Non targeted effects of ionising radiation Integrated Project

Transcription

1 Non targeted effects of ionising radiation Integrated Project

2 A new paradigm of Radiation Biology Targeted effects Classical paradigm of radiation biology DNA damage occurs during or very shortly after irradiation of the nuclei in targeted cells The potential for biological consequences can be expressed within one or two cell generations Non-targeted effects New evidence Bystander effect (BE) Genomic instability (GI) Adaptive response (AR) Clastogenic factors Delayed reproductive death Induction of genes by radiation Premature differentiation Low dose hypersensitivity Abscopal (out-of-field) effects 26/10/2006 Istituto Superiore di Sanità 2

3 BE GI priming dose challenge dose AR 26/10/2006 Istituto Superiore di Sanità 3

4 General objectives of the NOTE IP To investigate the mechanisms of non-targeted effects, in particular, bystander effects, genomic instability and adaptive response. To investigate if and how non-targeted effects modulate the cancer risk in the low dose region, and whether they relate to protective or harmful functions. To investigate if ionising radiation can cause non-cancer diseases or beneficial effects at low and intermediate doses. To investigate individual susceptibility and other factors modifying non-targeted responses. To assess the relevance of non-targeted effects for radiation protection and to set the scientific basis for a modern, more realistic, radiation safety system. To contribute to the conceptualisation of a new paradigm in radiation biology that would cover both the classical direct (DNA-targeted) and non-targeted (indirect) effects. 26/10/2006 Istituto Superiore di Sanità 4

5 General information Start date of the project: 1 September 2006 Duration: 48 months 19 partner organisations Coordinating organisation: STUK - Radiation and Nuclear Safety Authority Project coordinator: Prof. Sisko Salomaa EURATOM Specific Programme for Research and Training on Nuclear Energy, 6 th Framework Program Tentative budget: M Requested EC contribution: 6.33 M 26/10/2006 Istituto Superiore di Sanità 5

6 List of NOTE partners, part 1 No Organisation name Acronym Country Scientific contact person 1 Radiation and Nuclear Safety Authority STUK Finland Prof. Sisko Salomaa 2 University of Dundee UNIVDUN UK Prof. Eric G. Wright 3 Leipzig University UL Germany Dr. Guido Hildebrandt 4 MRC Radiation and Genome Stability Unit MRC UK Dr. Munira Kadhim 5 Imperial College ICFM UK Dr. Mark Little 6 Gray Cancer Institute GCI UK Dr. Kevin M. Prise 7 Belgian Nuclear Research Centre SCK-CEN Belgium Dr. Paul Jacquet 8 Dublin Institute of Technology RESC Ireland Dr. Fiona Lyng 9 National Institute of Health ISS Italy Dr. Maria Antonella Tabocchini 10 University of Leicester ULEICS UK Prof. Yuri Dubrova 26/10/2006 Istituto Superiore di Sanità 6

7 List of NOTE partners, part 2 No Organisation name Acronym Country Scientific contact person 11 McMaster University MAC Canada Prof. Carmel Mothersill 12 Atomic Energy of Canada Limited AECL Canada Dr. Ron Mitchel National Research Institute for Radiobiology and Radiohygiene National Research Centre for Environment and Health NRIRR Hungary Dr. Géza Sáfrány GSF Germany Dr. Werner Friedland 15 University of Pavia UNIPV Italy Prof. Andrea Ottolenghi 16 University of Erlangen-Nuremberg FAU Germany Dr. Franz Roedel 17 University of Duisburg-Essen UDE Germany Prof. George Iliakis 18 Norwegian Radium Hospital RR HF Norway Dr. Jostein Dahle 19 Ottawa Heart Institute Research Corporation OHIRC Canada Dr. Stewart Whitman 26/10/2006 Istituto Superiore di Sanità 7

8 WP1 WP6 WP7 Management activities Management board Administrative coordinator Sisko Salomaa WP leaders WP2 WP3 WP4 Infrastructures, training and mobility Kevin Prise Mechanisms of non-targeted effects Eric Wright Non-cancer diseases Guido Hildebrandt Factors modifying non-targeted responses Munira Kadhim Dissemination and exploitation activities Oleg Belyakov Task 1 Communication with public Riikka Laitinen-Sorvari Task 2 Relevance for radiation protection Sisko Salomaa Advisory committee WP5 Modelling of non-targeted effects Mark Little Task 3 Conceptualisation of new paradigm Oleg Belyakov 26/10/2006 Istituto Superiore di Sanità 8

9 Italian groups contribution to NOTE WP2 - Mechanisms of non-targeted effects Task 2.1 Bystander responses, adaptive response and genomic instability (DNA/chromosome damage and cell death) in different cell culture systems (ISS task leader) Task 2.3 Studies of signalling molecules in non-targeted effects Task 2.7 WP2 review and assessment WP5 - Modelling of non-targeted effects Task 5.0 Modeller-experimental interaction Task 5.1 Intracellular and local intercellular communication and damage mechanisms Task 5.2 Intercellular communication mechanisms in vitro (UNIPV task leader) Task 5.4 WP5 review and assessment 26/10/2006 Istituto Superiore di Sanità 9

10 WP2 - Mechanisms of non-targeted effects Medium-mediated BE to study diffusible species involved (co-culture approach) Studies on timing help to identify the various steps in the signal trasmission Dependence on radiation quality help to identify the mechanisms underlying the biological effects of radiations relevant in radiation protection (alpha source irradiator and g-rays at the ISS; C-ions at the LNS-INFN) 26/10/2006 Istituto Superiore di Sanità 10

11 WP2 - ISS Biological systems: End points: AG1522 primary human fibroblasts DNA damage (γh2ax; MN) ROS, NOS cell death HL60 human promyelocytes differentiation induction DNA damage WP2 - UNIPV Biological systems: End poin Biological systems: End points: ts: AG1522 primary human fibroblasts cytokine release modulation T98G human glioma cells (IL8,IL6,IL12,.) membrane receptor expression modulation 26/10/2006 Istituto Superiore di Sanità 11

12 WP5 ISS Modelling intracellular and local intercellular communication mechanisms in vitro to investigate adaptive response (AR) Examples of relevant points: priming dose induced modifications (radiation-induced damage to DNA and/or other molecules) DNA damage processing (DNA damage and repair activity represented by dynamical variables, using the methods of the Molecular Dynamics simulations) role of radiation quality (i.e., radiations of different types/energies) will be accounted for model improvement by inclusion of intercellular communication relation with other low dose effects (BE, GI,.) 26/10/2006 Istituto Superiore di Sanità 12

13 WP5 UNIPV Modelling intercellular communication mechanisms in vitro to investigate bystander effect (BE) Examples of relevant points: dependence on signal characteristics (e.g. diffusion coefficients) dependence on time after irradiation testing if signalled cells can in turn release the signals role of spatial distribution of cells role of signal depletion and degradation 26/10/2006 Istituto Superiore di Sanità 13

14 NOTE website At the moment public and secure NOTE IP websites are functioning at New NOTE IP public and secure websites will be available at the same address by month 3 of the project (tentatively, end of November 2006). 26/10/2006 Istituto Superiore di Sanità 14

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16 WP 2 (Mechanisms of non-targeted effects) is structured around a number of specific questions: What is the target for non-targeted effects? What cells produce signals? What is the trigger for the production of signals? What cells respond to signals? What intracellular processes are involved in responding to signals? What are the messengers of bystander responses? What are the mechanisms of non-targeted effects in tissues? What are the mechanisms of genomic instability perpetuation? What are the mechanisms of transgenerational instability? WP 3 (Non-cancer diseases) investigates if non-targeted effects can provide new mechanistic explanations for the development other diseases than cancer, by investigating: mechanisms of the induction of cardiovascular diseases in vitro and in vivo; inflammatory vs. anti-inflammatory effects; role of non-targeted effects in developmental defects. WP 4 (Factors modifying non-targeted responses) investigates: influence of genetic factors on the in vivo production of non-targeted effects; impact of genetic predisposition on non-targeted effects response in vitro; molecular mechanisms determination that contribute to the distinct radiation responses at low dose radiations in mice with different radiosensitivity; role of DNA repair and checkpoint responses. 26/10/2006 Istituto Superiore di Sanità 16

17 WP 5 (Modelling of non-targeted responses) approaches low dose effects by mathematical modelling in order to improve the understanding of the potential role of non-targeted effects in the development of different pathologies. In particular the following systems and endpoints will be modelled: intracellular and local intercellular communication and damage mechanisms; intercellular communication mechanisms in vitro; extracellular signalling mechanisms in vivo; genomic instability mechanisms in vivo. WP 6 (Integration activities) provide means for building the European Research Area and connecting with strong research groups in third countries by: development and better use of existing radiobiological infrastructures; strengthening collaborative RTD activity; supporting training and mobility of scientists; educating the next generation of European radiobiologists on non-targeted effects. WP 7 (Dissemination and exploitation activities) will provide means for communication with public and exploitation of NOTE results by the scientific community and stakeholder groups by organising: a public NOTE website; a workshop on the conceptualisation of the new paradigm; a workshop on the relevance of non-targeted effects for radiation protection. 26/10/2006 Istituto Superiore di Sanità 17