Modeling The Circadian Clock Of Neurospora Crassa And The DNA Damage Response Using System Biology Methods

System biology aims to establish a comprehensive model of the whole system through the research of the relationship and interactions of different modules of the biology system.In this thesis,we will research two typical biology systems using sys-tem biology method.We will first analyze the interaction between Neurospora crassa's circadian clock module and the ROS module.Secondly we will discuss the relation-ship between p53 dynamics and cell fate decision in the cells treated with cytotoxic anticancer drug Etoposide.In the first work,we build an integrated model which consists of the circadian clock pathways and the ROS module.In this model,ROS and circadian clock interacts with each other.ROS module influences the circadian clock through three methods:it up-regulates PP2A's activity;it promotes the transcription factor activity of WCC protein on FRQ protein;and it inhibits the formation of WCC compound.Circadian clock in turn influences the ROS module through its regulation of anti-oxygen proteins expression thus decreases the ROS level.By tuning the basal production rate of SOD and O-12,we reproduce the phenomenon that in experimentation ROS could regulate the period and phase of the circadian clock.Simulations show that in the three methods described above,the method that shows the most importance in regulating the period and phase of circadian clock is the first one,which is through the promotion of PP2A activity.In the second work,we establish a DNA damage response regulation model which contains the most important proteins:ATM,p53,Mdm2 and Wip1.This model contains the p53-Mdm2 and ATM-p53-Mdm2 negative feedback loop.Calculation results show higher dose of etoposide results in monotonic p53 increase without an oscillation phase and the p53 level is much higher.Whereas lower dose of etoposide results in periodic p53 pulses and the p53 level is moderate.The model reproduces the p53 bimodal switch as described in the experiment.The period and the relative level of p53 protein also fits.This thesis consists of four main components:In chapter 1,we introduce the elementary knowledge of system biology modeling,biochemistry modeling methods.We introduce the biology processes of circadian clock and p53-centered DNA damage response regulation network.Stochastic simulation algorithms proposed by Gillespie is also introduced.In chapter 2,we research the interaction between Neurospora crassa's circadian clock regulation pathways and ROS module,and the performance of the model under stochastic situations using SSA.In chapter 3,the DNA damage response regulation network is researched,we dis-cuss the relationship between DNA damage strength and p53 dynamics.Chapter 4 is the summary of this dissertation and perspectives for further research.