SOMATIC MUTATIONS IN CHILDREN

儿童体细胞突变

• 批准号: 2472538
• 负责人: BARRY Alan FINETTE
• 金额: $ 9.84万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-08 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2472538
• 关键词: DNA damage; age difference; child (0-11); clinical research; environmental toxicology; gene frequency; gene mutation; genetic disorder; genetic mapping; human genetic material tag; human population genetics; human subject; human tissue; hypoxanthine phosphoribosyltransferase; molecular pathology; mutagens; newborn human (0-6 weeks); passive smoking; tumor suppressor genes

DESCRIPTION: (Adapted from the Investigator's Abstract) The major objectives of this proposal are to study the mechanism and biological consequences of age-specific in vivo somatic genetic events in children. The hypothesis is that somatic mutations arising during fetal development and early childhood are more reflective of genetic changes with disease potential and environmental exposures than are mutations arising later in life. This hypothesis will be tested by three specific aims: 1) To complete studies comparing somatic mutational events that occur during fetal development and childhood with those that occur in adults; 2) To compare the prevalence of "illegitimate" V(D)J recombinase mediated mutations in a reporter gene, hprt, and a gene of disease significance, p53, and, 3) To determine the frequencies, spectra, and persistence of individual hprt mutations in newborns and children exposed to known genotoxic agents, and to correlate these molecular events with subsequent diseases. The frequency of somatic mutational events will be determined by the hprt T-cell cloning assay. Genetic analysis of hprt and p53 mutations will be performed using several methods: multiplex PCR, RT-PCR, IPCR, Southern blotting and DNA sequencing. These methods have previously been used for detailed molecular characterization of mutational events for inferences regarding genetic mechanisms and genotoxic monitoring. The research plan is designed to study the association/prediction between somatic mutations and specific diseases by determining: 1) whether the background frequency and mutational spectra of in vivo somatic mutations at the hprt locus in children are age-specific, reflecting unique biologic differences at the molecular level when compared to adults. These studies will provide information on the age dependent nature of mutational events in children and provide the database required for comparison studies in children with specific clinical diseases and genotoxic exposures; 2) if V(D)J recombinase mediated rearrangements captured at the hprt locus occur in a clinically specific tumor suppressor gene, p53. These studies may provide insights into the clinical effects of spontaneous age-specific mutagenic mechanism occurring during early human development; and 3) if somatic mutations induced by environmental exposures (cigarette smoke and chemotherapy) in children are predictive of subsequent somatic disease. The testing of potential mutagenic exposures in children is important since somatic mutational events during this period could have significant clinical consequences as well as long term effects as an adult. Results obtained from these studies will provide fundamental insights regarding the clinical relevance of age-specific, spontaneous and environmentally induced somatic mutations in children.

描述：（根据调查员的摘要改编） 该提案的目标是研究机制和生物学 儿童体内体细胞遗传事件的年龄特异性后果。 假设是在胎儿发育过程中产生的体细胞突变 幼儿期更反映疾病的遗传变化 潜力和环境暴露于以后产生的突变 生活。 该假设将通过三个特定目的进行检验：1） 比较胎儿期间发生的体细胞突变事件的完整研究 与成年人发生的人的发展和童年； 2）比较 “非法” V（d）J重组酶介导的突变的患病率 记者基因，hprt和疾病意义的基因，p53，3） 确定单个HPRT的频率，光谱和持久性 新生儿和儿童的突变暴露于已知的遗传毒性剂，以及 将这些分子事件与随后的疾病相关联。 频率 体突变事件将由HPRT T细胞克隆确定 测定。 将使用HPRT和p53突变的遗传分析 多种方法：多重PCR，RT-PCR，IPCR，Southern印迹和DNA 测序。 这些方法以前已用于详细的分子 突变事件的表征是针对遗传的推论 机理和遗传毒性监测。 该研究计划旨在研究 通过确定的体细胞突变和特定疾病：1）是否是否 体内体细胞突变的背景频率和突变光谱 儿童的HPRT基因座是特定年龄的，反映了独特的生物学 与成人相比，分子水平的差异。 这些研究 将提供有关突变事件年龄依赖性性质的信息 儿童并提供比较研究所需的数据库 患有特定临床疾病和遗传毒性暴露的儿童； 2）如果 V（d）J重组酶介导的重排在HPRT基因座发生 在临床特异性肿瘤抑制基因中，p53。 这些研究可能 提供有关自发年龄特异性的临床影响的见解 在人类早期发展期间发生的诱变机制； 3）如果 环境暴露引起的体细胞突变（香烟烟雾和 儿童的化学疗法可以预测随后的体细胞疾病。 这 对儿童的潜在诱变暴露的测试很重要，因为 在此期间的体细胞突变事件可能具有明显的临床 后果以及成年人的长期影响。 获得的结果 从这些研究中将提供有关临床的基本见解 特定年龄，自发和环境引起的体细胞的相关性 儿童的突变。