Model-based control of the temporal patterns of intracellular signaling <i>in silico</i>

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 to in silico control 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.

Logical design of oral glucose ingestion pattern minimizing blood glucose in humans

“…However, the inverse problem of optimizing an input pattern to achieve a specified output pattern is challenging. 33 Our success in identifying optimal input patterns through analysis of both the forward problem and inverse problem suggests that this approach is valid for biological systems. An obvious potential application is designing optimal ingestion patterns for various nutrients or combinations of nutrients such that the ingestion pattern that minimizes the peak value of blood glucose level can be logically designed.…”

“…Recently, we proposed a mathematical framework to estimate an input pattern that produces a defined output pattern. 33…”

Logical design of oral glucose ingestion pattern minimizing blood glucose in humans

“…Methodologically, construction of a mathematical model based on the experimental data as a forward problem is well-known. However, the inverse problem of optimizing an input pattern to achieve a specified output pattern is challenging (Murakami et al, 2017). Our success in identifying optimal input patterns through analysis of both the forward problem and inverse problem suggests that this approach is valid for biological systems.…”

“…There are many established methods that use complex ordinary differential equations to solve the forward problem of predicting output patterns, but few methods exist to solve the inverse problem of predicting input patterns. Recently, we proposed a mathematical framework to estimate an input pattern that produces a defined output pattern (Murakami et al, 2017).…”