A model of the mammalian circadian oscillator including the REV-ERBalpha module.
A model of the mammalian circadian oscillator including the REV-ERBalpha module.
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DOI：
10.11234/gi1990.15.3
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
S. Becker-Weimann;J. Wolf;A. Kramer;H. Herzel
中科院分区：
文献类型：
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作者：
S. Becker-Weimann;J. Wolf;A. Kramer;H. Herzel
许多细胞和生理过程都显示出大约24小时的节律。这种所谓的昼夜节律是基于一个连锁的负和正分子反馈回路系统。在这里，我们扩展了以前的昼夜节律振荡器模型，包括REV-ERBalpha作为一个额外的组件。这个新模型将使我们能够研究通过REV-ERBalpha的额外负反馈回路的功能。我们得到正确的周期和时钟组件之间的相位关系的昼夜节律振荡。对应于时钟基因突变的参数变化再现了实验结果：随着参数变化模仿Bmal 1（-/-）和Per 2（Brdm 1）突变，振荡不再存在。相反，如果我们使用反映Rev-erbalpha突变的参数集，则系统显示持续振荡。该模型还解释了Cry 1（-/-）和Cry 2（-/-）突变对昼夜节律周期的不同影响。扩展模型的模拟表明，原始模型是强大的，相对于纳入额外的组件。根据BMAL 1对Per 2/Cry转录激活的动力学，BMAL 1表达的增加导致时钟周期的增加或减少。这表明过表达实验可以帮助表征BMAL 1对Per 2/Cry转录的影响。
Many cellular and physiological processes have been shown to display a rhythm of about 24 hours. This so-called circadian rhythm is based on a system of interlocked negative and positive molecular feedback loops. Here we extend a previous model of the circadian oscillator by including REV-ERBalpha as an additional component. This new model will allow us to investigate the function of an additional negative feedback loop via REV-ERBalpha. We obtain circadian oscillations with the correct period and phase relations between clock components. Parameter variations that correspond to clock-gene mutations reproduce experimental results: With parameter variations mimicking the Bmal1(-/-) and the Per2(Brdm1) mutation the oscillations cease to exist. In contrast, the system shows sustained oscillations if we use a parameter set that reflects the Rev-erbalpha mutation. The model also accounts for the differential effect of the Cry1(-/-) and Cry2(-/-) mutations on the circadian period. The simulations of the extended model indicate that the original model is robust with respect to the incorporation of the additional component. Depending on the kinetics of the Per2/Cry transcriptional activation by BMAL1, an increasing BMAL1 expression leads to either an increase or decrease of the clock period. This indicates that overexpression experiments could help to characterize the impact of BMAL1 on Per2/Cry transcription.