SIGNALING AND MODELING IN LIVER FIBROSIS

SIGNALING AND MODELING IN LIVER FIBROSIS

All chronic liver diseases lead to the development of fibrosis characterized by excessive deposit of extracellular matrix, alteration of hepatocytes homeostasis and severe hepatic dysfunction.  Our project aims to characterize the impact of extracellular matrix remodeling in fibrosis and the induced tensional disregulation of hepatocytes including changes in proliferation-differentiation status.

Extracellular matrix remodeling: we study the involvement of matrix metalloproteases and disintegrins (ADAM and ADAMTS) in the development of liver fibrosis and tissue remodeling that promote liver tumor progression.  More specifically, we characterize these metalloproteases’ implication in the regulation of the pro-fibrotic cytokine TGF-β. To evaluate matrix remodeling and stiffness within tissue, we develop Second Harmonic microscopy- based methods.

Tension forces in control of hepatocytes proliferation-differentiation.  Using in vitro models, of hepatic normal and transformed cells cultured in type 1 collagen gels of variables rigidity, we characterize the effects of strengths on growth factors signaling and bioactivations of environmental contaminants. We determine the degree of reticulation, orientation and cross-links of collagen fibers as predictive markers of the reversibility of the liver fibrosis by SHG microscopy (Second Harmonic Genertaion) (in collaboration with the Institute of Physic of Rennes).

Susceptibility of hepatocytes to environmental contaminants. Our studies focus on food or environment contaminants potentially genotoxic in humans. We are investigating both metabolism activation, DNA adduct formation and DNA repair in human hepatocytes. Our challenge is to characterize the susceptibility of hepatocytes toward these chemicals depending of their proliferation and differentiation status during chronic liver diseases.

Integrative analysis and development of computational application. To obtain a more systemic view of liver fibrosis we develop integrative models based on mathematical and computational methods.  One of our project deals with a dynamic and discrete model of the pro-fibrotic TGF-β signaling pathway. These studies are developed in collaboration with IRISA-INRIA, Rennes.