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Environmental exposure: Susceptibility alleles in a DNA damage response pathway

环境暴露：DNA 损伤反应途径中的易感性等位基因

基本信息

批准号：
8391760
负责人：
PETER J. STAMBROOK
金额：
$ 47.92万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8391760
关键词：
Adverse effects Affect Alleles Antioxidants BRCA1 gene BRCA2 gene Benign CHEK2 gene Cell Cycle Cell Cycle Checkpoint Cells Characteristics Child DNA DNA Damage DNA Double Strand Break DNA Repair Data Disease Disease Progression Disease susceptibility Dose Environmental Exposure Exposure to Genes Genetic Variation Genome Stability Genomic Instability Genotype Health Hodgkin Disease Human Hypersensitivity Individual Ionizing radiation Knockout Mice Life Low Dose Radiation Malignant Neoplasms Measurable Measures Mediating Mitotic Recombination Modeling Mus Mutagenesis Mutation Neoplasm Metastasis Outcome Oxidative Stress PLK3 gene Pathway interactions Patients Penetrance Phenotype Phosphoric Monoester Hydrolases Phosphotransferases Plants Population Population Control Predisposition Process Proteins Radiation Recording of previous events Resistance Resources Risk Signal Pathway Signal Transduction Testing Uranium Variant Woman Work ataxia telangiectasia mutated protein cell injury chemotherapy cigarette smoking cohort disorder risk experience human PLK1 protein human disease malignant breast neoplasm member mouse model prevent programs repaired response tumor

项目摘要

DESCRIPTION (provided by applicant): When DNA is damaged, cells initiate a signaling cascade that results in cell cycle checkpoint arrest and repair of the damage or elimination of the damaged cells. One pathway that is activated following a double strand DNA break involves ATM and other DNA damage response proteins including CHEK2, Cdc25A, Plk3, BRCA1 and BRCA2. Several genes in this pathway, which contribute to genomic stability, have variant alleles that predispose to disease. This study focuses on mouse models and human cohorts who have had prior radiation exposure. The hypothesis is that variant alleles within the DNA damage response pathway may be benign or produce a modest risk, but that their adverse effects manifest more profoundly after exposure. One mouse model mimicks a CHEK2 variant that predisposes to breast cancer. Mice homozygous and heterozygous for this allele will be assessed for their inherent DNA repair capacity and whether they are more susceptible to disease and to mutagenesis, particularly to mitotic recombination and LOH before and after exposure. Other mouse models with deficiencies or variants in Plk3, BRCA2, and Cdc25A, have been made or are under construction. Additional models, dictated by the outcome of the human studies, will be produced. The human studies will utilize two unique cohorts with prior environmental exposure in the form of radiation who subsequently developed breast cancer. A control population consists of individuals who have experienced similar exposure but have not developed disease. The first cohort consists of patients who as children were treated with radiation for Hodgkin disease and years later developed breast cancer. The second cohort involves patients who worked at or lived in close proximity to the Fernald Uranium processing plant and have developed breast cancer. Specifically, we will ask whether variant alleles within the DNA damage response pathway, singly or in combination, are overrepresented in the affected population. When such alleles are identified, they will be modeled and tested in the mouse. Lastly, cells from affected individuals will be tested for genomic instability. In brief, this project assesses allelic variants within a pathway in two unique exposed populations and models the genotypes in mice. Since this pathway responds to damage induced by oxidative stress and since these alleles may sensitize to oxidative stress, the capacity of antioxidants to prevent disease in mouse models carrying variant alleles will be tested.

描述（由申请人提供）：当DNA受损时，细胞启动信号级联，导致细胞周期检查点停滞和损伤修复或受损细胞消除。在双链DNA断裂后被激活的一种途径涉及ATM和其他DNA损伤反应蛋白，包括CHEK2、Cdc25A、Plk3、BRCA1和BRCA2。该途径中的几个基因有助于基因组稳定性，具有易患疾病的变异等位基因。这项研究的重点是小鼠模型和人类队列谁有过以前的辐射暴露。假设是DNA损伤反应途径中的变异等位基因可能是良性的或产生适度的风险，但它们的不良影响在暴露后表现得更深刻。一种小鼠模型模拟了易患乳腺癌的CHEK 2变体。将评估该等位基因的纯合和杂合小鼠的固有DNA修复能力，以及它们是否更易患病和诱变，特别是暴露前后的有丝分裂重组和洛缺失。Plk3、BRCA2和Cdc25A缺陷或变异的其他小鼠模型已经建立或正在构建中。根据人体研究的结果，将制作更多的模型。人类研究将利用两个独特的队列，这些队列先前以辐射形式暴露于环境，随后患上乳腺癌。对照人群由经历过类似暴露但未发生疾病的个体组成。第一个队列由儿童时期接受霍奇金病放射治疗的患者组成，多年后发展为乳腺癌。第二个队列涉及在Fernald铀加工厂工作或居住在附近并患有乳腺癌的患者。具体而言，我们将询问DNA损伤反应途径中的变异等位基因，单独或组合，是否在受影响的人群中过度表达。当鉴定出这样的等位基因时，将在小鼠中对其进行建模和测试。最后，将对受影响个体的细胞进行基因组不稳定性测试。简而言之，该项目评估了两个独特暴露人群中一个途径内的等位基因变体，并模拟了小鼠的基因型。由于该途径响应氧化应激诱导的损伤，并且由于这些等位基因可能对氧化应激敏感，因此将测试抗氧化剂预防携带变体等位基因的小鼠模型中的疾病的能力。