Intracellular network attractor selection and the problem of cell fate decision.
Doctoral thesis, UCL (University College London).
This project aims at understanding how cell fate decision emerges from the overall intracellular network connectivity and dynamics. To achieve this goal both small paradigmatic signalling-gene regulatory networks and their generalization to highdimensional space were tested. Particularly, we drew special attention to the importance of the effects of time varying parameters in the decision genetic switch with external stimulation. The most striking feature of our findings is the clear and crucial impact of the rate with which the time-dependent parameters are changed. In the presence of small asymmetries and fluctuations, slow passage through the critical region increases substantially specific attractor selection by external transient perturbations. This has strong implications for the cell fate decision problem since cell phenotype in stem cell differentiation, cell cycle progression, or apoptosis studies, has been successfully identified as attractors of a whole network expression process induced by signalling events. Moreover, asymmetry and noise naturally exist in any integrative intracellular decision network. To further clarify the importance of the rate of parameter sweeping, we also studied models from non-equilibrium systems theory. These are traditional in the study of phase transitions in statistical physics and stood as a fundamental tool to extrapolate key results to intracellular network dynamics. Specifically, we analysed the effects of a time-dependent asymmetry in the canonical supercritical pitchfork bifurcation model, both by numerical simulations and analytical solutions. We complemented the discussion of cell fate decision with a study of the effects of non-specific targets of drugs on the Epidermal Growth Factor Receptor pathway. Pathway output has long been correlated with qualitative cell phenotype. Cancer network multitargeting therapies were assessed in the context of whole network attractor phenotypes and the importance of parameter sweeping speed.
|Title:||Intracellular network attractor selection and the problem of cell fate decision|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of BEAMS > Faculty of Maths and Physical Sciences > CoMPLEX - Maths and Physics in the Life Sciences and Experimental Biology|
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