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Title: Modeling complex cell regulation in the zebrafish circadian clock
Author: Heussen, R. K. M.
ISNI:       0000 0004 8497 7790
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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The interdisciplinary "systems biology" approach of combining traditional biological investigations with tools from the mathematical and computer sciences has enabled novel insights into many highly complex and dynamic biological systems. The use of models has, for instance, revealed much about the intricate feedback mechanisms and acute importance of gene regulatory networks, and one such network of special note is our internal time keeper, or circadian clock. The circadian clock plays a pivotal role in modulating critical physiological processes, and has also been implicated, either directly or indirectly, in a whole range of pathological states. This research project investigates how the underlying dynamics of the circadian clock in the zebrafish model organism may be captured by a mathematical model, considering in particular the entrainment effect due to external cues such as light. Simulated data is contrasted with experimental results from different light regime experiments to validate the model and guide its refinement. Furthermore, various statistical methods are implemented to process the raw data and support its analysis. Extending the initial deterministic approach to take into account stochastic effects and additive population level effects emerges as a powerful means of representing the circadian signal decay in prolonged darkness, as well as light initiated re-synchronization as a strong component of entrainment. Consequently, it emerges that stochastic effects may be considered an essential feature of the circadian clock in zebrafish. A further cornerstone of the project is the implementation of an integrated simulation environment, including a Sequential Monte Carlo parameter estimation function, which succeeds in predicting a range of previously determined and also novel suitable parameter values. However, considerable difficulties in obtaining parameter values that satisfy the entire range of important target values simultaneously highlights the inherent complexity of accurately simulating the circadian clock.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available