基于多尺度耦合动力学模型探讨生物钟对细胞DNA损伤应答的调控机制

The circadian clock and the DNA damage response are two global regulatory mechanisms that control many aspects of cellular physiology and present multi-scale spatial-temporal processes. Recent evidences showed that circadian clock affects cellular response to DNA damage, including p53-mediated DNA repair, cell cycle arrest and apoptosis. However, the dynamics mechanism of circadian control of DNA damage response remains elusive. In the present project, we will develop and couple the p53 signaling network, cell cycle arrest pathway, apoptosis pathway and circadian clock network on the basis of a nonlinear dynamics theory, then a discretization interface is employed to connect the flow of genetic information on the biochemical network and phenotypic markers, thereby linking intracellular signaling to physiological behavior of cell populations. The proposed integrated multi-scale model, combined with experimental validation, is further applied to clarify the effect of circadian clock on the DNA damage response. The obtained results will benefit for development and application of anti-cancer drugs based on appropriate circadian rhythms.

生物钟和DNA损伤响应是生物体的两种全局性调节机制，控制着细胞生理的各个方面以及细胞和个体对环境的适应。其作用方式均呈现从微观到宏观的时间－空间多尺度的系统特征。最近研究表明，生物钟可以调控DNA损伤响应，包括p53信号网络启动的DNA修复，细胞周期阻滞和凋亡等过程。然而，生物钟如何调控DNA损伤响应的动力学机制尚不清楚。本研究拟在整合的框架下，以非线性系统动力学理论为基础，构建和耦合细胞内p53信号网络、细胞周期阻滞网络、细胞凋亡通路网络和生物钟网络。并且通过离散化界面将细胞内生化网络上的信息流与表型建立联系，结合实验验证，构建基于此复杂系统的分子网络－细胞整合模型体系。并探讨应激信号干预下的细胞内信号和细胞群体的生理行为的相互作用机制。所得结果将为利用生物节律开发和应用抗肿瘤药物提供一定的理论依据。

生物钟和细胞周期是生物体的两种全局性调节机制，控制着细胞生理的各个方面以及细胞和个体对环境的适应。最近研究表明，生物钟调控细胞周期并影响细胞对药物的治疗效果。然而其动力学机制尚不清楚。本研究拟在整合的框架下，以非线性系统动力学理论为基础，耦合细胞周期网络、细胞凋亡通路网络和生物钟网络。并且通过离散化界面将细胞内生化网络上的信息流与表型建立联系，结合实验验证，构建基于此复杂系统的分子网络－细胞整合模型体系。并探讨应激信号干预下的细胞内信号和细胞群体的生理行为的相互作用机制。所得结果将为利用生物节律开发和应用抗肿瘤药物提供一定的理论依据。