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

项目摘要 在分子水平上表征人类群体的先进技术已经为 个性化的治疗策略，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高危人群。 给定疾病，部分基于已定义的功能缺陷(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初级预防干预，以改变疾病易感性。脱氧核糖核酸 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。 在精准预防的脉络中，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，因为这样的“携带者”将增加与暴露相关的病理风险。许多. 这些癌症或疾病特异的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编码序列的变化或细胞内的调节 已知可调节线粒体功能和DNA修复的代谢物，如NAD代谢物 路径，正如我们所展示的。然而，有许多缺陷只能通过直接分析才能检测到 基本基因组的完整性和细胞修复基因组能力的直接衡量 外源遗传毒素。回应RFA-ES-17-006：将基因组完整性检测扩展到人群 研究，我们提出的目标将提高我们检查人类基因组损伤和 基因组修复能力，揭示个体之间在离散时间点和内部的差异 五年期间的个人。基础水平前哨PBMCs的基因组完整性和DNA修复能力 接下来环境基因毒素的挑战将使用新开发的下一代 高通量DNA损伤检测平台。这个新平台的进步现在已经打开了大门 用于大规模人群队列的分析，为人类生物监测向前迈进了一大步 机遇。这些研究将首次提供一种纵向测量基因组完整性的方法 以社区为基础的队列，主要是非裔美国人后裔，并将提高我们审问人类的能力 基因组损伤和基因组修复能力的种群。

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.