具有转录和翻译时滞的基因调控网络以及Notch信号通路的动力学和生物学机制研究

Motivated by the issues in practical life science, this project is devoted to studying how the transcriptional and translational time delays affect the dynamical and biological mechanisms of genetic regulatory networks and Notch signaling pathway. First of all, based on established biological facts and experimental data, we will establish the dynamic models of genetic regulatory networks and explore the dynamical properties that include stability, periodic oscillation, bistability, multistability, almost periodic motion, chaos, etc., and biological functions, of such networks, in the presence of transcriptional and translational time delays, and set up the corresponding theoretical and numerical analysis methods. These results may provide valuable insights to the analysis, control, design and implementation of genetic regulatory networks. Second, given the centrality of transcriptional and translational time delays in the regulation of Notch signaling pathway, we will model the pathway systematically and analyze its dynamical behaviors, based on the existing experimental data and theoretical results. Furthermore, we intend to clarify and validate the effects of such delays on the dynamical and physiological mechanisms of the pathway through combining with experimental data. These obtained research results can provide clues to Notch-based cancer therapy and drug discovery. Finally, it should be believed that the research in this project not only helps to reveal the complex dynamical mechanisms of the representative delayed genetic regulatory networks as well as their evolution rules, but also plays an important role in promoting the development of other related disciplines and multi-disciplines.

本项目以实际的生命科学问题为驱动，主要研究转录和翻译时滞对基因调控网络以及Notch信号通路的动力学和生物学机制的影响。首先，根据既定的生物学事实和实验数据，建立基因调控网络的动力学模型，并探索在时滞效应下网络的稳定性、周期振荡、双稳态、多稳态、概周期运动、混沌等动力学特性及生物学功能，建立相应的理论和数值分析方法，为基因调控网络的分析、控制、设计和实现提供有益的见解。其次，鉴于转录和翻译时滞在调控Notch通路中的重要性，本项目将结合已有的实验数据和理论结果对该通路进行系统建模，分析其动力学行为，阐明这些时滞在该通路中的动力学及生理调控机制，并结合实验数据加以验证，研究成果可为以Notch为基础的癌症治疗和药物开发提供线索。最后，本项目的研究不仅有助于揭示以时滞基因调控网络为代表的复杂系统的动力学特征及演化规律，而且对推动其他相关学科及多学科交叉发展具有重要的作用。

本项目以实际的生命科学问题为驱动，主要研究时滞对基因调控网络以及Notch信号通路的动力学（包括稳定性、周期振荡、双稳态、双稳态的稳态转换、暂态混沌等）和生物学机制的影响。通过三年的研究，本项目在CD8 T细胞响应病毒抗原时滞模型的动力学建模和定性分析；时滞CDK1-APC反馈回路的分岔和振荡动力学；时滞-扩散miR-9/Hes1网络的稳定性和分岔；时滞在Notch信号通路介导的神经祖细胞命运决策动态协调中的复杂作用等几个方面取得了一些原创性研究成果。本项目的研究不仅有助于揭示以时滞基因调控网络为代表的复杂系统的动力学特征及演化规律，而且对推动其他相关学科及多学科交叉发展提供了新的思想和方法。本项目执行期间，相关研究结果在《IEEE Transactions on Neural Networks and Learning Systems》《IEEE/ACM Transactions on Computational Biology and Bioinformatics》《IET Systems Biology》《Discrete Dynamics in Nature and Society》等期刊发表论文4篇。