Systems Analysis of TNF and TRAIL Signalling Pathways in Hepatocytes

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Systems level understanding of complex biological pathways and networks requires knowledge of its units, structures and temporal processes. Hepatocellular carcinoma (HCC) is one of the commonest cancers world-wide. HCC is induced by inflammation, interfering with induction of apoptosis. As a result, therapeutic options for HCC are limited due to resistance to current therapies. Tumour necrosis factor (TNF) and the TNF-related apoptosis-inducing ligand (TRAIL) are two cytokines which differentially trigger inflammatory and apoptotic signalling in liver cells. Co-treatment with inhibitors of TNF, chemotherapeutic agents or irradiation results in TRAIL sensitisation of primarily TRAIL-resistant HCC cell lines whereas normally differentiated hepatocytes remain resistant. Within the Era SysBioPlus consortium we propose to investigate the dynamic regulation and threshold of TNF- and TRAIL-induced inflammatory and apoptotic signalling pathways in primary and transformed hepatocytes and to build topology-based models to identify critical points for pathway regulation. Our group will focus entirely on the analysis and perturbation of TNF- and TRAIL-induced signalling pathways primary human hepatocytes.