MATHEMATICAL ANALYSIS OF RESPONSE EXPERIMENTS IN CHEMICAL AND BIOCHEMICAL KINETICS, GENETICS AND MOLECULAR BIOLOGY
 

RESPONSE

   


Romanian version















 

 

Nr. contract: 061126/18.07.2006

Finantare: Buget de Stat - Autoritatea Nationalã pentru Cercetare Stiintificã
Programul
: Cercetare de excelenta -
 Modul 1: Proiecte de cercetare-dezvoltare complexe
Valoarea proiectului: 1.500.000 lei
Durata contractului: 26 luni
Autoritatea Contractantã
: INSTITUTUL DE FIZICA ATOMICA - PROGRAMUL CERES
Contractor
: Institutul de Statistica Matematica si Matematica Aplicata G. Mihoc - C. Iacob al Academiei Romane
Director proiect
: Dr. Marcel-Ovidiu Vlad
Aria tematica S/T
: 1.1 Stiinte de baza
Platforma tehnologica europeana
:
PT.11 Medicina inovativa 

 

   











  1. PROJECT PARTNERS              
 

 

Name of the Organization

CO

G. Mihoc - C. Iacob Institute of Mathematical Statistics and Applied Mathematics Bucharest - ISMMA (www.csm.ro) - Dr. Marcel-Ovidiu Vlad

P1

Ilie Murgulescu Institute of Physical Chemistry Bucharest - ICF (www.icf.ro) - Dr. Vlad Tudor Popa

P2

Institute of Biochemistry Bucharest - IB (www.biochim.ro) - Dr. Stefan Szedlacsek

     
                     

2. OUTLINE








 

The project involves the development of mathematical methods for the analysis of biochemical and gene networks based on response experiments. The research will have an important impact in understanding complex chemical and biological systems, resulting in progress of chemistry, chemical engineering, biochemistry, biology, genomics, and hence progress in medicine, which benefits all. The project will lead to interesting, non-trivial mathematical problems of probability theory and statistics.

The proposed research is a complex collaboration among three Institutes of the Romanian Academy and other four research organizations from Germany, Spain, United States and South Korea. We will develop both local approaches, for small subnetworks of an extended system, as well as global approaches, which deal with large networks as whole systems. For ‘in vivo’ and ‘single-molecule’ (DNA, RNA) systems, we will introduce special methods, which take into account the contributions of inter- and intramolecular fluctuations and of molecular crowding. We will develop models and response approaches for gene networks, based on biology and chemistry of genetic processes, and test them on networks of medical interest.

Human resources and part of material resources for the realization of the project are available. The project leader, Dr. Marcel O. Vlad, has a strong mathematical, physical and chemical background, has worked on the analysis of chemical and biochemical networks for 30 years, published over 150 papers in the field and spent extended periods of time in various laboratories from Western Europe, USA and Canada. Other project coordinators and their collaborators are mathematicians, statisticians, physical chemists and biochemists, top experts in their fields. Experimental tests will be carried out in Romania, where new purchases will be necessary, as well as abroad, where involved laboratories have the needed equipment.

 
                     
  3. OBJECTIVES                
 

In the post-genomic era a challenging and daunting task for scientists is elucidating the functions of the different genes and the ways in which these functions are expressed in molecular biology through different biochemical processes. In an attempt to solve this problem new biological disciplines are emerging, such as functional genomics, proteomics, metabolonics, resulting in a revolution in medicine. These new areas of research need new techniques and approaches for studying the structure and behavior of large networks of interacting genes and biochemical processes. The current methods in use lack generality or a rational basis: they are either based on the biological intuition of the researcher or use mathematical algorithms without a sound chemical or biological basis (for example Bayesian networks). Major research centers all over the world invest important amounts of material resources and human expertise for developing rational methods for the analysis of large biological networks. The proposed research is an attempt of developing such analysis techniques and of the pertaining experimental means.

The purpose of the presented research project is the development of mathematical methods for the analysis of biochemical and gene networks based on the use of response experiments. The analysis of structure and functions of biochemical and gene networks is very important for the progress of biochemistry, molecular biology and genetics. From the point of view of fundamental science, it makes it possible to understand the molecular mechanisms of life. The prospective applications are also very important: the analysis of biological networks opens the way for developing rational methods treating genetic diseases.

The project will develop, at the Institute of Mathematical Statistics and Aplied Mathematics (ISMMA), new types of response experiments for complex networks and new mathematical methods for the analysis of the data resulting from the proposed experiments. The experimental part is preliminary, it is supposed to give clues regarding the development of the response methods. Part of the experiments will be carried out in Romania, at the Institute of Physical Chemistry (ICF) and Institute of Biochemistry (IB). The necessary equipment is available in Romania to a certain extent and new purchases are necessary. Part of the experimental data will be provided by outstanding research centers in US (Stanford Genome Technology Center), Spain (Department of Biochemistry and Molecular Biology, Complutense University) and Germany (Department of Functional Genomics, Regensburg University). The institutions abroad have the necessary equipment and have agreed to help with the experiments. (see the attached letters: F_Moran, P_Oefner, R_Davies, S-H_Suh)

Due to the complexity of biochemical and genetic networks we intend to develop both local approaches, which focus on small parts of a large biochemical network, as well as global approaches, which deal with large biochemical networks as whole systems.

 
                     
  4. OVERVIEW             



Overview of the main research accomplishments, 2006-2008

                     
  5. REPORTED RESULTS             


a) Reported in 2006:


01) Marcel O. Vlad, Federico Morán, Vlad T. Popa, Stefan E. Szedlacsek, and John Ross, "Functional, fractal nonlinear response with application to rate processes with memory, allometry and population genetics" "Proceeding of the National Academy of Sciences USA (PNAS)", 2007, 104, 4798-4803

02) Federico Morán, Marcel.O. Vlad, M. Bustos, J. C. Triviño and J. Ross, "Species connectivities and reaction mechanisms from neutral response experiments", Journal of Physical Chemistry, A 2007, 111, 1844-1851



b) Reported in 2007:


03) Marcel O. Vlad, Alexandru Dan Corlan, Federico Morán, Peter Oefner and John Ross "Incremental parameter evaluation from incomplete data with application to the population pharmacology of anticoagulants" "Proceeding of the National Academy of Sciences USA (PNAS)", 2008, 105 4627-4632

03a) Marcel O. Vlad, Alexandru Dan Corlan, Federico Morán, Peter Oefner and John Ross Supplementary Annex to "Incremental parameter evaluation from incomplete data with application to the population pharmacology of anticoagulants", "Proceeding of the National Academy of Sciences USA (PNAS)", 2008, 105 4627-4632, 58 pages (published online)

04) Marcel O. Vlad, Alexandru Dan Corlan, Vlad T. Popa, and John Ross "On anti-portfolio effects in science and technology with application to reaction kinetics, chemical synthesis and molecular biology", "Proceeding of the National Academy of Sciences USA (PNAS)", 2007, 104 18398-18403

05) Marcel O. Vlad and John Ross "Analysis of experimental observables and oscillations in single-molecule kinetics", 27 pages, Chapter 8 from the book "Single Molecule Signals", editors E Barkai, F Brown, M Orrit and H Yang, World Scientific, 2008

06) Marcel O. Vlad, Nader Pourmand and Ron Davis "Dynamic averaging for reaction networks with random rate coefficients. Application to reaction kinetics in intracellular systems with crowding: transition from regular to fractal kinetics", Journal of Physical Chemistry A, in press



c) Reported in 2008:


07) Marcel O. Vlad, Alexandru D. Corlan, Federico Morán, Rainer Spang, Peter Oefner, and John Ross "Kinetic laws, phase-phase expansions, renormalization group, blood coagulation and INR calibration" Invited paper that will be published in a special volume of "The Proceeding of the National Academy of Sciences USA (PNAS)"

08) Benedict Anchang, Mohammad J. Sadeh, Juby Jacob, Marcel O. Vlad, Peter Oefner, and Rainer Spang "On Modelling the temporal interplay of molecular signalling and gene expression using dynamical nested effects" Invited paper that will be published in a special volume of "The Proceeding of the National Academy of Sciences USA (PNAS)" dedicated to Systems Biology

09) Marcel Ovidiu Vlad, Gianfranco Cerofolini and Peter Oefner "Random activation energy model: from disordered kinetics, to population genetics and genomics", Special chapter that will be published in a book concerning single molecule kinetics and disordered kinetics, in preparation at "World Scientific" publishing house

10) Marcel Ovidiu Vlad, Gianfranco Cerofolini and Peter Oefner "Overdispersed molecular clocks: applications in disordered kinetics and genetics", Special chapter that will be published in a book concerning single molecule kinetics and disordered kinetics, in preparation at "World Scientific" publishing house