) Human exposure to densely ionizing radiation occurs environmentally on the earth and in space. Occupational exposures to neutrons also occur in the nuclear power industry and near medical accelerators. While most of these exposures involve irradiation with a very low fluence of high LET radiations, the carcinogenic risks of such exposures remain poorly understood. The goals of the proposed investigation are focused to test the hypothesis that densely ionizing radiations, such as accelerated iron ions, are more potent inducers of a persistent state of genomic instability in human lymphoid cells, as compared with sparsely ionizing radiations such as energetic protons. Karyotypic heterogeneity will serve as an initial indicator of genomic instability. More comprehensive experiments are outlined to evaluate other features of chromosomal-scale instability, including increased rates of mutation at defined sequences within the human genome. The applicant will also delineate the molecular mechanisms involved in maintenance of persistent and progressive radiation-induced instability. In particular, she will test the hypothesis that low fluence exposures to high LET radiations induce instability through increased rates of aberrant recombination leading to loss of heterozygosity, as assayed along a segment of chromosome 17q. She presents an experimental plan to test the hypothesis that programmed cell death masks expression of persistent genomic instability following low fluence exposure to densely ionizing iron ions or comparable doses of protons. Specific experimental approaches are outlined to determine when programmed cell death is of critical importance in the selective removal of heavily damaged cells at early times post-exposure, at later times to weed out late-arising clones with inappropriately rearranged genomes, or a combination thereof. The proposed investigations will provide quantitative and mechanistic information regarding iron ion- and proton-induced genomic instability. The approaches outlined focus on the genesis of the types of heritable alterations that have often been associated with human carcinogenesis. The results obtained will be of specific importance in the assessment of radiation risks to astronaut health. The results obtained with low fluence iron-ion exposures will serve as a model for terrestrial exposures to radon and neutrons.
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