Hawker, M (2024) Cracking the calcium code: modelling molecular determinants of calcium signalling in health and disease. Doctoral thesis, Liverpool John Moores University.

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Abstract

The release of calcium ions into the cytoplasm of a cell through inositol-1,4,5 trisphosphate receptors plays a vital role in various physiological processes within the human body. Examples include the secretion of saliva in salivary glands and insulin in pancreatic beta-cells, the contraction of heart muscles and the firing of neurons. Calcium is essential for these functions to occur properly. A dysregulated calcium signalling system has been linked to a large variety of human diseases, such as neurological diseases, heart disease, diabetes and abnormal salivary gland function. Mathematical models of the calcium signalling system can provide interesting insights into inositol-1,4,5 trisphosphate receptor and calcium dynamics. For example, we can ask: how does mutation affect the frequency of calcium events and how does the behaviour of the inositol-1,4,5 trisphosphate receptor differ between cell types? In this thesis, we develop a calcium puff model based on integrodifferential equations. Our model is parameterised using stationary single channel and calcium puff data from HEK-3KO cells, obtained through collaboration with the Yule Lab, Rochester. In Chapter 2, analysis of stationary single channel and calcium puff data is conducted. We compare the results from three calcium puff data sets and parameterise three statistical distributions using interpuff interval data. The statistical distributions are evaluated qualitatively and quantitatively, concluding with the best fit. In Chapter 3, we introduce a calcium puff model based on integrodifferential equations. Our model expands current calcium puff models by enabling investigation of the memory of an inositol-1,4,5 trisphosphate receptor and the impact of differing lengths on calcium dynamics. In Chapter 4, we parameterise our mathematical model using experimental data from healthy and mutated inositol-1,4,5 trisphosphate receptors, initially presented in Chapter 2.
Using our mathematical model, one can directly relate the integral terms to the delayed response of the inositol-1,4,5 trisphosphate receptor, observed in patch clamp experiments. Furthermore, our novel mathematical models, parameterised with experimental data, offer a deeper insight into the prolonged effects of alterations to the inositol-1,4,5 trisphosphate receptor on the calcium signalling system. This extends our understanding beyond the time frames achievable in experimental conditions.

Item Type:	Thesis (Doctoral)
Uncontrolled Keywords:	Piecewise deterministic Markov processes; Integrodifferential equations; Stochastic calcium dynamics; Hybrid stochastic systems; Time delayed Markov models
Subjects:	Q Science > QA Mathematics Q Science > QH Natural history > QH301 Biology Q Science > QM Human anatomy
Divisions:	Computer Science and Mathematics
SWORD Depositor:	A Symplectic
Date Deposited:	11 Nov 2024 14:25
Last Modified:	11 Nov 2024 14:26
DOI or ID number:	10.24377/LJMU.t.00024638
Supervisors:	Siekmann, I, Kelly, R, Cao, P and Sneyd, J
URI:	https://researchonline.ljmu.ac.uk/id/eprint/24638

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