Mechanisms and Pathways Controlling Genomic Instability In Vivo

体内控制基因组不稳定性的机制和途径

• 批准号: 7275839
• 负责人: Wendy W Kuhne
• 金额: $ 4.68万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275839
• 关键词: Affect; Aging; Animal Model; Cells; Complex; Condition; DNA Damage; Development; Dose; Dose-Rate; Engineering; Environmental Exposure; Fishes; Future Generations; Gene Silencing; Gene Transfer Techniques; Generations; Genetic; Genetic Recombination; Genomic Instability; Homologous Gene; Human; Individual; Ionizing radiation; Japanese Killifish; Measures; Medical Surveillance; Modeling; Numbers; Organism; Pathway interactions; Pattern; Radiation; Risk; Technology; Testing; Time; Tissues; Transgenes; Vertebrates; Work; base; body system; cancer risk; gene conservation; gene repair; in vivo; novel; radiation effect; response

DESCRIPTION (provided by applicant): The project is to investigate radiation-induced .genomic instability, defined as a phenomenon whereby radiation related genetic damage manifests itself one or more cell generations following the generation in which damage was inflicted. Although the mechanism is not fully understood, it is believed that both DNAtargeted and non-DNA targeted effects of. radiation contribute. Genomic instability increases the risk of cancer, potentially affects tissue aging, and presents a risk to unexposed future generations. In contrast to conventional radiation effects, genomic instability has a complex and possibly nonlinear dose-response relationship, and is thus particularly relevant to low dose and low dose-rate environmental exposures. This project will identify genetic pathways that protect against radiation-induced genomic instability in vivo. It will use a novel whole-animal model, the Japanese Medaka fish (Oryzias latipes), that is similar to higher vertebrates in terms of organ systems and pattern of development and has homologs of most mammalian DNA damage surveillance and repair genes. Of relevance to work proposed here, medaka is a genetically tractable model with established technologies for transgenesis and gene silencing, where large numbers of individuals can be phenotypically screened, and with a short generation time facilitating multigenerational studies. Genomic instability will be measured in vivo based on a locus-specific test based on an unstable, engineered transgene. Individual aims are: (1) to characterize the tissue-specific dose response to low dose ionizing radiation using somatic recombination as an indicator of genomic instability, (2) to investigate how the tissue-specific response to low dose ionizing radiation is modified as a function of genetic and phenotypic background, and (3) to identify conditions under which genomic instability is transmitted to future generations and to identify factors that modify transgenerational risk. The significance of this study is to provide an opportunity to identify germline pathways of radiation response on an organism-wide scale that is not feasible in higher vertebrate models. Because of the high degree of functional gene conservation among vertebrates, mechanisms identified in the O. latipes model can readily be evaluated in mammalian species and the results then extrapolated to human. ,

描述（由申请人提供）： 该项目旨在研究辐射引起的基因组不稳定性，其定义为一种现象，即辐射相关的基因损伤在受到损伤的一代或多代细胞中表现出来。尽管其机制尚不完全清楚，但据信DNA靶向和非DNA靶向都有作用。辐射贡献。基因组不稳定性会增加患癌症的风险，可能影响组织老化，并对未接触过基因组的子孙后代带来风险。与传统的辐射效应相比，基因组不稳定性具有复杂且可能非线性的剂量反应关系，因此与低剂量和低剂量率环境暴露特别相关。该项目将确定可防止体内辐射引起的基因组不稳定性的遗传途径。它将使用一种新颖的整体动物模型，即日本青鳉鱼（Oryzias latipes），该模型在器官系统和发育模式方面与高等脊椎动物相似，并且与大多数哺乳动物 DNA 损伤监测和修复基因具有同源性。与这里提出的工作相关的是，青鳉是一种遗传上易于处理的模型，具有成熟的转基因和基因沉默技术，可以对大量个体进行表型筛选，并且世代时间短，有利于多代研究。基因组不稳定性将根据基于不稳定的工程转基因的基因座特异性测试进行体内测量。个人目标是：（1）使用体细胞重组作为基因组不稳定性的指标来表征对低剂量电离辐射的组织特异性剂量反应，（2）研究如何将对低剂量电离辐射的组织特异性反应修改为遗传和表型背景的功能，以及（3）确定基因组不稳定性传递给后代的条件，并确定改变跨代风险的因素。这项研究的意义在于提供了一个机会，以在整个生物体范围内识别辐射反应的种系途径，这在高等脊椎动物模型中是不可行的。由于脊椎动物之间功能基因高度保守，O. latipes 模型中确定的机制可以很容易地在哺乳动物物种中进行评估，然后将结果外推到人类。 ,