RADIATION, CHROMOSOMAL ABERRATIONS, AND RELATIVE BIOLOGI

辐射、染色体畸变和相关生物学

• 批准号: 6377036
• 负责人: JOEL S BEDFORD
• 金额: $ 19.02万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377036
• 关键词: DNA damage; X ray; alpha radiation; cell line; chromosome aberrations; fibroblasts; fluorescent in situ hybridization; gamma radiation; linear energy transfer; radiation genetics; relative biological effectiveness

DESCRIPTION (adapted from applicant's abstract) The broad objective of this research is to better understand processes involved in the induction of chromosomal aberrations by ionizing radiation to help identify promising avenues of approach for future studies of molecular mechanisms. Perhaps more importantly, since various particular chromosomal translocations are required for many cancers, the project should shed some light on the question of radiation thresholds for cancer induction which is a key issue for radiation protection standards. The focus is on the dependence of RBE on the microscopic distributions of energy deposition in normal human cells where these energy deposition patterns can be manipulated to test specific hypotheses about the nature of aberration formation. The first hypothesis is that most exchange aberrations develop as a result of a damaged region of DNA interacting with an undamaged region (e.g., a recombinational misrepair?), as opposed to an alternative hypothesis involving interaction (misrejoining) of two damaged regions in close proximity. This would be studied by comparing the induction of exchange aberrations after exposing cells to 5 MeV alpha particles with that from damage after decay of 125IUdR incorporated into DNA. The ionization density is similar for these two radiations (~ 6 KeV within a 50 nanometer diameter sphere), but the spacing between the densely ionizing spheres is different for the two radiations. For alpha particles, the spheres are packed closely together to produce densely ionizing tracks 50 microns or so in length; in contrast, the spheres produced by disintegrations of 125I are separated spatially. Therefore, if two damaged regions must be in close proximity for an exchange to occur, the alpha particles would produce more exchanges than 125I disintegrations that deliver the same dose to the nucleus as the alpha particles. On the other hand, if only one damaged region is required, the effectiveness of the two radiations should be approximately the same. The second hypothesis is that for sparsely ionizing radiations, the densely ionizing track ends produce virtually all of the biological effect. This is based on observations of RBEs of 2 to 3 for Al or C ultrasoft x-rays. The test would involve comparing aberration induction by 14CTdR incorporated into DNA relative to 3HTdR incorporated into DNA. For 3H (range ~0.45 microns) virtually all tracks would originate and terminate in the nucleus, but for 14C beta particles (range ~37 microns) almost none of the tracks would end in a cell nucleus. Therefore, if the hypothesis were correct, 14C particle tracks should have almost no biological effect, and for a given dose to the nucleus, incorporated 3HTdR should be much more effective than incorporated 14CTdR. Since some chromosomal translocations are prerequisite for many cancers, basic knowledge of how chromosomal translocations are formed by radiation should help to better understand the hazards of radiation exposure as well as basic processes involved in oncogenesis. In a practical sense, the results of this study would be directly relevant to the question of thresholds for radiation oncogenesis.

描述(改编自申请人的摘要) 这项研究的广泛目标是更好地理解过程 参与电离诱发的染色体异常 辐射有助于确定未来研究的有希望的途径 分子机制。也许更重要的是，由于各种特殊情况 许多癌症都需要染色体易位，该项目应该 阐明了诱发癌症的辐射阈值问题 这是辐射防护标准的一个关键问题。重点放在 能量沉积的微观分布对径向效应的影响 在正常的人体细胞中这些能量沉积模式可以被操纵 测试有关像差形成性质的特定假设。第一 假说认为，大多数交换像差的形成是由于 与未受损区域相互作用的DNA区域(例如重组 错误修复？)，而不是涉及交互作用的替代假设 (重新连接)紧密相连的两个受损区域。我们将对此进行研究 通过比较将细胞暴露于5℃后对交换像差的诱导 掺入~(125)IUdR的MEVα粒子及其衰变后的损伤粒子 变成DNA。这两种辐射(~6keV)的电离密度相似 在直径50纳米的球体内)，但密集的 两种辐射的电离球是不同的。对于阿尔法粒子， 球体紧密堆积在一起以产生密集的电离轨道50 微米左右的长度；相反，通过解体产生的球体 125I在空间上是分开的。因此，如果两个损坏的区域必须位于 在近距离发生交换时，阿尔法粒子会产生 比125i解体更多的交易所提供相同剂量的 原子核作为阿尔法粒子。另一方面，如果只有一个受损区域 是必需的，则两种辐射的有效性应大致为 一样的。第二个假设是，对于稀疏的电离辐射， 密集的电离轨道端产生了几乎所有的生物效应。 这是基于对Al或C超软X射线的RBES为2到3的观测。 这项测试将包括比较14CTdR掺入后的像差诱导 相对于3HTdR掺入到DNA中的DNA。对于~3H(范围~0.45微米) 如果不是14C，几乎所有的径迹都将在原子核开始和终止 贝塔粒子(范围约37微米)几乎没有一个轨迹会以 细胞核。因此，如果假设是正确的，14C粒子跟踪 应该几乎没有生物效应，对于给定剂量的细胞核， 合并3HTdR应该比合并14CTdR有效得多。 由于一些染色体易位是许多癌症的先决条件，基础 关于辐射如何形成染色体易位的知识应该会有所帮助 为了更好地了解辐射暴露的危害以及基本 参与肿瘤发生的过程。在实际意义上，这一点的结果是 研究将与辐射阈值问题直接相关。 致癌作用。