Influence On Dynamic Behavior In Mammalian Circadian Clock By Rev-erb

Almost all living organisms，ranging from Cyanobacteria to human, display circadianrhythms in physiology, metabolic activity and behavior. Along evolution， livingorganisms, themselves have developed a specific mechanism---Circadian Clock，whichcoordinates various circadian rhythms in different tissues and organs， and enablesorganisms to adapt to natural environmental changes. In mammals, the main clock islocated in the suprachiasmatic nucleus (SCN), whose generation is based on thecoordination expression of the core clock genes through the transcription-translationfeedback loop. Disruption to circadian rhythms usually can lead to dysfunction evendisease，such as cardiovascular disease, diabetes, obesity and so on．With the completion of the Human Genome Project (HGP) and the constantimprovement of molecule biology techniques, many clock gens and their regulatorynetworks have been discovered and understood. Compared with mammalian, there is noclock gene similar as Rev-erb in Cyanobacteria and Neurospora. While both of them canmaintain the circadian rhythm. Previous studies have the common view that the circadianclock of mammals acts on the genomic level to coordinate internal behavioral andphysiological via the transcription-translation feedback loops of gene Clock and Bmal1，while the nuclear Rev-erb receptor just acts the role that form an accessory feedback loopwhich contributes to clock function. It is strange that the system would lose oscillation inRev-erb knockout mice. In this dissertation, we based on the biological background andthe advantages of a mathematical model in integrating data and analyzing multiplefeedback loops，built a brand new model on the circadian clock of mice. And then we usedthe computer to simulate, analyze the influence on dynamic behavior in mammaliancircadian clock by Rev-erb. Our simulations and theoretical analysis show that:Firstly, knock out of Rev-erb in mice can lead to loss of oscillation, when weenhance the strength of Rev-erb, the oscillation will recover. This demonstrates that Rev-erb has an essential role in the mammalian circadian clock.Secondly, we found that the system will oscillate or not depends on the relativestrength between E-box and RRE-box, and it occurs an hopf bifurcation for the periodoscillation. There is a range about their conditions, within which the system would have anoscillation otherwise it will lose oscillation and tend to be steady at last.Finally, the period of the system will get shorter along with the intensive strength ofRev-erb,while the strength of others are constantly such as Cry. But change of the periodis not so big，it means that Rev-erb has the role to maintain the robustness of the period.All the results indicate that Rev-erb has an essential role in the mammalian circadianclock. It cannot be simply explained as a putative driving force of molecular oscillations.Perhaps，it is formed because of maintaining circadian rhythm and adapting to thecomplex environment in the long-term evolution. With it, the conditions for oscillation alsobecomes more demanding. In recent years, some biological experiments also show thatfasting glucose,free fatty acid and triglyceride levels will appear in the blood ofRev erb/mice. These findings further demonstrate that the nuclear receptors Rev-erb isnot just as a putative driving force of molecular oscillations. These also might change ourview on the clock molecular circuitry and the role of Rev-erb.