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Models of Regulatory Processes in a Living Cell

#B-642


Mathematical Models and Software Development for Investigation of Regulatory Processes in a Living Cell

Tech Area / Field

  • BIO-INF/Bioinformatics/Biotechnology
  • BIO-CHM/Biochemistry/Biotechnology
  • INF-SOF/Software/Information and Communications

Status
3 Approved without Funding

Registration date
17.11.2000

Leading Institute
National Academy of Sciences of the Republic of Belarus / Institute of Heat and Mass Transfer, Belarus, Minsk

Supporting institutes

  • Belarussian State University, Belarus, Minsk

Collaborators

  • University of Leeds / School of Biology/ Leeds Institute of Biotechnology and Agriculture ( LIBA)/ Center for Plant Sciences, UK, Leeds

Project summary

The purpose of the project: The mathematical models and software development and modeling of mechanisms of intracellular regulatory processes, mainly that mediated with calcium ions (Ca).

The control of all processes in a living cell, including the control of the genetic information implementation, is realized by means of ramified chains of specific reactions. Each such reaction results in a change of quantity of definite substances (regulatory substances, or "second messengers"), and each such change serves a signal to switch subsequent links in regulation circuits. Calcium is the most universal mediator in signal transduction. The changes in its concentration operate huge number of different processes in all living cells. Such multifunctionality is possible due to: complex spatial-temporal organization of Ca-signal; branching of control circuits and cross-talk between calcium path of a signal transduction with other pathways. The project is dedicated to the development of methods and techniques for these complex processes investigation.

The importance and relevance of the project’s subject are testified with issuing the special journal "Cell Calcium" (New-York) and large number of publications devoted to this problem in other journals, including such authoritative as Nature and Science. Nevertheless, because of complexity of a considered system and large variety of organisms and cell types, the available knowledge is fragmentary and the creation of an integrated picture of intracellular regulation is the problem of the future yet [Bootman M.D., Berridge M.J., Lipp P. (1997) Cell 91: 367-373]. The considerable contribution to its solution can be made with usage of the mathematical modeling tool with demonstrated efficiency in regard to research of complex systems.

The impact of the proposed project on the progress in the field of processes in a living cell investigation. The created models and programs will allow: To predict dynamics of Ca-mediated intracellular processes; To check up hypotheses concerning mechanisms of intracellular processes, that is strongly hindered in a natural experiment because of the influence of a large number of different addition factors; To receive new information concerning intracellular systems properties ("to compute" its properties). The creation of such models will serve as a step to the construction of more general (now lacking) model tracking all path of a signal from external stimuli up to genes expression switching. Apart from construction of the models the project intends also advancing of experimental techniques, in particular, creation of the software for increase of veracity of measurements in Ca concentration (that is also a severe problem). The solution of the project’s task 4 will promote a clarification of mechanisms of a microwave radiation action on intracellular processes.

All participants of the project are the highly qualified scientists with the wide range expertise in weapons, particularly, in development of mathematical models, software and research experiments in the field of rocket technology, nuclear weapon, laser weapon. They published more than 400 works in total. In connection with conversion last years the participants of the project seek to apply their experience and knowledge for the peaceful purposes, in particular in the field of biology and medicine. This project is the prolongation and development of the personal activities in the field of cell processes modeling. Some preliminary results have been published (eight publications) and were reported on international and national conferences.

Expected results.

The project belongs to the category of basic research and to the category of applied research. As a consequence of four tasks solution the following results will be obtained:

1. Mathematical models of Ca ions dynamics, taking into account all known mechanisms of changes in Ca concentration.


2. Models and programs describing dynamics of other components of intracellular regulation system apart from Ca dynamics.
3. The software for Ca concentration measurement.
4. Models and software for estimation of probable effect of electromagnetic radiation on biological objects.

The expected results have advantages in contrast to competitive technologies, in particular:

advantages before available models:


– the created models of Ca dynamics in cytoplasm have a much more degree of generality. In particular, the models take into account a spatial heterogeneity and multiplicity of transport systems subtypes with different characteristics. In available models these factors were omitted;
– the alternative models of Ca dynamics in a cell nucleus don’t exist now;
– the same concerns to models of coupled dynamics of Ca and others second messengers;
– the existing measurement techniques don’t take into account the kinetics of Ca-probe binding when calculating Ca concentration based on aequorin emission. That results in considerable inaccuracies of measurements.

advantages before the experimental research techniques:


– effectiveness (as a rule, a numerical experiment duration is much less than that of a natural experiment);
– small cost (mathematical modeling doesn’t require expensive equipment and materials);
– modeling allows investigating a system behavior in such conditions that it is difficult to realize in an experiment.

Application of the project’s results:

In biological and medical scientific institutions conducting research of intracellular signals. In ecology for refinement of lands contaminated with lead or with radioactive strontium (phytoremediation). For diagnostic purposes in hematology and oncology (software for image analysis). In public health services for danger degree estimation of a microwave radiation effect on human organism and for development of measures on its reduction. In medicine (in particular, in a neurology) for development of nontraditional methods of treatment by means of effect of electromagnetic radiation with specially fitted parameters [Sidorenko A.V. (1999) The analysis of animal bioelectric brain activity influenced by microwaves or by the introduction of strichnine. Bioelectrochemistry and Bioenergetics 48: 223-226].

Software for modeling of Ca ions dynamics and Software for processing of experimental results may have commercial significance.

It is supposed the copyrights protection on the software products of the project.

Meeting ISTC Goals and Objectives.

The project will address ISTC objectives, as it:


– provides the opportunity for the project participants possessing knowledge and skills related to weapons of mass destruction to redirect theirs talents and experience to the peaceful activity (in this case, to the research of intracellular processes);
– promotes the integration of the project participants into the international scientific community because it intends tight cooperation and dialogue between the project participants and foreign scientists conducting research of intracellular processes;
– supports basic and applied research of this project for peaceful purposes, in particular that concerning to environmental protection, and encourages in the solution of fundamental scientific problem of intracellular processes regulation.

Scope of activities.

Duration of activities under the project: 3 years. Two institutions participate in completion of the project: A.V.Luikov Heat and Mass Transfer Institute of the National Academy of Sciences of Belarus (HMTI) (leading institution, 8 persons) and Byelorussian State University (BSU) (3 persons).

The project intends the solution of four interconnected tasks:

1. Modeling of Ca-signal initialization, Ca dynamics in a cytoplasm and in a cell nucleus (5 stages) (HMTI, BSU).


2. Modeling of cross-talk between Ca-mediated signal transduction pathway and other intracellular control systems (3 stages) (HMTI).
3. Modeling of Ca concentration measurement and development of the software for data interpretation (3 stages) (HMTI).
4. Research of mechanisms of microwave radiation effect on intracellular Ca dynamics (2 stages) (BSU).

Role of Foreign Collaborators.

During implementation of the project the cooperation with the foreign scientists is supposed, particularly:


– information exchange concerning a course of research implementation and about the results obtained;
– data exchange relating objects of research;
– collaborator participation in an estimation of the models and testing of the programs;
– usage of developed models for interpretation of experimental results obtained in the research conducted by the collaborator;
– realization of joint working seminars;
– preparing the joint publications.

Technical Approach and Methodology.

There are preliminary results (partially published) regarding all four tasks of the project.

The main tool for the project tasks solving is the construction of mathematical models describing dynamics of a system considered. The models are constructed on the basis of the universal physical and chemical laws (conservation laws, transport equations, kinetic equations) with usage of data for particular intracellular systems known from the literature. The solution of kinetic equations will be fulfilled with usage of the method developed by the project’s authors [Krasovskaya L.I., Britch M.A. (1994) Proceedings of the Academy of Sciences of Belarus. A chemical sciences series, N4, P. 69-76 (in Russian)]. The essence of the method consists in transition to an equivalent system of integral equations with the subsequent series expansion of integrands. For refinement of numerical values of parameters it is supposed to make the experimental research on model systems, particularly to make measurement of a spatial-temporal distribution of diffusing substances concentration with subsequent solution of inverse problem for a set of diffusion and kinetics equations.


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