HIGH LET RADIATION & GENOMIC INSTABILITY IN HUMAN CELLS

描述：(申请人描述) 人类暴露在高密度电离辐射的环境中 在地球和太空中。职业暴露于中子也发生在 核电工业和近乎医疗加速器。虽然其中的大多数 曝光包括用极低剂量的高LET进行照射 关于辐射，这种暴露的致癌风险仍然很低。 明白了。拟议调查的目标是测试 假设高密度电离辐射，如加速铁离子， 是基因组持续不稳定状态的更有效的诱因 与稀疏电离辐射相比，如 高能质子。核型的异质性将作为初始 基因组不稳定的指标。更全面的实验是 概述以评估染色体尺度不稳定性的其他特征， 包括人类体内特定序列的突变率增加 基因组。申请者还将描述涉及的分子机制。 在维持持续性和渐进性辐射引起的不稳定性方面。 特别是，她将测试低通量暴露于 高LET辐射通过增加畸变率而导致不稳定性 重组导致杂合性丧失，如沿片段进行的分析 染色体17q。她提出了一项实验计划来检验这一假设 程序性细胞死亡掩盖了持久性基因组的表达 低通量暴露于高电离铁离子或 相当剂量的质子。概述了具体的实验方法。 确定细胞程序性死亡的时间是至关重要的。 在暴露后早期选择性地移除严重受损的细胞，在 以后通过不适当的重新排列来淘汰后期出现的克隆 基因组，或它们的组合。拟议的调查将提供 有关铁离子的定量和机理信息--和 质子诱导的基因组不稳定性。概述的方法侧重于 可遗传改变类型的起源通常是 与人类癌症的发生有关。所取得的成果将是 对宇航员进行辐射风险评估的特殊重要性 健康。在低通量铁离子暴露下所得到的结果将是有用的。 作为地球上氡和中子暴露的模型。

DESCRIPTION: (Applicant's Description) 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.