GENOMIC INSTABILITY IN HIGH LET CARCINOGENESIS

描述：(申请人描述) 这项研究的目的是确定辐射诱导的作用 辐射致癌中的基因组不稳定性。之前的研究已经导致了 申请人提出一个模型，将基因组不稳定性确定为 多步骤序列中最早的细胞事件导致 辐射诱发的癌症。以确定是否诱发不稳定 与癌症发展有机械联系需要信息 在诱导、维持和繁殖基因组不稳定性上获得 活着。与这一应用程序特别相关的是演示结果 高LET辐射和低LET辐射效应之间的质的差异。如果 基因组的不稳定性是至关重要的，可以预测辐射 质量应该影响它的程度和性质。这些研究针对的是 检验假设和确定效果的几个基本问题 作为辐射质量的函数。具体地说，这项研究的目的 1)确定细胞环境对诱导的影响， 基因组不稳定性的持久性和传播性 辐射质量。研究将通过以下方式检查延迟不稳定的诱导 小鼠乳腺上皮细胞中的伽马射线、质子、中子和铁颗粒 经体外和体内照射的细胞。重点将放在以下方面： 细胞间的相互作用和细胞增殖。2)确定以下方面的影响 参与细胞周期检查点控制的“关键”基因的变化 以及辐射诱导的不稳定性中的细胞凋亡。研究将测试是否 高、低LET照射后的基因组不稳定性与 细胞周期检查点控制的变化及其程度 细胞程序性死亡会影响其繁殖。3)描述蜂窝 参与辐射引起的不稳定性发展的过程。至 检测DNA修复机制是否参与诱导和繁殖 对于不稳定，影响修复过程的代理将被用于 改善辐射后不稳定性的发展。体内/体外 模型为辐射诱导的详细研究提供了机会 基因组不稳定性测试之间是否存在机械联系 辐射诱发的不稳定性和致癌以及是否存在 作为辐射质量函数的差异。

DESCRIPTION: (Applicant's Description) The objective of this research is to determine the role of radiation-induced genomic instability in radiation carcinogenesis. Previous studies have led the applicant to propose a model identifying genomic instability as the earliest cellular event in the multi-step sequence leading to radiation-induced cancer. To determine whether the induction of instability is mechanistically linked to cancer development requires information be obtained on induction maintenance, and propagation of genomic instability in vivo. Of particular relevance to this application are results demonstrating qualitative differences between effects of high and low LET radiations. If genomic in-stability is critical, it would be predicted that radiation quality should influence its degree and nature. These studies address several issues fundamental to testing the hypothesis and determining effects as a function of radiation quality. Specifically, the aims of this research are: 1) Determine the influence of cell environment on induction, persistence, and propagation of genomic instability as a function of radiation quality. Studies will examine induction of delayed instability by gamma rays, protons, neutrons and iron particles in mouse mammary epithelial cells irradiated in vitro and in vivo. Emphasis will be on the role of cell-cell interactions and cell proliferation. 2) Determine the impact of alterations in "critical" genes involved in cell cycle checkpoint control and apoptosis in radiation-induced instability. Studies will test whether genomic instability after high and low LET irradiation is associated with alterations in cell cycle check point control and the degree to which programmed cell death influences its propagation. 3) Characterize cellular processes involved in the development of radiation-induced instability. To test whether DNA repair mechanisms are involved in induction and propagation of instability, agents which influence repair processes will be used to modify development of instability post-irradiation. The in vivo/in vitro models provide an opportunity for detailed studies of radiation-induced genomic instability to test whether there is a mechanistic link between radiation-induced instability and carcinogenesis and whether there are differences as a function of radiation quality.