Modeling Of Bcl-2 Protein Suppressed Calcium Signaling And Bifurcation Analysis Of Two-pool Model

Calcium ion(Ca²⁺)is a signal for both life and death in cells.It regulates almost all physiological activities in the body by the oscillations in calcium concentration and thus plays a crucial role in cell fate determination.The thesis contains two parts,modeling of Bcl-2 protein suppressed calcium signaling and bifurcation analysis of a two-pool model.The oscillating calcium signal is mainly mediated by the IP₃R channel located on the endoplasmic reticulum membrane.Either directly or indirectly,anti-apoptotic protein Bcl-2 can regulate Ca²⁺release from IP₃R channel,thereby determining the cell fate.In the first study,based on recent experimental results,a mathematical model is constructed to describe the signaling pathway of Ca²⁺release regulated by Bcl-2 indirectly.The model output fits nicely with the experimental data.So the model theoretically demonstrates that Bcl-2 can suppress calcium signaling.After the robustness test of the model,bifurcation theory was used to analyze the role of some key components in the signaling pathway and predict their effects on calcium oscillations.This study not only reveals the dynamics of Bcl-2 on inhibiting Ca²⁺release,but also plays a guiding significance in relevant biological experiments.In addition to the IP₃R channel,there is another Ca²⁺release channel on the endoplasmic reticulum membrane,i.e.,the RyR channel.According to the different sensitivities of the two channels to Ca²⁺,the two-pool model described in detail the mechanism of intracellular calcium oscillations under the action of the two kinds of calcium channels.However,the Hill coefficients in this model are too high to do mathematical analysis.In the second study,using the knowledge of nonlinear dynamics,and we analyze the model after reducing the Hill coefficients,and compare the dynamic behaviors to these produced by the original two-pool model.According to the theory of bifurcation,the key parameters selected by the results of parameter sensitivity analysis,are studied on the effects of calcium oscillations.By analyzing the biological significance of these parameters,this study provides a theoretical basis for the intervention of calcium signaling from a system-level perspective.