HZE RADIATION INDUCED CHROMOSOMAL INSTABILITY

描述：(申请人描述) 本应用程序的主要目的是更好地表征和 理解可遗传基因组现象的机制 低传代培养的正常人细胞的不稳定性 暴露于铁等高原子序数高能(HZE)粒子 原子核和其他高LET带电粒子。建议的重点是 关于高频延迟性染色体不稳定的研究表明 申请者和其他人在暴露于如此高的LET辐射后看到过。 为了更好地描述这一现象，申请人设计了具体的 目的是(1)仔细确定启动的剂量-反应关系 不稳定和随之而来的任何稳定或复杂像差的积累， (2)跟踪单个细胞后代的不稳定性的发展 以了解可继承财产是否以及如何在 世系，(3)决定可遗传的染色体不稳定性状 以显性或隐性的方式通过测量发展或 在融合辐射形成的杂交种中缺乏这一特性的发展 和未受辐射的细胞，以及(4)检查 染色体对突变不稳定性的发展，至少在 HPRT基因座。关于机制，他将审查是否有可能 (5)不稳定的发展与诱发的改变有关。 在细胞应对氧相关自由基损伤的能力中 比较氧分压从20降到2的情况下的发育情况 百分比，更典型的是正常人体组织中的水平；所有 以前对这种现象的研究是在空气中进行的，即， 大约20%的氧气。他还会比较时间和数量 染色体不稳定性的表达所需的细胞加倍。 最后，他将检验这样一种假设，即穿过一个细胞的细胞质 具有一个或多个高LET颗粒的细胞而不是细胞核就足够了 导致染色体不稳定。 关于辐射引起的染色体不稳定的知识是 对于理解为什么辐射，特别是高辐射，可能非常重要 让辐射，是一种“完全的致癌物”。不稳定的诱因 将允许多步骤致癌过程涉及其他较低的 频率突变和染色体重排继续进行 总体概率与观察到的致癌频率一致 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.