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：
7575486
负责人：
PETER J. STAMBROOK
金额：
$ 47.78万
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 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7575486
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 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 public health relevance 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. PUBLIC HEALTH RELEVANCE: This project seeks to define genetic changes in a signaling pathway that contribute to susceptibility to breast cancer following environmental exposure. The program utilizes genetically modified mice that harbor variant genes that mimic gene variants found in human populations and that contribute to cancer. We will also ask whether such variants are over-represented in women who have had defined radiation exposure and now have developed breast cancer.

描述（由申请人提供）：当DNA损坏时，细胞会启动信号级联反应，从而导致细胞周期检查点停滞并修复受损细胞的损坏或消除。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。该途径中有助于基因组稳定性的几个基因具有易于疾病的变异等位基因。这项研究的重点是先前辐射暴露的小鼠模型和人类同类。假设是，DNA损伤响应途径内的变体等位基因可能是良性或产生适度的风险，但暴露后它们的不良反应更加深刻地表现出来。一种小鼠模型模仿易于乳腺癌的CHEK2变体。该等位基因的纯合子和杂合的小鼠将根据其固有的DNA修复能力，以及它们是否更容易受到疾病和诱变，尤其是在暴露前后的有丝分裂重组和LOH。在PLK3，BRCA2和CDC25A中具有缺陷或变体的其他小鼠模型已经制造或正在建设中。将产生由人类研究结果决定的其他模型。人类研究将以两种独特的队列利用先前的环境暴露，以辐射的形式，后来患有乳腺癌。对照人群由经历过类似但未发生疾病的人组成。第一批队列由儿童接受霍奇金疾病的辐射治疗的患者组成，多年后患有乳腺癌。第二个队列涉及在弗纳德铀加工厂附近工作或居住的患者，并患有乳腺癌。具体而言，我们将询问DNA损伤响应途径中的变体等位基因在受影响的人群中单独或合并中是否代表过多。当确定这些等位基因时，将在鼠标中对其进行建模和测试。最后，受影响个体的细胞将测试基因组不稳定性。简而言之，该项目评估了两个独特的裸露人群中途径中的等位基因变体，并模拟了小鼠的基因型。由于该途径对氧化应激引起的损害做出反应，并且这些等位基因可能对氧化应激敏感，因此将测试抗氧化剂在携带变异等位基因的小鼠模型中预防疾病的能力。公共卫生相关性：该项目旨在定义信号传导途径中的遗传变化，这在环境暴露后导致对乳腺癌的易感性。该程序利用了携带模仿人群中发现的基因变异的变异基因的转基因小鼠，并有助于癌症。我们还将询问此类变体是否在定义辐射暴露并现在已经患上乳腺癌的女性中代表过过多。