HZE RADIATION INDUCED CHROMOSOMAL INSTABILITY

描述：（申请人的描述） 本申请的广泛目的是更好地表征和 了解遗传性基因组遗传现象的机制 在低传代培养的正常人细胞中诱导的不稳定性， 暴露于高原子序数高能（HZE）粒子，例如铁 核和其他高LET带电粒子。 建议的重点 研究是关于高频率的延迟染色体不稳定性， 申请人和其他人在暴露于这种高LET辐射后看到的。 为了更好地表征该现象，申请人设计了具体的 目的是（1）仔细确定剂量-反应关系， 不稳定性和随后的任何稳定或复杂的像差的积累， (2)随着个体细胞后代不稳定性的发展， 看看是否，以及如何，可继承的财产产生和分离， 谱系，（3）确定是否遗传染色体不稳定性状 通过测量发展或 在通过融合辐照形成的杂交体中缺乏这种性质的发展 和未照射的细胞，和（4）检查之间的可能的相关性， 染色体与突变不稳定性的发展，至少在 HPRT基因座。 关于机制问题，他将研究是否有可能 （5）不稳定性的发展与诱导蚀变有关 细胞科普氧相关自由基损伤的能力， 比较在氧张力从20降低到2的情况下的这种发展 %，这是正常人体组织中更典型的水平;所有 以前对该现象的研究是在空气中进行的，即， 大约20%的氧气 他也会比较时间和数量 表达染色体不稳定性所需的细胞分裂。 最后，他将测试一个假设，即穿越细胞质的一个 具有一个或多个高LET颗粒的细胞而不是细胞核是足够的 以诱导染色体不稳定性。 关于辐射诱发染色体不稳定性的知识 对于理解为什么辐射，特别是高辐射， LET辐射，是一种“完全致癌物”。 不稳定性的诱发 将允许多步致癌过程， 频率突变和染色体重排， 总体概率与观察到的癌症诱导频率一致 在辐射暴露后。

DESCRIPTION: (Applicant's Description) The broad purpose of this application is to better characterize and understand mechanisms involved in the phenomenon of heritable genomic instability induced in low passage cultured normal human cells following exposure to high atomic number high energy (HZE) particles such as iron nuclei and other high LET charged particles. The focus of the proposed studies is on the high frequency delayed chromosomal instability that the applicant and others have seen after exposure to such high LET radiations. To better characterize the phenomenon, the applicant has designed specific aims to (1) carefully determine dose-response relationships for initiation of instability and follow accumulation of any stable or complex aberrations, (2) follow the development of instability in the progeny of individual cells to see if, and how, the heritable property arises and segregates in the lineage, (3) determine whether the heritable chromosomal instability trait behaves in a dominant or recessive manner by measuring the development or lack of development of this property in hybrids formed by fusing irradiated and unirradiated cells, and (4) examine the possible correlation between the development of chromosomal versus mutational instabilities, at least at the HPRT locus. With regard to mechanisms, he would examine the possibility that (5) the development of instability is related to an induced alteration in the ability of cells to cope with oxygen related free radical damage by comparing such development under an oxygen tension reduced from 20 to 2 percent, as is more typical of the levels in normal human tissues; all previous studies on the phenomenon have been carried out in air, i.e., approximately 20 percent oxygen. He would also compare time versus number of cell doublings required for the expression of chromosomal instabilities. Lastly, he would test the hypothesis that traversal of the cytoplasm of a cell and not the nucleus with one or more high LET particles is sufficient to induce chromosomal instability. Knowledge concerning radiation induced chromosomal instability is potentially very important for understanding why radiation, especially high LET radiation, is a "complete carcinogen". The induction of an instability would allow the multi-step oncogenic process involving otherwise low frequency mutations and chromosomal rearrangements to proceed with an overall probability consistent with observed cancer induction frequencies after radiation exposure.