DNA损伤致p53-Mdm2相互作用的动力学模型

最新实验结果表明，在受到各种辐射而引起DNA损伤后，在单体细胞和群体细胞情况下，细胞中的p53蛋白浓度表现为非衰减振荡和衰减振荡两种不同的动力学行为.通过研究p53-Mdm2负反馈回路的非线性动力学行为，分析了各种(特别是DNA损伤、p53和 Mdm2蛋白浓度三者之间)动力学关系，提出了一个能同时描述这两种不同动力学行为的非线性模型. 关键词： p53-Mdm2负反馈回路 非衰减振荡和衰减振荡 非线性动力学模型     

DNA损伤致p53-Mdm2相互作用的非线性动力学模型(英文)

p53-Mdm2相互作用在DNA损伤的细胞响应方面起着非常重要的作用。最新实验结果表明,在受到各种辐射损伤而引起DNA损伤后,细胞中的p53蛋白浓度在单体细胞和群体细胞情况下,表现为非衰减振荡和衰减振荡两种不同的动力学行为。通过研究p53 -Mdm2负反馈回路的非线性动力学,分析了各种（特别是DNA损伤,p53和Mdm2浓度三者之间的）动力学关系,提出了一个能同时描述这两种不同动力学行为的非线性模型。 Exploring the nonlinear dynamics of the negative feedback loop composed of p53 and Mdm2 proteins, we propose a signal-response model to study the dynamical mechanism of the different oscillatory behaviors for the activities of p53 and Mdm2 proteins both in individual and population of cells. It is shown that the sustained and damped oscillatory dynamics could be described in a unified way when the dynamics of damage-derived signal is properly introduced.     

基于DNA损伤的蛋白调控网络研究

细胞生长的每个阶段都离不开蛋白质相互作用.研究细胞周期的功能、调控机理及参与调控的蛋白质之间的关系对生物工程等领域有重大的应用价值.本文通过研究电离辐射下生物体细胞的DNA损伤后,细胞内以p53为核心的扩展蛋白调控网络的功能、原理及其自修复机理,在现有蛋白网络基础上引入更多蛋白网络调控因子来建立蛋白调控网络,仿真模拟更为全面的细胞周期进程;并且从复杂网络图论和细胞周期调控两个方面分析扩展PMP调控网络的抗扰能力及自修复机理,结果表明:1)蛋白网络在对抗环境中出现的小扰动时具有较强的稳定性.但在面对蓄意攻击时网络的稳定性较差.2)受损的DNA能否被修复取决于p53蛋白的动力学行为,即低损伤与中损伤情况下,p53可诱导细胞周期进程阻滞来完成细胞的自修复;而当高损伤或过损伤时,p53蛋白浓度表现为周期振荡行为并诱导细胞凋亡.     

时滞与噪声影响 Notch信号通路动力学的模型化研究

本文基于Hill动力学与Michaelis-Menten方程,建立理论模型研究时滞与噪声影响Notch信号通路动力学.研究发现,her1、her7基因转录的时滞性在很大程度上调控着Notch信号通路的动力学行为.由于时滞性的调控,Notch系统动力学经历Hopf分岔,由稳态转变为周期演化特性.通过考察Notch信号通路的噪声效应,我们发现,由于噪声的扰动,Notch系统周期振荡动力学改变.在较小噪声幅值条件下,Notch信号通路中改变的周期节律性可以通过时滞得以平衡恢复,由此表明了her1、her7转录的时滞性促进了Notch信号通路的周期振荡.对于较强噪声环境,时滞效应很难改变Notch信号的巨大突变,其信号通路动力学行为被噪声影响.理论结果符合实验,并揭示了时滞与噪声对Notch信号通路动力学的一种调控机制,可为设计阻止Notch功能异常导致的多种疾病和癌症的通路治疗方案提供理论依据.     

辐射致DNA损伤及相关生物-化学-物理问题(英文)

介绍了在DNA辐射损伤以及相关生物、物理、化学问题的一些研究工作。重点是径迹结构、DNA双链断裂和细胞学终点的关系。P53-Mdm2负反馈回路在DNA损伤的细胞响应方面起重要作用,用一个简单的模型研究了P53-Mdm2负反馈回路相互作用的动力学行为。Some of recent works are presented on radiation induced DNA damage being carried out at China Institute of Atomic Energy （CIAE） and related bio-chemi-physical problems. Emphasis is placed on track structure and its relation to the cell end-point, and a simple model proposed to study the dynamical behavior of P53-Mdm2 interaction which plays pivotal role in cellular response to DNA damage.     

Hes1调控 AKT-MDM2-p53-PTEN通路的一种物理机制

基于Hill动力学与Michaelis-Menten方程，建立理论模型研究发状分裂相关增强子1(hairy and enhancer of split 1,Hes1)调控蛋白激酶B (Protein Kinase B,AKT)-鼠双微体2 (Murine Double Minute2,MDM2)-抗癌基因p53(p53)-第10号染色体缺失的磷酸酶及张力蛋白同源的基因(Phosphatase and tensin homolog deleted on chromosome ten,PTEN)通路的一种物理机制.研究发现，Hes1通过与PTEN结合抑制PTEN表达，并调控AKT信号.表明了Hes1蛋白的合成，以及Hes1与PTEN相互作用调控AKTMDM2-p53-PTEN通路信号，将会有效地控制细胞结果 . Hes1作为AKT-MDM2-p53-PTEN信号通路中上游调节的重要因素，还可以在一定程度上通过影响p53蛋白功能，改变p53对肿瘤的抑制性.理论结果可用于预测Notch通路信号异常诱导的致癌性，并进一步揭示了Notch信号通路影响细胞AKT-MDM2-p53-PTEN通路的激活...     

VPRBP 蛋白与Abl 激酶诱发、抑制前列腺癌的 一种物理机制

在本文基于Hill动力学与Michaelis-Menten方程,建立理论模型研究VPRBP蛋白与Abl激酶诱发、抑制前列腺癌的一种物理机制.研究发现,DNA损伤使得ATM(共济失调毛细血管扩张症突变)很快激活,并激活上调p53蛋白表达,DNA损伤的后续破坏会在很大程度上通过p53表达上调而被抑制. VPRBP通过上调MDM2蛋白的激活水平,使得p53表达水平异常,进而无法正常抑制前列腺癌的发生发展.通过考察Abl在前列腺癌进程中的作用发现,Abl使得AKT的表达水平下调,由于Abl对AKT的抑制作用,致使在AKT信号通路中MDM2表达水平受到抑制,进而稳定p53表达.由此表明了,过少的Abl对AKT的抑制程度减弱,不仅使得细胞代谢出现紊乱,而且还会促使p53正常的周期表达水平异常,对DNA损伤诱发的肿瘤抑制性减弱,进而促进前列腺癌的发生发展.基于本文模型,可以预测VPRBP与Abl作为诱发、抑制前列腺癌的调节剂对现有和潜在的抗癌治疗较为敏感. VPRBP与Abl在诱发、抑制前列腺癌过程中的时滞效应,导致信号通路中p53与PTEN蓄积量增多、AKT蓄积量减少,以及Plk1周期振荡相位转移...     

模型化研究两细胞间基因、蛋白耦合振荡中的噪声效应

本文基于Hill动力学与Michaelis-Menten方程，建立理论模型研究两细胞间基因、蛋白耦合振荡中的噪声效应.研究发现，在Notch信号通路中，两细胞间基因、蛋白耦合振荡呈现了周期振荡特性，表明了细胞间信号传导的同步振荡特性.“内在”噪声和“外在”噪声对两细胞间基因、蛋白耦合振荡有着不同的作用.内噪声有利于细胞间Notch信号通路中各基因、蛋白表达再次提升.外噪声诱导通路中基因、蛋白的表达水平降低，周期振荡变得阻尼.内、外噪声共同作用不仅可使得基因表达适当并呈现出持续振荡模式，而且还可使得细胞间基因转录合成相应的蛋白过程呈现出持续振荡模式.从而表明了基因表达的内、外噪声共同作用有利于控制细胞间基因激活、蛋白合成保持周期节律性.本文理论结果揭示了内外噪声对细胞间Notch信号通路动力学的一种调控机制，确定了内外噪声各自的调控效应，澄清了内外噪声共同作用调控体系持续周期振荡的物理机制，理论结果符合实验，可为设计阻止Notch体系基因、蛋白变异导致的多种疾病和癌症的通路治疗方案提供理论依据.     

自催化三分子模型内噪声随机共振

运用化学Langevin方程 ,数值研究了内噪声对单个和单向耦合自催化三分子模型动力学行为的影响 .研究发现 ,对于单个振子体系 ,内噪声可以诱导持续振荡 ,而且随着系统尺度的增大 ,信噪比经过一个极大值 ,从而证明了内噪声随机共振和最佳尺度效应的存在 ;对于单向耦合系统 ,信噪比还随耦合强度的变化而经过极大值 .此外 ,边界条件对耦合体系的内噪声随机共振行为有很大影响 ,非零流条件下 ,耦合可以增强内噪声随机共振 ,而零流条件下 ,耦合会抑制随机共振 ;当耦合强度适宜时 ,每个振子发生随机共振时的尺度几乎相同 ,表明最佳体系尺度和耦合强度有助于体系达到最佳的化学反应状态 .     

基于Kramers逃逸速率的Duffing振子广义调参随机共振研究

以二维Duffing振子的随机共振为研究对象,提出Duffing振子的广义调参随机共振. 以Kramers逃逸速率为基础,建立了Duffing振子随机共振的判别函数,阐述了Duffing振子在不同噪声强度及信号频率输入条件下的广义调参随机共振规律,并给出了Duffing振子广义调参随机共振的一般方法. 关键词： Duffing振子 随机共振 Kramers逃逸速率 广义参数调节     

Oscillatory expression and variability in p53 regulatory network

The effect of delay, nonlinearity and noise on oscillatory motion is of permanent interest for theoretical and experimental research. Here we explore a negative feedback loop between p53 and Mdm2 with a time delay, which is a key circuit in the response of cells to damage. This circuit shows noisy sustained oscillations in individual human cells following DNA damage, and damped oscillations at the cell population level. We demonstrate the effect of delay on the oscillation, and the correlation in time course. In a multi-species system, the events at different time points which span a time delay are coupled even when the delay is large compared with the other characteristic times of the system. We also clarify that the dynamics at the single-cell level appears to be coherent resonance, and the origin of the damped oscillation at the macroscopic level out of the sustained ones at the single-cell level can be ascribed to the dephasing process which is induced by the interplay between nonlinearity and noise. The findings are consistent with experimental observations and advance our understanding of the dynamics of the p53 network.     

A unified model for studying DNA damage-induced p53–Mdm2 interaction

Exploring the nonlinear dynamics of the negative feedback loop composed of p53 and Mdm2 proteins, we propose a signal–response model to study the dynamical mechanism of the different oscillatory behaviors for the activities of p53 and Mdm2 proteins both in individual and populations of cells. It will be shown that the sustained and damped oscillatory dynamics could be described in a unified way when the dynamics of the damage-derived signal is properly introduced.     

A mathematical model of a P53 oscillation network triggered by DNA damage

Taking the interaction between a DNA damage repair module, an ATM module, and a P53--MDM2 oscillation module into account, this paper presents a mathematical model of a P53 oscillation network triggered by a DNA damage signal in individual cells. The effects of the DNA damage signal and the delay time of P53-induced MDM2 expression on the behaviours of the P53 oscillation network are studied. In the oscillatory state of the P53--MDM2 oscillator, it is found that the pulse number of P53--P oscillation increases with the increase of the initial DNA damage signal, whereas the amplitude and the period of P53--P oscillation are fixed for different initial DNA damage signals, and the period numbers of P53--P oscillations decrease with the increase of time delay of MDM2 expression induced by P53. These theoretical predictions are consistent with previous experimental results. The combined negative feedback of P53--MDM2 with the time delay of P53-induced MDM2 expression causes oscillation behaviour in the P53 network.     

Landscapes of non-gradient dynamics without detailed balance: stable limit cycles and multiple attractors

Landscape is one of the key notions in literature on biological processes and physics of complex systems with both deterministic and stochastic dynamics. The large deviation theory (LDT) provides a possible mathematical basis for the scientists' intuition. In terms of Freidlin-Wentzell's LDT, we discuss explicitly two issues in singularly perturbed stationary diffusion processes arisen from nonlinear differential equations: (1) For a process whose corresponding ordinary differential equation has a stable limit cycle, the stationary solution exhibits a clear separation of time scales: an exponential terms and an algebraic prefactor. The large deviation rate function attains its minimum zero on the entire stable limit cycle, while the leading term of the prefactor is inversely proportional to the velocity of the non-uniform periodic oscillation on the cycle. (2) For dynamics with multiple stable fixed points and saddles, there is in general a breakdown of detailed balance among the corresponding attractors. Two landscapes, a local and a global, arise in LDT, and a Markov jumping process with cycle flux emerges in the low-noise limit. A local landscape is pertinent to the transition rates between neighboring stable fixed points; and the global landscape defines a nonequilibrium steady state. There would be nondifferentiable points in the latter for a stationary dynamics with cycle flux. LDT serving as the mathematical foundation for emergent landscapes deserves further investigations.