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Control Analysis of the Sickly Cell: Assessing the Insidious Diseas es Caused by Pollution

Objective


Foreseen Results

The project will :
devise methods to diagnose sickliness caused by agents that affect several enzymes simultaneously
devise methods that have a very much increased ability to detect agents that cause small effects on metabolic enzymes
produce biomathematical models of cell metabolism in the healthy and in various sickly states, which allow the simulation of the effects of various mixtures of pollutants and of various treatments
will do the above with emphases on the main pathways of cell metabolism, i.e. glycolysis, oxidative phosphorylation, amino acid synthesis
will deal both with ideal and the more realistic, channelled metabolism

The project's benefits, i.e. imprived methods for the diagnosis and therapy of sickliness stemming from environmental pollution, will be achieved
by disseminating the results on the relevant literature and
through a follow-up project which will commercialise the results as a combined information, diagnostic strategy and modelling package
Syndromes recognized as diseases mostly result from substantial lesions in molecular components of the human body with strong negative effects on the functioning of the latter. Many of these have long been studied and for some, effective therapies have been developed. Other syndromes are more elusive, either because function is less severely affected, because regulation rather than mechanism is compromised, or because they cannot be ascribed to a single cause. Environmental pollution causes somewhat enhanced risks of fairly rare, acute diseased on the one hand. On the other hand, it may often cause many, more elusive, syndromes of "sickliness" in a large fraction on the population. Because the symptoms are subtle, because the molecular causes are diverse, and pleiotropic, there is much less experience in dealing with the elusive, pleiotropic sickliness than with clear-cut disease.

This project deals with the diagnosis of such sickliness, with identification of the responsible pollutants and with suggestions for treatment, such as by alteration in the diet. The project will focus on cellular sickliness. The underlying concept is that such sickliness is caused by the simultaneous partial interference with several molecular processes in the living cell. The interference is such that none of the processes is by itself hampered severely, but that the cumulative effect of all the partial interferences suffices to reduce functioning of the cell as a whole. The biochemical basis behind the idea is that pollutants such as heavy metals tend to interfere with several metabolic enzymes at the same time, e.g. by interfering with their S-H groups. Traditional biochemistry is equipped for dealing with strong lesions at individual enzymes, but not for dealing with the effect of many simultaneous minor lesions at various enzymes. Therefore this project enlists the more modern Metabolic Control Analysis (MCA), which was designed to deal with the effects of small disturbances of enzyme activity on functional fluxes. MCA involves both quantitative experimentation and biomathematical analysis and has its origin both in Eastern and in Western Europe.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Vrije Universiteit Amsterdam
Address
1087,De Boelelaan
1081 HV Amsterdam
Netherlands

Participants (5)

Institute of Enzymology, Biological Research Centre - Hungarian Academy of Sciences
Hungary
Address
29,Karolin Ut
1113 Budapest
Kaunas Medical Academy
Lithuania
Address
4,Eiveniu Street
3007 Kaunas
Moscow State University 'Lomonosov'
Russia
Address

119899 Moskva
UNIVERSITAT DE BARCELONA
Spain
Address
Avda Diagonal 645
08028 Barcelona
Université Victor Segalen - BordeauxII
France
Address
146,Rue Léo Saignat
33076 Bordeaux