Ziel
A. BACKGROUND
Current state of knowledge. The human diet contains significant amounts of amines and amine-related compounds that are present either naturally or as a result of food processing or storage. Some of these compounds are known to be hazardous to health, while the dangers associated with others are poorly understood. On the other hand, some are beneficial to health. Thus, there is a need to bring together information from diverse scientific areas and disciplines in order to evaluate the potential risks or benefits to human health of dietary amines.
Dietary amines biogenic (biologically active) amines derived from dietary amino acids, such as tyramine and histamine; the polyamines, spermine, spermidine and putrescine; the heterocyclic amines, which include quinolines and their derivatives; the N-nitrosamines. Some of these amines, such as nitrosamines, have clear toxicological profiles with psychoactive, vasoactive, mutagenic and carcinogenic properties. Others are beneficial - polyamines are essential for optimal growth and development of mammalian cells. In addition to the amines themselves amine-related compounds such as nitrate and nitrite can be harmful, especially when present in large amounts.
Importance of increasing knowledge. Tables of the concentration of some of these compounds in European diets have been published in the scientific literature. Much of this data has been derived from a previous COST action (917). The knowledge, which is now required to build upon this information, is
(a) how the compounds are absorbed from the gut
(b) how the compounds are metabolised in the body
(c) how the absorbed compounds affect the cells of the body
(d) an understanding of the interactions between amines and macromolecules and of the tissue specificity of amine-related or -regulated genes or of underlying signal transduction systems.
in order that recommendations about the optimum dietary content of the different compounds can be made and the public can be informed of healthy eating insofar as these amines are concerned. An important part of the COST Action is the inclusion of projects which may provide novel approaches to treatment of cancer and to the development of new strategies against food-borne pathogens. These projects are linked scientifically through amine metabolism.
European dimension. The hazards of some dietary amine-related compounds are probably different in different regions of the EU. For example, in the Netherlands, nitrate concentrations in water supplies are high. Thus, problems concerning the toxicity of nitrate, which occurs mainly due to its reduction to nitrite - which in turn interacts with haemoglobin to form inactive methaemoglobin - are greater than elsewhere. Nitrite is used in inorganic fertilisers throughout Europe, on the other hand, and is present in many vegetables, some of which can contain as much as 75-80% of the total daily intake. Sodium nitrite is also used as a food preservative, especially in cured meat. The hazards of both of these uses need to be assessed as part of the broader picture of amines and amine-related compounds. Similar justifications apply to the other amines and amine-related compounds, which have relevance throughout Europe, but which, for local dietary reasons, may be more important to some regions than others.
Often, the hazardous compounds result from cooking. Heterocyclic amines, quinolines, quinoxalines and their derivatives are formed in protein containing foods such as fish and meat during heating of food and frying and broiling are two processing methods known to produce high amounts to these amines. The results from epidemiological studies involving these amines are controversial, however a means of limiting or controlling the amounts of these mutagenic and carcinogenic agents in thermally treated foods is required.
Expected benefits. The beneficial outcome of the COST Action will be fundamental scientific knowledge under categories (a) to (d) above, which will enable rational and meaningful recommendations about this group of dietary compounds to be made to health professionals and the general public. It may also lead to new therapies for cancer, through inhibition of the synthesis of essential amines, and infectious disease again linked to modulation of amine metabolism.
International implications. The USA has a united approach to dietary recommendations via the National Institutes of Health and for food quality through the Food and Drug Administration. Europe has limited mechanisms for achieving such united advice. By working together as a large European research group, the COST Action will have the critical mass and breadth of expertise to provide a competitive advantage over groups working on similar topics in the USA and Japan.
Reasons for COST Action. The reason a COST Action is required, rather than alternative frameworks for funding, is that this is clearly a wide-ranging and diverse area of research far beyond the scope of any individual laboratory. The projects in individual countries are financed by national governments or commercially. For this reason a COST Action is the best framework for the planned work. A coordinated European programme of research in this area will bring together a broad knowledge base and will ensure that the key questions relating to amines and amine derived compounds are addressed in a productive manner to ultimately provide recommendations to improve human nutrition and health.
B. OBJECTIVES AND BENEFITS
The main objective of the Action is to assess and report on (i) hazards posed by amines and amine-related compounds in food and (ii) benefits of dietary amines and amine-related compounds, in order to make recommendations for their concentrations in different diets consumed across Europe.
By pooling knowledge from different disciplines, recommendations will be made concerning what constitutes an "amine healthy" diet for individuals. Specific advice will be proposed for patients with diseases such as cancer as to the therapeutic value of different amine-containing diets.
In order to achieve the main objective, groups of scientists from different countries will meet to achieve the following sub-objectives:
(i) a risk assessment of selected common dietary amines and their derivatives in man
(ii) a description of the cellular and molecular changes induced in living cells by these amine and amine-derived compounds
(iii) how new processing technologies (high pressure, electric pulsed fields, ionising radiation, etc.) affect amine concentrations in processed foods
(iv) recommendations for average daily intake (ADI) of individual amines or groups of amines in man in both health and disease.
(v) identification of target sites in human amine metabolism that, using inhibitors, analogues or gene therapy approaches, may lead to new means of treating or preventing disease, particularly cancer
(vi) identification of target sites in bacterial amine metabolism that may be used to control food-borne pathogens
Expected Benefits:
This Action will result in a much clearer understanding of the role of dietary amines and their derivatives in human nutrition, health and disease. By understanding how these compounds act within the cell it is expected that adverse reactions between related compounds can be predicted and, more importantly, avoided, and that recommendations can be made regarding the daily consumption of specific amines and amine derivatives across all European diets. Understanding the mechanism of amine action will provide vital insight into the role of these substances in human diseases such as cancer and amine intolerance and it is expected that this work will provide sound advice on diets containing amines for individuals and patients with such conditions. Possible spin-offs include new anticancer drugs targeted at amine metabolism and antibiotics.
The goals of this Action are to:
(i) provide a unified approach to health advice on amines in the diet in Europe
(ii) provide a detailed risk assessment of categories of dietary amines
(iii) develop simple, cheap and reliable analytical methods to measure amines
(iv) develop novel processing methodologies to reduce amine content of foods
(v) identify novel targets for potential anticancer or antibacterial agents.
Currently, individuals from the various scientific disciplines such as food science, biochemistry, molecular biology and chemistry rarely meet even when working in similar research topics. Under the COST Action, researchers from academia, the food industry, the agricultural industry, pharmaceutical industry and research institutes will combine resources and knowledge in order to lead the world in research on dietary amines in nutrition and health. By combining and coordinating the research efforts through the work packages, working groups and workshops the COST group will be in a strong position to advise EU industry and EU and national governments on labelling of products, average daily intake, legislation etc. Appendix I lists the scientists and countries interested in this Action.
C. SCIENTIFIC PROGRAMME
In this Action there will be 3 work packages, with each programme being divided into 2 or 3 working groups as best fits the aims of the Action outlined in Section B. The work packages are interactive and interdependent: the data from WP 1 will be related directly to the metabolic processes investigated in WP 2. Similarly, the information provided by WP 1 and 2 will be used to direct the genomic studies in WP 3. The link between the work packages will therefore be the amines investigated. Work package 1 will investigate the bioavailability and utilisation of amines in the diet; work package 2 will determine amine metabolism in specific tissues; and work package 3 will determine what specific mRNAs and proteins are altered by individual amines. Thus, for example, polyamines will feature in all three work packages, providing common theme of scientific
interest and information linking the different work packages together. In this way a substantial body of knowledge and therefore understanding of the role of groups of amines in human nutrition will be developed. Initially, the amines and related compounds to be studied will be the genotoxic amines, such as the heterocyclic amines and the nitrosamines, the polyamines, the nitrates and nitrites.
Work Package 1: "Amines and food safety"
Working group 1A: Risk assessment of amines in diet
Working group 1B: Effect of processing on amine formation
Aims:
The aims of this work programme are to evaluate the risk of amines in the diet and to determine how food processing influences these risks. Both qualitative and quantitative data on adverse health effects of amines will be collected and used to provide essential information to the appropriate regulatory authorities to allow ADI and MDI values to be determined across Europe, taking into account the differences in diet North versus South. The effect of novel processing technologies on amine concentrations will be also evaluated, to develop new procedures that will decrease formation of hazardous amine compounds.
Objectives:
The major objectives are to:
- assess the risk of the presence of selected amines in the diet, considering differences between countries. MDI must be determined and compared to ADI
- determine the bio-availability of amines for consumers by evaluating the absorption, distribution and metabolism data in healthy and sick individuals
- evaluate the effect of traditional and new food-processing methods on their formation and
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to develop new techniques and processes to reduce amine production to a minimum
- investigate the interaction between amines and other food related compounds: additives, ingredients (vegetables, spices, fruits) and micro-organisms
- develop simple, inexpensive and reliable analytical procedures based on HPLC methodology to determine amine content of foods
- recommend maximum allowable levels or limits for inclusion in regulations and to provide useful information to producers about the risks of these substances
- study and propose ways to provide information of the risk to the most sensitive consumers through appropriate product labelling
Work Package 2: "Regulation of amine metabolism and nutritional intervention"
Working Group 2A: Transgenic models for amine related gene expression.
Working Group 2B: New technologies for nutritional and metabolic intervention in amine metabolism.
Working group 2C: Control of food-borne pathogens - amine metabolism: a novel intervention target
Working Group 2A: Molecular models for amine related gene expression
Aims:
This work group aims to develop molecular models to study the physiological responses to selected amines and their metabolic products. The new models produced in this part of the Action will also be used in Work Programme 3 for genomic studies.
In addition, this work package aims to purify quantities of recombinant key-proteins in amine metabolism to analyse structure/function relationships in the chosen model systems. Specific inhibitors of physiologically relevant amine associated reactions will be developed and antibodies will be raised to key proteins to facilitate understanding of these areas in amine metabolism that are currently poorly understood.
Objectives:
The major objectives are to:
- characterisation of tissue-specificity of the regulation of amine metabolism and identify the cis- and trans-elements involved in these responses
- investigate amine metabolism by overexpression and antisense strategies
- establish the cause-effect relationships for the observations made at the molecular level as well as comparisons between different organisms
- study the regulation of gene expression from cells transfected with recombinant constructs including cis-elements of key-protein promoters
- develop new markers for prognosis and diagnosis of amine related pathologies
- isolate and characterise new amine-related genes; for instance, the transport genes.
Working Group 2B and C: New technologies for nutritional and metabolic intervention in amine metabolism.
Aims:
The aim of this working group is to synthesise novel amine analogues directed against key enzyme reactions to facilitate our understanding of amine function. Here, specialists in organic and physical chemistry will collaborate with groups experienced in metabolic control of amine metabolism (Working Group 2A). Characterisation of drugs and natural food components that regulate amine production and metabolism will constitute a basis for nutritional intervention with respect to amine metabolism in terms of chemotherapy and chemoprevention. The possibility that some food-borne pathogens have an unusual pathway of amine metabolism that could be used as a novel target for therapeutic intervention will be addressed.
Objectives:
The major objectives are to:
- produce novel inhibitors of amine metabolism for use in disease prevention and therapy
- evaluate the potential of pharmaceuticals acting on amine metabolism either as chemotherapeutics or chemopreventatives
- characterise the mechanism of action of natural amines and amine derived compounds with potential therapeutic or economic importance
- develop specific antibodies to monitor changes in amine metabolism in disease
- develop new methods of detecting diseases related to impaired amine metabolism
- determine the activity of non-toxic amine decarboxylase inhibitors and analogues as potential inhibitors of food-borne pathogens in foods
Work Package 3: Functional genomics of amines
= Working Group 3A: Physiological genomic responses to amines
= Working Group 3B: Pathological genomic responses to amines
Aims:
The aim of this work package is to provide a comprehensive understanding of the role of amines in normal cellular physiology and pathology by using molecular profiling approaches to examine cellular mRNAs, translational efficiency and protein expression at the genomic level. The model systems to be used in this work will include human cell lines with and without mutations in amine biosynthesis and amine metabolism, transgenic and transformed cell lines and cells treated with selected amine inhibitors and analogues. High-density cDNA arrays will be used in conjunction with fractionated RNA polysome preparations to determine steady-state mRNA levels and
translational efficiency of thousands of genes simultaneously. In addition, 2-D gels in conjunction with Matrix assisted Laser Desorption/Ionisation Time of Flight (MALDI-TOF) and Quadrapole Time of Flight (Q-TOF) mass spectrometry will be used to analyse and selectively identify several thousand proteins directly.
Objectives
The major objectives are to:
- determine the specific genes transcriptionally influenced by amines
- detect mRNAs translationally influenced by amines
- detect proteins affected by amines
- compare the above changes in normal and tumour cells.
The preliminary studies will compare normal cells before and after treatment but will be extended to include pathological responses once the initial characterisation has been carried out.
D. ORGANISATION AND TIMETABLE
D.1. Organisation:
The COST Action will be organised as described in "Rules and Procedures for Implementing COST Actions". The Management Committee (MC) will coordinate the Action with individuals appointed as Working Group co-ordinators who will be responsible for organising their Working Group and for producing reports and co-ordinating workshops within their group. MC meetings and workshops will be held concurrently with the MC meeting normally following the workshop. All Groups will work in parallel with cross fertilisation as a key issue in all research strategies. The first activity of the Action proper will be a general workshop involving all Working Groups. The aim of this initiating workshop is to provide "state of the art" knowledge from all participants and to set goals and initiate the work programme for each Working Group. This general workshop will be
repeated at the end of years 3 and 5 of the Action. The last workshop will bring together all the results of the Action and will culminate in a review publication covering all aspects of the Action. Each general workshop will produce a publication summarising the initial knowledge in the field (year 1); mid term progress (year 3) and the final results (year 5). The chair of the Action will co-ordinate the General Workshops. In addition to the general workshops, joint workshops will be held between Working Groups. The aim of these joint sessions is to maximise the cross fertilisation of ideas between the multidisiplinary groups.
The milestones of this Action will be at the end of years 1, 3 and 5 when the aims, successes and future directions of the Action will be closely examined and reiterated. Throughout the Action the workshops and STSM will be assessed critically in order to continue to achieve our goals.
Short term scientific missions (STSM) will be encouraged to facilitate interaction between laboratories and to ensure that exposure to new technology is optimised across Europe. Suggestions for STSM will be made during workshops and decisions on STSM applications will be made by the MC. It is anticipated that approximately four rounds of STSM (years 2-5), with 10 scientist exchanges each year, will take place. Reports of STSM will be required and these will be reviewed by the MC.
A web site will be established and the Action, its aims and objectives and reports of meetings will be published on the home page that will be updated after each workshop. A web site co-ordinator will be appointed by the MC.
D.2. Timetable
A five year programme is proposed for this Action. The reasons for this are twofold:
(i) some of the studies outlined require long term follow up in order to fully evaluate the hazards. This is especially for the risk assessment studies in WP 1.
(ii) the use of developing new technologies requires time for all participants to have access to the facilities and understanding being developed.
A five-year programme is necessary to gain maximum scientific progress and enable all projects to come to fruition. The greatest success will be achieved if there is sufficient time after each workshop for significant scientific progress to be made in each WP. It is estimated the time required between workshops is approximately 24 months.
All participants will be welcome to attend any workshop. There will be time allocated within each general workshop for discussion on future developments within the area. The MC will meet 8 times over the 5 years, always in association with a workshop, to ensure the smooth running of the Action and set goals for the next period of the Action. The timetable of Activities is shown in Table 1. The first MC meeting will bring together and introduce all the interested parties and will be the forum to plan the first workshop
All Work Programmes and Working Groups are therefore, as described in section B, related and interactive. The scientists who have shown interest in this Action are listed in Appendix 1.
E. ECONOMIC DIMENSION
To date, 40 individuals from the following 17 COST countries have actively participated in the preparation of the Action or otherwise indicated their interest :-
Austria Belgium Bulgaria
Czech Republic Finland France
Germany Hungary Ireland
Italy Netherlands Norway
Poland Portugal Spain
Sweden United Kingdom
Other countries and several industrial companies have also shown interest and support for this Action.
On the basis of national estimates provided by the representatives of these countries the overall cost of the activities to be carried out under the Action has been estimated, in 2001 prices, at roughly EURO 13 million.
The national costs per annum have been estimated from data available from the representatives of the countries interested in joining the Action. The cost covers approximately 86 person years per year over a 5-year project (430 person years). This estimate is valid under the assumption that all the countries mentioned above but no other countries will participate in the Action. Any departure from this will change the total cost accordingly.
F. DISSEMINATION
Findings from the Action will be published as series of special publications following each general workshop. These publications will be distributed to all interested countries where they will provide a major resource for researchers in the field. In addition, all participants will publish in the scientific literature in the usual fashion. Each working group coordinator will submit an annual report to the MC and regular reports will be sent to the EC. Where appropriate contacts will be made with the Food Standards Agency appraising them of important findings. A web site will be established which will give free access to all the information arising from the Action, except where confidentiality clauses are in force. The web site will be updated after each workshop and will have a discussion page for interaction with the general public. Abstract books will be produced for each workshop for all participants and interested parties.
Wissenschaftliches Gebiet (EuroSciVoc)
CORDIS klassifiziert Projekte mit EuroSciVoc, einer mehrsprachigen Taxonomie der Wissenschaftsbereiche, durch einen halbautomatischen Prozess, der auf Verfahren der Verarbeitung natürlicher Sprache beruht. Siehe: Das European Science Vocabulary.
CORDIS klassifiziert Projekte mit EuroSciVoc, einer mehrsprachigen Taxonomie der Wissenschaftsbereiche, durch einen halbautomatischen Prozess, der auf Verfahren der Verarbeitung natürlicher Sprache beruht. Siehe: Das European Science Vocabulary.
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