ApoNET - Systems Analysis of Death - Receptor Signalling Networks.
Hepatocellular carcinoma is one of the most common forms of cancers worldwide. Therapeutic options are limited due to chemo-resistance to current therapies, mostly caused by failure to undergo cell death (apoptosis). To understand how the apoptosis signalling networks are regulated in normal hepatocytes and dysregulated in cancer is of key importance for the design of effective cancer therapies.
Systems level understanding of complex biological pathways and networks requires knowledge of its units, structures and temporal processes. In this project we will investigate the dynamic regulation and threshold of apoptotic and non-apoptotic signalling pathways induced by death receptor signalling in normal and malignantly transformed hepatocytes. Our project aims to understand and predict the basic biological system that governs pro- and anti-apoptotic signalling in normal versus transformed hepatocytes triggered by death receptor signalling. We will build Dynamic Nested Effects Models (D-NEM) based on our data to identify critical points for pathway regulation. These statistical models will be used to reconstruct pathway activity in hepatocytes.
In addition to providing specific insight into apoptosis signalling on a systems level in normal versus transformed cells, we expect that our study will also lead to new insights on principal mechanisms of inflammation-induced tumourigenesis and of therapy resistant tumours. Thereby, these studies will increase our knowledge as to how resistance can be overcome in a tumour-specific manner, ultimately providing new and improved approaches to therapy and diagnosis.