title: Model-based control of the temporal patterns of intracellular signalingin silico.
abstract: The functions of intracellular signal transduction systems are determined by the temporal behavior of intracellular molecules and their interactions. Of the many dynamical properties of the system, the relationship between the dynamics of upstream molecules and downstream molecules is particularly important. A useful tool in understanding this relationship is a methodology to control the dynamics of intracellular molecules with an extracellular stimulus. However, this is a difficult task because the relationship between the levels of upstream molecules and those of downstream molecules is often not only stochastic, but also time-inhomogeneous, nonlinear, and not one-to-one. In this paper, we present an easy-to-implement model-based control method that makes the target downstream molecule to trace a desired time course by changing the concentration of a controllable upstream molecule. Our method uses predictions from Monte Carlo simulations of the model to decide the strength of the stimulus, while using a particle-based approach to make inferences regarding unobservable states. We applied our method toin silicocontrol problems of insulin-dependent AKT pathway model and EGF-dependent Akt pathway model with system noise. We show that our method can robustly control the dynamics of the intracellular molecules against unknown system noise of various strengths, even in the absence of complete knowledge of the true model of the target system.
authors.affiliation: Department of Systems Science, Graduate School of Informatics, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; CREST, Japan Science and Technology Agency, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Department of Systems Science, Graduate School of Informatics, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Department of Mathematics, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan; CREST, Japan Science and Technology Agency, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Koyama
authors.affiliation: Department of Systems Science, Graduate School of Informatics, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; CREST, Japan Science and Technology Agency, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Oba
authors.affiliation: Department of Biological Sciences, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; CREST, Japan Science and Technology Agency, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kuroda
authors.affiliation: Department of Systems Science, Graduate School of Informatics, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; CREST, Japan Science and Technology Agency, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Ishii
keywords: EGF-dependent Akt pathway; Monte Carlo filter; insulin-dependent AKT pathway; intracellular signal transduction; particle filter