|Title of PhD thesis:|| ||Spatio-temporal Dynamics of the Wnt/beta-catenin Signaling Pathway: A Computational Systems Biology Approach|
|Reviewers:|| ||Adelinde M. Uhrmacher (Rostock, Germany)|
| ||Arndt Rolfs (Rostock, Germany)|
| ||James Faeder (Pittsburg, USA)|
Human neural progenitor cells (hNPCs) are a new prospect for neuron replacement therapy in the context of neurodegenerative diseases, e.g. Parkinson's disease. ReNcell VM cells are hNPCs cultured in vitro that allow to investigate and understand the mechanisms of neuron differentiation, before clinical studies can be performed. The Wnt/beta-catenin signaling pathway is involved in ReNcell VM cell differentiation. A first step to understand its role in this biological process is to investigate the spatio-temporal dynamics of its signaling proteins.
This dissertation employs in the cyclic workflow of computational systems biology, deploying both wet- and dry-lab experiments, to investigate the spatio-temporal dynamics of Wnt/beta-catenin pathway in ReNcell VM cells. By means of cellular and molecular biology techniques, quantitative kinetics analyses of the pathway's signaling proteins are performed. These show biphasic kinetics during the first three days of physiological differentiation.
A computational model of ReNcell VM cell population is developed to investigate in silico the sources of the biphasic kinetics observed in vitro. The in silico experiments describe the impact of the cell asynchrony w.r.t. the cell cycle on the protein dynamics and give insights about the role of self-induced Wnt signaling in the cell population. A stochastic investigation reveals discrepancies in the deterministic approximation and emphasizes the importance of stochastic approaches for modeling biological systems. We propose additional wet-lab experiments in order to validate the in silico predictions, and hence close the loop of computational systems biology.
Mazemondet, O., Hubner, R., Frahm, J., Koczan, D., Bader, B.M., Weiss, D.G., Uhrmacher, A.M., Frech, M.J., Rolfs, A. & Luo, J. (2011), "Quantitative and kinetic profile of Wnt/β-catenin
signaling components during human neural progenitor cell differentiation", Cellular & Molecular Biology Letters. PMID: 21805133
Leye, S., Mazemondet, O. & Uhrmacher, A.M. (2010), "Parallel analysis with FAMVal to speed up simulation-based model checking", In Proceedings of the Fourth European Modelling Symposium on Mathematical Modelling Computer Simulation, IEEE Computer Society [DOI]
Mazemondet, O., John, M., Maus, C., Uhrmacher, A.M. & Rolfs, A. (2009), "Integrating Diverse Reaction Types Into Stochastic Models - A Signaling Pathway Case Study in the Imperative Pi-Calculus", In Proceedings of the 2009 Winter Simulation Conference., pp. 932-943. Institute of Electrical and Electronics Engineers, Inc. [DOI]