Introduction

The main goal of the project is to develop a unique scientific workshop that incorporates the methods of control engineering and systems theory in order to analyze the influence of main and supporting regulatory signals of intracellular processes.Different analysis methods will be used in the project, such as mathematical modeling, numerical simulations of deterministic and stochastic models, bifurcation study and sensitivity analysis with respect to a complex biological systems. The authors propose to look at a single cell as on a complex control system with multiple feedback loops of variable parameters. Changes of the specific parameters may lead to the blockade of certain intracellular interactions, as well as may induce different diseases states, for example cancer. From the perspective of systems theory such situation corresponds to the changes in the type of equilibrium points and/or locations of the systems bifurcation points.The authors propose a comprehensive approach to the problem of restoring appropriate functioning of the cellular system. Models of the certain signaling pathways will be built with specificity to the cancer problem, including the analysis of cell behavior, equilibrium points and bifurcations. Also, studies of signals anomalies in terms of the tendency to induce cancer will be performed.The next step will include the sensitivity analysis used in order to create a parameters ranking that reflects the key processes necessary for the functioning of investigated biological pathways. These processes will be analyzed in terms of the option to choose the appropriate controls aimed at restoring the proper functioning of the system.It is worth to note that as a part of its parent institution the authors of the project have access not only to an efficient computing cluster, necessary for the effective study of complex deterministic and stochastic models, but also to a strong biological background. It allows to obtain specific experimental data illustrating the behavior of the studied objects.  In particular, the experience obtained through the experimental studies will help to identify the structure of the investigated signaling pathways that will allow to determine parameters of the created models, differences in the functioning of normal systems (healthy cells) and systems with altered parameters (tumor cells). In the final stage of the project, the gained knowledge will allow to verify the effectiveness of the proposed controlling signals.The proposed approach of cells as a complex biological control systems, where diseases conditions occur due to some changes in specific parameters, is unique on a national scale. The methodology and consequential scientific workshop, which is based on a comprehensive approach to the problem of identifying structure and parameters of the system by experiments, modeling, simulation and sensitivity analysis, is unique world-wide. The methods used in the project will allow to identify targets for the implementation of appropriate controls and develop the control protocols.Positive results of the proposed project may contribute to the application of created scientific workshop and incorporation of methodology used for personalized therapy, improving its performance and reducing the inconveniences for the patients.

Goal

The projects main goal is the creation of a unique scientific workshop which will incorporate methods of control engineering and systems theory in order to analyze the influence of main and supporting controlling signals on the course of intracellular processes.

Tasks

Modification of the p53 signaling pathway model build by the project manager in order to reflect the impact of p53 on the cell cycle and introduced controlling signals.Experimental determination of parameters in the designed model, in respect to the control object (normal cells, breast cancer, bone cancer).The analysis of equilibrium points in the created models, bifurcation study and sensitivity analysis. Determination of parameters ranking and finally identification of potential targets for the therapy.Identification of optimal controlling signal protocols, based on simulation study, in terms of minimizing side effects (normal cells death ratio) while restoring appropriate functioning of the system (death or inhibition of cancer cells proliferation).Analysis of equilibrium points and displacement of bifurcations points after the introduction of optimal control.Experimental verification of developed controls in terms of their effectiveness.

Contractors

Project manager

Krzysztof Puszyński

Contractors

Monika Kurpas, Katarzyna Jonak, Roman Jaksik, Krzysztof Puszynski, Anna Lalik

Results

Articles