From biological data to molecular modelisation; application to TGF-beta signaling and hepatic fibrosis

Jérémy Gruel

Hepatic fibrosis is a complex pathology, it is mainly due to chronic
viral or toxic aggressions. In this context, hepatic stellate cells
are the main producers of the excess of extra-cellular matrix
modifying liver normal activity. The main pro-fibrotic cytokine is
the TGF-beta and a perturbation of the TGF-beta signaling pathways is
observed in hepatic stellate cells in the pathological context.

Here, we propose a study aimed at a better understanding of the
cellular regulation perturbations induced by the TGF-beta in the
fibrotic context, this using bioinformatics means.

In the first part of this work, we study the impact of the protein
ADAM12 on TGF-beta receptors trafficking. Using a combination of
differential models and qualitative experimental data, we obtain
predictions about the modifications induced by ADAM12 in this system.

In the second part of this work, we study the transcriptional
signatures present in the promoters of genes regulated by various
cytokines, including TGF-beta. In this study, we propose an algorithm
allowing, after selecting a gene of interest, to gather genes
potentially sharing the same expression regulation mechanisms than the
gene of interest.