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Title: A systems modelling study of the integrated stress/damage response and nutrient signalling network
Author: Hall, Philip
Awarding Body: University of Newcastle upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2016
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The disposable soma theory predicts that levels of maintenance and repair are influenced by resource availability. The interplay of cell signalling response to stress and damage with nutrient sensing networks presents an opportunity to further our understanding of how this influence is achieved. A systems modelling approach is applied to address three related problems, allowing an in-depth examination of underlying biochemical dynamics of these complex networks. p53 is a well-known regulator of G1 phase cell-cycle checkpoints. As part of a collaborative effort I have examined its role in regulating p21 senescence signalling in response to DNA damage. In support of a computational model, I generated experimental data showing that lower doses of radiation, applied over a longer time period, were able to produce a similar population probability of senescence as a single high dose. The activation of mTORCl by amino acids is well established, but the effect of amino acids on the rest of the Insulin/IGF signalling pathway is less clear. Again in a collaborative effort, we generated models representing multiple possible regulatory inputs of amino acids into Insulin/IGF signalling. These calibrated models underwent a combinatorial selection and merging process, based on comparative goodness of fit, determining the most likely candidate inputs to be IRS1, AMPK and mTORC2 which were then confirmed experimentally. FOXO3a transcription factor sits at a junction, regulated by ROS, IGF (via AKT) and DNA damage (via p53 and ATM) and regulating energy availability (via AMPK) and senescence (via p53). Using a systems modelling approach I explore the dynamics of IGF/FOXO signalling under conditions of chronic oxidative stress and find a novel activation of mTORCl by ROS via TSC1/2. Together this thesis represents an in-depth study of the interplay between nutrient, stress and damage signalling, revealing potential dynamics for the effect of nutrients and chronic stress on the early stages of cellular senescence.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available