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.     

Mdm2生成速率调控的p53-Mdm2振子的全局动力学和稳定性

肿瘤抑制蛋白p53的动力学在一定程度上可以决定DNA损伤后的细胞命运.p53的动力学行为与p53信号通路中p53-Mdm2振子模块密切相关.然而,p53的负调控子Mdm2的生成速率的增加使其在一些癌细胞中过表达.因此探讨Mdm2生成速率对p53动力学的影响有重要意义.同时,PDCD5作为p53的激活子也调控p53的表达.因此,本文针对PDCD5调控的p53-Mdm2振子模型,通过分岔分析获得了Mdm2生成速率所调控的p53的单稳态、振荡以及单稳态与振荡共存的动力学行为,且稳定性通过能量面进行了分析.此外,噪声强度对p53动力学的稳定性有重要的影响.因此,针对p53的振荡行为,探讨了噪声强度对势垒高度和周期的影响.本文所获得的结果对理解DNA损伤后的p53信号通路调控起到一定的指导作用.     

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.     

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.     

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...     

Fisher方程的有界衰减振荡解

为了研究非线性发展方程的有界衰减振荡解,特选取Fisher方程为例. Fisher方程在描述激发介质的非数值模型(如Belousov-Zhabotinsky (BZ)反应)中, 其解的振幅取负值是有意义的.应用平面动力系统理论,研究了Fisher方程有界行波解存在的条件, 利用LS解法和线性化解法给出了其有界衰减振荡解的近似解析表达式,并进行了误差估计.     

邻氨基苯甲酸BZ反应体系中的振荡与混沌：I.SCTR实验研究和非线…

本文研究了ＣＳＴＲ中邻氨基苯甲酸苯甲酸ＢＺ反应体系的振荡行为，总结了非化条件下各反应物浓度和流速变化以及温度变化对体系振荡反应的影响规律；同时还考察了催化条件下的体系振荡行为，发现了Ｍｎ（Ⅱ）催化出现复杂振荡筢应序列，非线性动力学理论分析的结果表明复杂振荡是由体系动力学本质决定的确定性行为，并发现由周期走向混沌的演变过程中存在倍周期分岔（或慢周期分岔）迹象；同时，还通过计算分维，研究反应条件对体系     

一个跃变电路切换系统的振荡行为及分岔机理分析

本文研究两个非线性电路系统通过开关组成的时间切换系统的复杂振荡行为及其产生机理.利用开环运算放大器放大倍数为极大值的特性,即运算放大器总是处于正的或负的饱和状态,当输入电压从负过零变正时,输出电压从正饱和状态跃变为负饱和状态,本文选择子电路系统中的非线性部分为跃变函数.首先对两个子系统进行了稳定性分析,给出了不同参数条件下的振荡行为,然后在子系统单个参数在一定范围内变化,而其他参数保持不变的情况下,研究了切换系统的复杂振荡特征,并分析了其产生机理.由于子系统方程的非光滑性和切换带来的整个系统的非光滑性,使得整个系统的周期振荡轨迹有四个切换点,随着参数的变化,周期振荡轨线与非光滑分界面发生擦边分岔,导致周期振荡分裂成两个对称的周期振荡.并且研究了切换点位置改变对整个系统周期振荡行为的影响以及切换点处的分岔机理.     

格子气的声振荡衰减

采用格子气数值方法模拟了共振腔中气体声振荡衰减过程．计算结果表明：格子气中声振荡衰减的规律和经典理论结果一致；衰减系数随频率增加而减小，并且随密度增加而减小．该结果可以用来说明一些大学统计物理教科书中的一个经典例子存在不完善之处．本中采用了一种新的扭转9-bit格子气模型和并行计算方法，这些结果对今后研究格子气中的热声问题有参考价值．     

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.     

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.     

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.     

Radiation-induced robust oscillation [2mm]and non-Gaussian fluctuation

There have been many recent studies devoted to the consequences of stochasticity in protein circuitry. Stress conditions, including DNA damage, hypoxia, heat shock, nutrient deprivation, and oncogene activation, can result in the activation and accumulation of p53. Several experimental studies show that oscillations can be induced by DNA damage following nuclear irradiation. To explore the underlying dynamical features and the role of stochasticity, we discuss the oscillatory dynamics in the well-studied regulatory network motif. The fluctuations around the fixed point of a delayed system are Gaussian in the limit of sufficiently weak delayed feedback, and remain Gaussian along a limit cycle when viewed tangential to the trajectory. The experimental results are recapitulated in this study. We illustrate several features of the p53 activities, which are robust when the parameters change. Furthermore, the distribution in protein abundance can be characterized by its non-Gaussian nature.     

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.     

Oscillatory Activities in Regulatory Biological Networks and Hopf Bifurcation

Exploiting the nonlinear dynamics in the negative feedback loop, we propose a statistical signal-response model to describe the different oscillatory behaviour in a biological network motif. By choosing the delay as a bifurcation parameter, we discuss the existence of Hopf bifurcation and the stability of the periodic solutions of model equations with the centre manifold theorem and the normal form theory. It is shown that a periodic solution is born in a Hopf bifurcation beyond a critical time delay, and thus the bifurcation phenomenon may be important to elucidate the mechanism of oscillatory activities in regulatory biological networks.     

Mathematical Modeling of Linear Docking. I. Determination of Regions of Binding of Protein Molecules

We report on the results of mathematical simulation of the interaction of various sequences of proteins Mdm2, P53, and Nap1 in accordance with the developed algorithms that were used for identifying the region of binding of various proteins during the formation of biological complexes P53–Mdm2, Mdm2–Mdm2, and Nap1–Nap1. The approach developed in this work will make it possible to determine active regions of binding of polypeptide chains of various proteins and to choose and synthesize highly selective peptides that will be bound in the active center of a protein and will lead to its activation or inhibition and blocking of its biological functions.