Analysis of calcium metabolism in biological systems using different model-based approaches

Mathematical modeling has been launched as a powerful tool for studying metabolism in biological systems as biological complexity propels interdisciplinary application of engineering methods to solve biological/physiological questions. Models simulate various scenarios in metabolism and make it possible to explore the structured function and regulation of metabolism, which could be impossible or impractical using experimental methods. Calcium metabolism has been an important topic due to its essentiality in human health. A complex coordination of biochemical regulators and organic actions balances calcium metabolic pathways to maintain serum calcium concentration according to internal and external conditions. Here, three types of mathematical modeling approaches are illustrated in the study of calcium metabolism although they are not completely separable. Statistical approaches, particularly multiple regression, have been used to build a model based on indentified relationships between calcium metabolic pathways and mechanistic variables which influence calcium metabolism. Statistical modeling was used to develop a simple and cost-effective method for estimating fractional calcium absorption by validating it against conventional methods. Calcium kinetic modeling has been used to estimate calcium metabolism at steady-state by fitting the model simulation to experimental data studied under specific conditions. In this dissertation, calcium kinetic modeling was used to fit long-term calcium isotopic data (calcium-41) to estimate bone resorption rate, and to simulate dynamics in bone balance. Finally, mechanistic models are able to depict dynamic responses in mechanisms which constitute calcium metabolism, and predict calcium metabolic behavior in response to system perturbations. Mechanistic modeling was used to analyze dynamics in bone cell populations responding to the regulatory network, and to propose prospective research of developing a model for whole calcium metabolism. Cross-linkage between calcium metabolism and modeling approaches offers effective evaluation and better understanding of calcium metabolism and its regulation. Illustrated models in this study are expected to be a platform for prospective model-based research. For example, a comprehensive model which integrates published models may be used to uncover poorly understood mechanisms, such as the regulatory system of calcium metabolism in adolescents, and to design clinical experiments to characterize calcium related diseases for population and individuals