In system biology, mathematical models have long tradition are used to understand complex biological control processes/ systems, for example, circadian clock oscillatory mechanism. Circadian rhythms (~24 hour) is ubiquitous in almost the living species ranging from mammals to cyanobacteria shows the robustness of key oscillatory features such as the phase, period and amplitude against external and internal variations. These autonomous oscillations are formed by the complex interactions of the interactive molecules. A transcriptional-translational feedback loop is typically characterized as a common principle for this sustained oscillations. Recently studies, it has broadly been established that the robustness of biochemical oscillators, like the Drosophila circadian clocks, can be generated by interlocked transcriptional-translational feedback loops, where two negative feedback loops are coupled through mutual activations. The mechanisms by which such coupling protocols have survived out of many possible protocols remain to be revealed. To address this question, we investigated two distinct coupling protocols: activator-coupled oscillators (ACO) and repressor-coupled oscillators (RCO). We focused on the two coupling parameters: coupling dissociation constant and coupling time delay. Interestingly, the ACO was able to produce anti-phase or morning-evening cycles, whereas the RCO produced in-phase ones. Deterministic and stochastic analyses demonstrated that the anti-phase ACO provided greater fluctuations in amplitude not only with respect to changes in coupling parameters but also to random parameter perturbations than the in-phase RCO. Moreover, the ACO deteriorated the entrainability to the day-night master clock, whereas the RCO produced high entrainability. Considering that the real, interlocked feedback loops have evolved as the ACO, instead of the RCO, we first proposed a hypothesis that the morning-evening or anti-phase cycle is more essential for Drosophila than achieving the robustness and entrainability.九州工業大学博士学位論文 学位記番号:情工博甲第352号 学位授与年月日:令和2年9月25日1 BACKGROUND|2 THE DYNAMICS MODELS OF CIRCADIAN RHYTHMS|3 MODELING THE INTERLOCKED NEGATIVE FEEDBACK LOOPS|4 ROBUSTNESS OF THE INTERLOCKED CIRCADIAN OSCILLATORS|5 ENTRAINABILITY OF THE COUPLED OSCILLATORS|6 CONCLUSIONS AND FUTURE WORK九州工業大学令和2年
