RISC-RAD
DNA damage responses, genomic instability and radiation-induced cancer: the problem of risk at low and protracted doses
Informazioni Generali
- Coordinatore:
- CEA - COMMISSARIAT A L'ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES (Francia)
- Responsabile:
- SARAN ANNA - SSPT-TECS-TEB (CASACCIA)
- Ruolo ENEA:
- PARTNER
- Sito WEB:
- Sito WEB non disponibile
Programmi Europei
- Programma:
- Sesto Programma Quadro EURATOM (2002-2006) -> Euratom radioprotezione (IP - Progetto Integrato)
Descrizione e Attività
Descrizione Generale
Radiation protection requires a thorough understanding of low dose ionising radiation. Currently extrapolation from high doses is necessary to estimate the effects of low doses. Furthermore, it is critically important to have an appreciation of the variation in individual responses to radiation among the human population. Present estimates of the risks from radiation exposure are based largely on the "average" individual in an exposed population. However, clinical observations of adverse reactions to radiotherapy indicate large variations in individual radio sensitivity. Quantification of risk requires the identification of new parameters taking into account these differences in radiation responses. Therefore, a detailed knowledge of the mechanisms by which radiation induces cancer is essential. In this project, leading European research teams join forces to understand the various steps involved in the multistage process of radiation-induced tumorigenesis through detailed analysis of DNA damage responses (repair, checkpoints, apoptosis), genomic instability as well as mechanisms/genetics and modelling of radiation tumorigenesis. The research in this project will answer the following specific questions: (i) who is at risk? ; (ii) when do the factors modifying risk exert their influence? ; (iii) what are the mechanisms through which risk factors act? ; (iv) Is there a link between radio sensitivity of individuals (short term) and susceptibility to cancer (Late after exposure)? The consortium will apply innovative and state of the art technology (genomic, polemics, advanced fluorescence microscopy, RNA interference, gene knock-in technology). We stress that the identification of genetic variables in the processing of radiation induced DNA damage is vital for re-evaluation of current radio-protective measures and the development of future protective procedures.
Attività svolta da ENEA
ENEA participates in two of the RISC RAD Workpakages, WP3 and WP4. Work carried out under WP3 primarily aims at providing quantitative data on tumorigenesis due to exposure to low doses of ionizing radiation (down to <100mGy) in a radiation sensitive mouse model carrying mutations in the Patched (Ptc1) gene, the best example of a gene influencing radiation tumor risk in the human population. In addition, work in WP3 is centered on understanding the initiating events in mouse radiation cancer, and the relationships between initial radiation-induced damage to DNA and the appearance of early tumor-associated cellular events, together with their contribution to multistage neoplasia, genetic susceptibility. Work carried out at ENEA under RISC-RAD WP4 investigates the genetic factors in mouse radiation tumorigenesis. Genetic mapping of modifiers of radiation carcinogenesis susceptibility in the Ptc1 mouse model has been carried out through generation and phenotypic characterization of mouse crosses with outbred skin carcinogenesis-resistant and -susceptible (Car-R and Car-S, respectively) mouse lines previously generated by phenotypic selection in the ENEA laboratories, followed by genetic linkage analysis at high resolution. ENEA coordinates the integration proposal with the following objectives: To gain information on the involvement of HR and/or NHEJ in radiation-induced tumorigenesis; to clarify tumor-associated genetic and epigenetic events in radiation-induced medulloblastoma tumorigenesis; to elucidate early/late radiation-associated cytogenetic and molecular events in medulloblastoma tumorigenesis through analysis of preneoplastic cerebellar lesions of different developmental stage; to provide expression profiles of spontaneous and radiation-induced medulloblastomas.