GENOMIC INSTABILITY IN HIGH LET CARCINOGENESIS

High Let 致癌过程中的基因组不稳定性

• 批准号: 6173394
• 负责人: ROBERT L ULLRICH
• 金额: $ 24.49万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6173394
• 关键词: DNA repair; animal genetic material tag; apoptosis; breast neoplasms; carcinogen testing; gene mutation; high energy particle; laboratory mouse; linear energy transfer; mammary epithelium; mutagen testing; mutagens; radiation carcinogen; radiation carcinogenesis; radiation genetics; tissue /cell culture; tumor suppressor genes

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.

描述：（申请人的描述） 本研究的目的是确定辐射诱导的作用 放射致癌过程中的基因组不稳定性。 先前的研究已导致 申请人提出一个模型，将基因组不稳定性识别为 多步骤序列中最早的细胞事件导致 辐射诱发的癌症。 判断是否诱发不稳定 与癌症的发展有机械联系，需要信息 获得的诱导维持和基因组不稳定性的传播 体内。 与该应用特别相关的是结果证明 高和低 LET 辐射效果之间的质的差异。 如果 基因组的不稳定性至关重要，预计辐射 质量应影响其程度和性质。 这些研究解决 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。 具体而言，本研究的目的 是：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作为函数 辐射质量。 研究将通过以下方式检验延迟不稳定的诱导 小鼠乳腺上皮中的伽马射线、质子、中子和铁粒子 细胞在体外和体内受到照射。 重点将放在 细胞间相互作用和细胞增殖。 2) 确定影响 参与细胞周期检查点控制的“关键”基因的改变 和辐射诱导的不稳定性中的细胞凋亡。 研究将测试是否 高和低 LET 照射后的基因组不稳定性与 细胞周期检查点控制的改变及其程度 程序性细胞死亡影响其增殖。 3) 表征细胞 涉及辐射引起的不稳定性发展的过程。 到 测试 DNA 修复机制是否参与诱导和增殖 不稳定的情况下，影响修复过程的试剂将被用来 改变辐照后不稳定性的发展。 体内/体外 模型为详细研究辐射引起的 基因组不稳定性来测试之间是否存在机械联系 辐射引起的不稳定性和致癌作用以及是否存在 差异作为辐射质量的函数。