Mammalian Circadian Clock Influence On Cell Division

So far, the cell division cycle and the circadian clock represent two major cellular rhythms existed in almost all life in vivo. It has recently been recognized that these two periodic processes are coupled in multiple ways, given that several molecular components of the cell cycle network are controlled in a circadian manner. Because PER2is the circadian core clock protein and experiments has shown that PER2mutation may cause a high incidence of cancer, this research paper mainly focus on the entrainment of cell division driven by the circadian clock protein PER2. The biological experimental evidence came from our partners-MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University. We mainly provided the selection of candidate genes, and the building of the forecasting mathematical model.Generally,the circadian clock has a more robust period but a relatively larger amplitude variation. In contrast, the cell cycle often needs a more robust amplitude, although the period varies significantly. Here an important question arises:when using the circadian clock to entrain cell cycle, we need consider how to avoid or reduce the impact of the larger amplitude changes in the upstream circadian rhythms on the cell cycle?To understand the above question, our practices are as follows:Firstly, integrated the mathematical models of the circadian rhythm and cell cycle established by predecessors. Combining theoretical analysis and experimental data generation, we introduced a specific example of the core clock protein PER2driving the core promoter of the cell cycle-regulated cyclin E gene; Secondly, under the conditions of maintaining the regulatory structure and dynamics, we simplified the model as far as possible and abstracted a "triangular structure". By numerical simulation, we explored the advantages of the "triangular structure" to solve the above question; Thirdly, adding some random noise, we attempted to predict the consequences of the circadian clock protein PER2mutation may lead to by means of probabilities; Fourthly, by utilization of the simplified model retaining the essence and the probabilistic model, we carried out some preliminary theoretical inquiry about the filter effects and the probability of the tumorigenesis. The thesis draws the following main results:First, the cell may evolve to the oscillation state from a stable steady state by PER2mutation. This will give rise to some unnecessary cell divisions, and may cause increased risk of oncogenic potential. Second, the "triangular structure" proposed in our model can effectively reduce the impact of the larger amplitude changes in the upstream circadian rhythms on the cell cycle. Third, the simplified model can maintain the regulatory structure and dynamics, and we show that PER2mutation may cause a high incidence of cancer. Finally, the theoretical analysis once again confirms the credibility of these results of the simulations.