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IONIZING RADIATION INDUCED MUTATION IN ENDOGENOUS GENES

电离辐射诱发内源基因突变

基本信息

批准号：
2154180
负责人：
W DAVID SEDWICK
金额：
$ 22.72万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-03-01 至 1995-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2154180
关键词：
DNA damage X ray aminoacridines bleomycin carmustine gene deletion mutation gene mutation ionizing radiation mutagens nucleic acid sequence point mutation polymerase chain reaction radiation carcinogenesis radiation genetics radiobiology southern blotting tissue /cell culture

项目摘要

Mutations at recessive alleles have been implicated as a causative factor in the development of cancer and other genetic diseases. Ionizing radiation causes mutations which often affect multiple genetic loci. Radiation-induced damage, therefore, may have a high potential to "uncover" pre-existing mutations or by producing multilocus deletions, sensitize the cells to the phenotypic consequences of future mutations in recessive alleles which have become hemizygous. This proposal explores the hypothesis that the probability an agent will cause expression of mutations at recessive alleles is dependent on its relative propensity to cause intragenic (mutations within a gene) and multilocus (mutations resulting in deletion or modification of multiple contiguous genetic loci) lesions. Four agents, gamma radiation, 2-amino-N6-hydroxyadenine (AHA), UVC radiation, and 4-(9-acridinylamino)methanesulfon-m-anisidide (mAMSA), which are expected to cause different proportions of intragenic and multilocus lesions, will be the focus of this study. Proposed experiments are directed toward evaluation of a model for expressed mutations at recessive alleles, through quantification and analysis of intragenic versus multilocus lesions at homozygous, heterozygous and hemizygous gene targets. The spectrum of damage caused by the selected agents will be determined and the effects of repeated exposure to these mutagens on the frequency and characteristics of lesions which inactivate a homozygous gene will be analyzed. The model in this proposal postulates that multilocus lesions enhance the risk for mutation, cancer and other genetic diseases from a second mutational event. Accordingly, the goal of these investigations is to augment the understanding of factors which may govern the interaction between intragenic lesions and multilocus lesions.

隐性等位基因的突变被认为是一个致病因素癌症和其他遗传疾病的发展。电离辐射引起的突变往往影响多个基因位点。因此，辐射引起的损害很有可能“暴露”出来。预先存在的突变或通过产生多基因座缺失，细胞的表型后果的未来突变的隐性已成为半合子的等位基因。本提案探讨了一种假设，即一种因子将导致突变表达的概率在隐性等位基因是依赖于它的相对倾向，基因内（基因内的突变）和多位点（导致多个连续遗传基因座的缺失或修饰）损伤。四种药物，伽马射线，2-氨基-N6-羟基腺嘌呤（AHA），UVC 辐射，和4-（9-吖啶氨基）甲磺酰-间-茴香胺（mAMSA），预计会导致不同比例的基因内和多位点病变，将是本研究的重点。拟议的实验是针对评估隐性基因表达突变的模型，等位基因，通过定量和分析基因内与纯合、杂合和半合基因靶点的多位点病变。将确定所选制剂造成的损害范围，重复暴露于这些诱变剂对频率和病变的特点，其中一个纯合子基因将是分析了该建议中的模型假设多位点病变增加突变，癌症和其他遗传疾病的风险，第二次突变事件。因此，这些调查的目的是增加对可能支配相互作用的因素的理解，基因内病变和多位点病变之间的关系。