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

基本信息

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
项目类别：
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

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

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项目摘要

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）：该项目是为了研究辐射诱导的。基因组不稳定性，定义为一种现象，与辐射相关的遗传损伤表现出自身在造成损害的一代之后的一个或多个细胞世代。尽管该机制尚未完全理解，但据认为，DNATARGET和非DNA的靶向效应均未完全理解。辐射贡献。基因组不稳定性增加了癌症的风险，可能影响组织衰老的风险，并为未暴露的子孙后代带来风险。与常规辐射效应相反，基因组不稳定性具有复杂且可能是非线性剂量反应关系，因此与低剂量和低剂量率环境暴露尤其相关。该项目将确定预防体内辐射诱导的基因组不稳定性的遗传途径。它将使用一种新型的全动物模型，即日本Medaka Fish（Oryzias latipes），在器官系统和发育模式方面与较高的脊椎动物类似，并且具有大多数哺乳动物DNA损伤监视和修复基因的同源物。与此处提出的工作相关的是，Medaka是一种具有遗传处理的模型，具有既定的转基因和基因沉默技术，可以表型筛选大量个体，并且短期促进了多代研究。基因组不稳定性将基于基于基因座的特异性测试，基于基于不稳定的工程转基因的基因座特异性测试。个体的目的是：（1）用体细胞重组作为对低剂量电离辐射的组织特异性剂量反应作为基因组不稳定性的指标，（2）调查如何将组织特异性响应定为低剂量电离辐射如何修饰，以识别基因型和表型的情况下的状况，并确定基因上的条件，并确定基因型的函数（3）风险。这项研究的意义是提供一个机会，以在较高的脊椎动物模型中识别范围内的种系辐射反应途径，这是不可行的。由于脊椎动物之间具有高度的功能基因保护，因此可以在哺乳动物物种中轻松评估O. latipes模型中确定的机制，然后将结果推向人类。，，，，