Xiangyu gave a GBCB seminar

Speaker: Xiangyu Yao (Jacky), GBCB Doctoral Candidate

Title: Robustness of Oscillations in Models of the Mammalian Circadian Clock

Abstract: The circadian rhythm aligns bodily functions to the day/night cycle and is important for our health. The rhythm originates from an intracellular, molecular clock mechanism that mediates rhythmic gene expression. It is long understood that transcriptional negative feedback with sufficient time delay is key to generating circadian oscillations. However, some of the most widely cited mathematical models for the circadian clock suffer from problems of parameter ‘fragilities’. That is, sustained oscillations are possible only for physically unrealistic parameter values. A recent model by Kim and Forger nicely incorporates the inhibitory binding of PER2, a key clock protein, to its transcription activator BMAL1, but oscillations in their model require a binding affinity between PER2 and BMAL1 that is orders of magnitude larger than observed binding affinities of protein complexes. To rectify this problem, we make several physiologically credible modifications to the Kim-Forger model, which allow oscillations to occur with more realistic binding affinities. The modified model is further extended to explore the potential roles of supplementary feedback loops in the mammalian clock mechanism. Ultimately, accurate models of the circadian clock will provide better predictive tools for chronotherapy and chrono-pharmacology studies