Dynamic Modeling Of Intracellular Calcium Response In Biological Cells Induced By Physical And Chemical Stimuli

Calcium ion is an important second messenger of many cells, and plays a vital role in cell physiology. In general, intracellular Ca2+ concentration is in homeostasis in vivo. However the Ca2+ channels on the membrane or calcium stores will be activated under physical and chemical stimuli, which can introduce Ca2+ inflow through membrane or Ca2+ release from calcium stores, and then activate dynamic response of cytosolic free Ca2+. The intracellular Ca2+ dynamic response has a special significance for living cells to maintain normal physiological state. For example, the abnormal dynamic responses of the intracellular Ca2+in vascular endothelial cells(VECs) may cause endothelial cell dysfunction whichclosely relates to atherosclerosis; the Ca2+ dynamic responses in spermatozoa associate with a variety of physiological phenomena including sperm motility, capacitation, hyperactivation and acrosome reaction.In this thesis, the intracellular Ca2+ dynamic responses in two different kinds of human cells (VECs and spermatozoa) under the stimuli of different physical or biochemical stimuli have been investigated by mathematical modeling. For VECs, there has existed an academic controversy of whether the direct or the indirect mechanism is critical to the molecular mechanism of intracellular Ca2+ dynamic response activated by shear stress. In this paper, the direct mediation effect of transient receptor potential vanilloid4 (TRPV4-C1) is taken into account for the first time, combining with the indirect mechanismof Ca2+ signaling pathways through P2X4 Ca2+ channels and P2Y receptors which are activated by the endogenously released ATP induced by fliud shear stress, and the fact that the TRPV4-C1channels are regulated by the intracellular Ca2+ and IP3 concentrations, a novel dynamic model of calcium signaling dynamic response in VECs induced by fliud shear stress and ATP has been proposed. Based on the dynamic model, the simulation results show that while the direct activation of TRPV4-C1by shear stress is critical, endogenously released ATP may play an insignificant role in the process of intracellular Ca2+ response to shear stress, the model proposed here can be used to clarify the controversy of direct or indirect molecular mechanism of intracellular Ca2+ response in this area.For human spermatozoa, a mathematical model of calcium dynamic response mediated by CatSper channel induced by progesterone is proposed for the first time here to study the activation process of human CatSper channels and the intracellular Ca2+ dynamic response, by introducing the mechanism of double Ca2+ stores in the neck, an update dynamic model has been developed. The dynamic model and simulation results lead to not only a better understanding of Ca2+ dynamic behavior and CatSper channel properties under stimulus of progesterone, but also an effective prediction of new phenomena like the Ca2+ oscillations, which will providea basefor further quantitative investigation for the interaction between extracellular fluid mechanics and intracellular biochemistry.In conclusion, our research suggests that, using the method of system dynamic modeling to study the systems of cellular biology can not only help us to better understand existing experimental phenomena and biological mechanisms, but also to conduct simulation experiments to reduce experimentail consumables and save experimental time, to predict new findings to assist further biological experiments as well. The dynamic models proposed in this thesis will also provide the methodological base for quantitative control of cellular physiological functions by the regulation of physical and biochemical stimuli.