Rb/E2F1通路调控细胞增殖和凋亡的动力学机制研究

项目名称： Rb/E2F1通路调控细胞增殖和凋亡的动力学机制研究

项目编号： No.11204126

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 物理学I

项目作者： 张小鹏

作者单位： 南京大学

项目金额： 24万元

中文摘要： Rb/E2F1通路对细胞增殖和凋亡过程中均有重要的调控作用。转录因子E2F1既可以促进细胞增殖，又可以引起细胞凋亡。因此，E2F1扮演着肿瘤抑制因子和致癌蛋白的双重角色。肿瘤抑制蛋白Rb是E2F1最重要的负调控因子。本项目将基于已有的实验数据，构建理论模型，刻画Rb/E2F1信号网络如何对细胞生长信号和应激刺激（如致癌应激和DNA损伤）做出应答。我们将采用微分方程组来描述网络蛋白及其他组分的动力学，运用统计物理和非线性动力学的概念和方法，研究E2F1和Rb两种蛋白的后翻译修饰状态（如磷酸化和乙酰化）对E2F1水平和活性的影响，揭示E2F1指导细胞在增殖和凋亡两种命运之间做出抉择的动力学机制。我们还将探讨在生长信号和DNA损伤同时存在时，Rb/E2F1网络如何决定细胞命的命运。本项目有望加深人们对于E2F1生物功能复杂性的理解，为针对Rb/E2F1通路的癌症靶向治疗提供某些线索。

中文关键词： 原癌基因激活；DNA损伤；细胞增殖；细胞凋亡；双稳态

英文摘要： The Rb/E2F1 pathway regulates both cell proliferation and apoptosis.As a transcription factor，E2F1 is essencial for cell proliferation but also triggers apoptosis. Thus, it may act as either a tumor suppersor or an oncoprotein.The potent tumor suppresor Rb is the most important negaitve regulator of E2F1. In this project,we will develop theoretical models to reveal the response of the Rb/E2F1 signaling network to growth signal and stresses(like oncogenic stress and DNA damage) based on existing experimental data.Coupled differential equations will be used to chracterize the dynamics of the concentrations of the proteins and other species in the network.Using the concepts and methods in both statistical physics and nonlinear dynamics,we will investigate the effects of the posttranslational modifications (like phosphorylation and acetylation) of Rb and E2F1 on the abundance and activity of E2F1,and explore how E2F1 makes a decision between cell proliferation and apoptosis.Further, we will study the determination of the cellular outcomes by the Rb/E2F1 network in the presence of competition between growth factors and DNA damage. This project may advance the understanding of the complexity in the biological fuunctions of E2F1 and provide some cues for cancer therapy targeting the Rb/E2F1 pathway.

英文关键词： oncogene activation；DNA damage；cell proliferation；apoptosis；bistability