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Modeling the cell cycle: From deterministic models to hybrid systems

机译:建模细胞周期:从确定性模型到混合系统

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摘要

The cell cycle is a complex biological system frequently investigated from a mathematical perspective. In fact, over the past years a huge number of deterministic mathematical models describing the dynamics and the regulation of this process have been proposed. A crucial point concerning the cell cycle modeling is the combination of continuous and discrete dynamics in order to obtain results which are coherent with the biological context. To face with this problem we propose a novel approach to the mathematical modeling of biological processes based on the use of hybrid systems. This new methodology essentially consists in a model reduction (using the modified Prony's method) which allows to define the crucial features of the dynamical system. The final aim is to implement a corresponding hybrid system which preserves the properties of the starting deterministic model. Thus, we implemented a methodology which allows to describe the cellular system by combining continuous behavior with discrete events by using the hybrid automata technology. In this way we try to overcome some drawbacks of the deterministic approach, especially regarding the possibility to introduce new variables during simulation and the associated variation of parameters in a more efficient way than the continuous method can do. We applied this innovative methodology to the reconstruction of a simplified hybrid model concerning one of the crucial mammalian cell cycle control point. In particular, we investigated the role of the transcription factors E2F in the R-point transition. The resulting hybrid model preserve the properties of the deterministic one and it allows the identification of the parameter which controls the transition from the inactive (quiescent) to the active state (R-point transition) after the mitogenic stimulation. At the best of our knowledge no hybrid model for the R-point transition are available in literature.
机译:细胞周期是一个复杂的生物系统,经常从数学角度进行研究。实际上,在过去的几年中,已经提出了大量描述该过程的动力学和调节的确定性数学模型。关于细胞周期建模的关键点是连续和离散动力学的结合,以获得与生物学环境相一致的结果。面对这个问题,我们提出了一种基于混合系统的生物过程数学建模的新方法。这种新方法实质上包括模型简化(使用改进的Prony方法),该模型允许定义动力学系统的关键特征。最终目的是实现一个相应的混合系统,该系统保留了初始确定性模型的属性。因此,我们实现了一种方法,该方法允许通过使用混合自动机技术将连续行为与离散事件相结合来描述蜂窝系统。这样,我们试图克服确定性方法的某些缺点,特别是考虑到在仿真过程中引入新变量的可能性以及与连续方法相比更有效的方式引入相关的参数变化。我们将这种创新方法论应用到有关关键哺乳动物细胞周期控制点之一的简化​​杂交模型的重建中。特别是,我们研究了转录因子E2F在R点过渡中的作用。最终的混合模型保留了确定性模型的属性,并且可以识别控制有丝分裂刺激后控制从非活动(静态)到活动状态(R点过渡)的过渡的参数。据我们所知,文献中没有用于R点过渡的混合模型。

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