Measuring genomic DNA damage and DNA repair capacity in longitudinal population samples - a step towards precision prevention

测量纵向群体样本中的基因组 DNA 损伤和 DNA 修复能力——迈向精准预防的一步

• 批准号: 10817292
• 负责人: Robert W Sobol
• 金额: $ 52.99万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10817292
• 关键词: Measuring; genomic; DNA; damage; repair

Project Summary Advanced technologies for characterizing human populations at the molecular level have set the stage for personalized therapeutic strategies that may also provide an opportunity for personalized prevention. Personalized or ‘Precision Prevention’ would therefore provide an opportunity to identify those at high risk for a given disease, in part based on defined functional defects (such as a defect in genome maintenance), so as to advise for targeted screening and primary prevention interventions early in life to alter disease susceptibility. DNA repair pathways maintain the integrity of the genome and thereby help prevent the onset of cancer, disease and aging phenotypes and play a significant role in the cellular and organismal response to environmental exposures. In the vein of precision prevention, identifying those with functional defects in the maintenance of genome integrity would be a first step as such ‘carriers’ would have an increased risk of exposure-associated pathologies. Many of these cancer- or disease-specific DNA repair defects can be detected using current "omics" technologies such as evaluating changes in mRNA expression, alterations in the DNA coding sequence or modulations in cellular metabolites such as NAD+ metabolites known to regulate mitochondrial function and regulate DNA repair pathways, as we have shown. However, there are many defects that can only be detected from a direct analysis of basal genome integrity and a direct measure of the cellular capacity to repair the genome in response to exogenous genotoxins. In response to RFA-ES-17-006: Expanding Genome Integrity Assays to Population Studies, we propose Aims that will advance our capacity to examine human populations for genome damage and genome repair capacity, illuminating variations between individuals at discrete time-points as well as within individuals across a five-year period. Genome integrity and DNA repair capacity in sentinel PBMCs at basal level and following challenge by environmental genotoxins will be evaluated using a newly developed next-generation high-throughput DNA damage detection platform. The advances of this new platform have now opened the door for the analysis of large-scale population cohorts, providing a huge step forward in human biomonitoring opportunities. These studies will provide the first look at a longitudinal measure of genome integrity in a community-based cohort of mostly African American descent and will advance our capacity to interrogate human populations for genome damage and genome repair capacity.

项目概要 在分子水平上表征人类群体的先进技术为 个性化治疗策略也可能为个性化预防提供机会。 因此，个性化或“精准预防”将提供一个机会来识别那些高风险人群。 给定疾病，部分基于定义的功能缺陷（例如基因组维护缺陷），以便 建议在生命早期进行有针对性的筛查和一级预防干预，以改变疾病易感性。 修复途径维持基因组的完整性，从而有助于预防癌症、疾病和 衰老表型，并在细胞和生物对环境暴露的反应中发挥重要作用。 本着精准预防的精神，识别那些在维持基因组完整性方面存在功能缺陷的人 这将是第一步，因为此类“携带者”会增加许多与暴露相关的病症的风险。 这些癌症或疾病特异性 DNA 修复缺陷可以使用当前的“组学”技术来检测，例如 评估 mRNA 表达的变化、DNA 编码序列的改变或细胞的调节 已知可调节线粒体功能和 DNA 修复的代谢物，例如 NAD+ 代谢物 然而，正如我们所表明的，有许多缺陷只能通过直接分析来检测。 基础基因组完整性和细胞修复基因组能力的直接测量 响应 RFA-ES-17-006：将基因组完整性测定扩展到人群。 研究中，我们提出的目标将提高我们检查人类基因组损伤的能力，并 基因组修复能力，阐明个体在离散时间点以及内部的差异 五年期间个体前哨 PBMC 基础水平的基因组完整性和 DNA 修复能力。 并将使用新开发的下一代技术来评估环境基因毒素的挑战 高通量 DNA 损伤检测平台的进步现已打开大门。 用于分析大规模人群，为人类生物监测迈出了一大步 这些研究将首次对基因组完整性进行纵向测量。 以社区为基础的队列，主要由非裔美国人后裔组成，将提高我们审问人类的能力 群体的基因组损伤和基因组修复能力。