Obiettivo To make rational judgements in radiation protection, it is necessary to extrapolate to low doses and low dose rates, and to have an appreciation of variation in response to ionizing radiation among the human population. This can be done with confidence only if we have a detailed knowledge of the mechanisms by which radiation induces cancer and genetic disorders. The proposal is a comprehensive multi-disciplinary approach to understanding the molecular basis of ionizing radiation sensitivity in humans. It focuses on (i) the identification of radiation-sensitive individuals, (ii) a mechanistic understanding of radiation sensitivity, and (iii) the consequences of radiation-induced DNA damage and repair for human health. The proposal contains three experimental approaches:(A) Identification of genes and gene products influencing radiosensitivity,(B) Function of gene products from the molecular to the whole organism level,(C) Consequences of deficiencies in these genes for cells,laboratory animals and humans. To identify ionizing radiation-sensitive individuals, cells from patients with abnormal responses will beexamined for radiosensitivity and repair defects. To understand the mechanisms of radiation sensitivity, the isolation and characterization of genes relevant for cellular responses is indispensable. New radiosensitive mammalian mutants will be isolated to identify genes and to ;assess the biological impact of repair systems. Genes influencing radiosensitivity, including those controlling the cell cycle response to ionizing radiation, and gene products will be isolated and characterized employing a variety of molecular approaches. Cell free systems will be developed to analyse functions of genes and to reconstitute the repair system in vitro. Special emphasis will be given to the characterization of the Ku and DNA-PK proteins recently discovered in one of our laboratories to play a key role in radiation-induced DNA break repair. At the cellular level the influence of chromatin structure, cell cycle progression and terminal differentation on radiosensitivity will be assessed. Together these different approaches cover all important aspects of repair of DNA double strand breaks known to be a major cause of cell lethality and chromosome aberrations. To assess the consequences of ionizing radiation-induced damage a variety of endpoints will be studied including analysis of mutations and apoptotic responses. Transgenic mice carrying defects in genes determining radiosensitivity corresponding to those identified in humans, will be constructed and will be used to investigate the relationship of the molecular defect to the development of disease after exposure to radiation and will allow study of tissuespecific carcinogenesis. In this way the genetic control of radiationinduced carcinogenesis will be elucidated. The achievements obtained in this proposal will contribute to a better risk estimation for radiation induced cancer and more insights will be gained in the contribution of genetic factors to radiation risk. Programma(i) EAEC-NFS 2 - Specific research and training programme in the field of nuclear safety and safeguards, 1994-1998 Argomento(i) 040102 - Repair of, and recovery from, DNA damage and radiation sensitivity Invito a presentare proposte Data not available Meccanismo di finanziamento CSC - Cost-sharing contracts Coordinatore Rijksuniversiteit Leiden Contributo UE Nessun dato Indirizzo 72,Wassenaarseweg 2300 RA Leiden Paesi Bassi Mostra sulla mappa Costo totale Nessun dato Partecipanti (5) Classifica in ordine alfabetico Classifica per Contributo UE Espandi tutto Riduci tutto Erasmus Universiteit Rotterdam Paesi Bassi Contributo UE Nessun dato Indirizzo Dr. Molenwaterplein 3000 DR Rotterdam Mostra sulla mappa Costo totale Nessun dato GSF-RESEARCH CENTER FOR ENVIRONMENT AND HEALTH Germania Contributo UE Nessun dato Indirizzo Ingolstädter Landstrasse 1 85764 Neuherberg Mostra sulla mappa Costo totale Nessun dato Institut Curie Francia Contributo UE Nessun dato Indirizzo 26,Rue d'Ulm 75231 Paris Mostra sulla mappa Costo totale Nessun dato MRC Cell Mutation Unit Regno Unito Contributo UE Nessun dato Indirizzo University of Sussex Falmer BN1 9RR Brighton Mostra sulla mappa Costo totale Nessun dato Rijksuniversiteit Leiden Paesi Bassi Contributo UE Nessun dato Indirizzo 2333 AA Leiden Mostra sulla mappa Costo totale Nessun dato
