between
genetic variants and susceptibility to alcoholic liver fibrosis have been identified to
date. Transforming growth factor (TGF)-β is considered the master pro-fibrogenic
cytokine, driving fibrosis in response to various modes of injury. This central role
makes every modifier locus of the response to TGF-β mediated hepatic injury a
candidate gene for fibrosis susceptibility. The aim of this project is to identify the
modifier genes of TGF-β mediated injury, using hepatocytes isolated from genetically
distinct inbred mouse strains. Hepatocytes are highly responsive to TGF-β. Their
demise leads to activation of Kupffer cells and subsequent release of inflammatory
cytokines as well as activation of hepatic stellate cells with enhanced expression of
growth factors and extracellular matrix components. Here, we propose to avail of a
genetic reference population generated from progeny of inbred mouse lines
C57BL/6J and DBA/2J, also known as BXD recombinant inbred lines. The genetically
distinct hepatocytes from these mouse lines will be challenged with TGF-β, and
phenotypic differences (cellular damage, gene expression) will be quantified to
delineate differences in response. Quantitative trait locus mapping, i.e. linkage
analysis in the BXD panel, will enable us to identify the genetic loci that underlie
differential responses to TGF-β by allelic variation. This experimental framework will
allow us to assess the orthologous human regions and candidate genes for
contribution to fibrogenesis susceptibility in defined human cohorts.