Identification and characterisation of complement factor C5 as quantitative trait
gene that modifies liver fibrogenesis in mono- and polygenic mouse models
(SFB/TRR 57)
Progressive liver fibrosis as the common consequence of all chronic liver diseases is
a major medical and economic challenge, since there are no effective treatment
options except liver transplantation. Environmental and host (genetic) factors
contribute to variable fibrosis progression rate among individual patients, albeit the
genetic factors that modify liver fibrogenesis have yet to be defined. This project
focuses on the gene encoding complement factor C5, which we identified as fibrosis
risk factor in previous genome scans in experimental crosses of inbred mouse strains
(Nat Genet 2005;37:835-843), thus representing a potential molecular target for
therapeutic interventions. The molecular mechanisms underlying the fibrogenic
effects of C5 are dissected in transgenic mouse models generated using recombined
bacterial artificial chromosomes. These mice overexpress C5 or show specific
deletions of the receptors C5R1 or C5L2. As complementary approach, the
antifibrotic effects of new intervention strategies (peptidomimetic receptor
antagonists) are assessed during the activation of isolated primary hepatic stellate
cells in vitro and during liver fibrogenesis in vivo. Furthermore, we analyze the role of
C5 in a novel congenic mouse model of non-toxic (spontaneous) liver fibrogenesis
(BALB-Abcb4-/-) and study anti-C5 strategies in this experimental framework. The
results of this project might not only be relevant for patients with rapid progression of
liver fibrosis (e.g. after liver transplantation) but for fibroproliferative diseases in other
organs and the development of antifibrotic therapies in general.