2016 Conference on Computational Modelling with COPASI
Manchester Institute of Biotechnology, 12th – 13th May, 2016
1 - Newcastle University, UK
Keywords: Systems Biology, Ageing, Disposable Soma, Nutrient Allocation, ROS, IGF Signalling, AKT, FOXO3a, mTOR
The disposable soma theory predicts that levels of maintenance and repair are influenced by resource availability. The interplay between the FOXO-Sestrin-p53 signalling network regulating stress and damage response and the IRS1-Akt-mTOR-AMPK nutrient sensing network monitoring resource availability offer an opportunity to further our understanding of how this influence is achieved. These two signalling systems are deeply embedded with complex interactions (such as AKT and MDM2, pTEN and PIP3 and FOXO with AMPK and TSCs) involving multiple feedbacks which govern cellular outcome such as growth arrest, apoptosis, senescence or proliferation. This project proposes to build on and extend our current experimental and computational work to develop a well parameterised dynamic computational model of this integrated network.
FOXO is a well characterised protein which affects cellular growth, division and apoptosis in response to DNA damage signals. It achieves this due to its activity as a transcription factor for many genes including those for AMPK, Rictor, Sestrins and many others within the nutrient sensing network. FOXO is however regulated by the Insulin signalling pathway via AKT phosphorylation. AMPK activates TSC complex to inhibit mTOR complex 1 in response to energy stress and inhibits growth whilst encouraging autophagy. It is also directly and indirectly regulated by p53 and other damage response elements. It is these elements amongst others that are important for the investigation of this interplay between nutrients and stress. However there is division about how the nutrient signalling pathways, such as Insulin like pathway, are affected by chronically stressful conditions, such as a high redox environment. Some suggest that, over an extended period, ROS actually works to maintain transcription (contrary to established view) in order to maintain the levels of repair proteins and allow for a high protein turnover to remove damaged components. The application of an integrative systems biology approach is ideally suited to disentangling the complexity of the interaction and we will use this to address divergent views as outlined above.
Using the tools developed in our laboratories, we generated the data and models required which allow us to test predictions on cell fate in both stress/damage response and nutrient sensing networks. These developments were then combined to examine differences in physiological state in response to combinatorial effects of altered nutrient levels, environmental stress and perturbed intracellular processes.