HIGH LET RADIATION & GENOMIC INSTABILITY IN HUMAN CELLS

描述：（申请人的描述） 人类暴露于高密度电离辐射发生在环境上， 地球和太空 职业性中子暴露也发生在 核能工业和近医疗加速器。 虽然大多数这些 曝光涉及高LET的非常低的能量密度的辐照 辐射，这种暴露的致癌风险仍然很低 明白 拟议调查的目标集中在测试 假设密集电离辐射，如加速铁离子， 是基因组不稳定性持续状态的更有效诱导剂， 人类淋巴细胞，与稀疏的电离辐射相比， 高能质子 核型异质性将作为初始 基因组不稳定性指标。 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， 包括人类基因组中特定序列的突变率增加 基因组 申请人还将描述所涉及的分子机制 维持持续和渐进的辐射引起的不稳定。 特别是，她将测试低通量暴露于 高LET辐射通过增加畸变率引起不稳定性， 杂合性缺失：一种导致杂合性缺失的重组，如沿着一个片段测定的 染色体17q。 她提出了一个实验计划来验证这个假设 程序性细胞死亡掩盖了持续性基因组 低通量暴露于密集电离铁离子后的不稳定性， 相当剂量的质子。 概述了具体的实验方法 以确定程序性细胞死亡何时在 在暴露后早期选择性去除严重受损的细胞， 以后的时间，以淘汰晚出现的克隆与不适当的重新排列 基因组或其组合。 拟议的调查将提供 关于铁离子的定量和机械信息， 质子诱导的基因组不稳定性 所概述的方法侧重于 遗传变异的起源， 与人类致癌有关。 获得的结果将是 对航天员辐射风险评估的特殊重要性 健康 低通量铁离子暴露获得的结果将服务于 作为地球暴露于氡和中子的模型。

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.