Objective
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.
Fields of science (EuroSciVoc)
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
2300 RA Leiden
Netherlands
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.