Urinary DNA Adductomics for the Assessment of Exposure to Cancer Risk Factors

用于评估癌症危险因素暴露情况的尿液 DNA 加合物组学

• 批准号: 10506391
• 负责人: Marcus Stanley Cooke
• 金额: $ 13.83万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-06 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10506391
• 关键词: Aging; Area; Cancer Detection; DNA; DNA Adduction; DNA Adducts; DNA Damage; Data Analyses; Degenerative Disorder; Deoxyribonucleosides; Development; Disease; Environmental Exposure; Evaluation; Exposure to; Generations; Genome; Health; Human; Individual; Knowledge; Malignant Neoplasms; Measures; Mentors; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Nature; Neurodegenerative Disorders; Nuclear; Parents; Pathogenesis; Play; Population; Preparation; Process; Public Health; Research; Risk; Risk Factors; Role; Route; Techniques; Testing; Training; Urine; adduct; cancer prevention; cancer risk; career; career development; disorder risk; environmental agent; experience; human disease; mitochondrial dysfunction; mitochondrial genome; nucleobase; repaired; urinary

PROJECT SUMMARY Exposure to environmental and endogenous agents, which can induce DNA damage to both the nuclear and mitochondrial genomes, represents 80-90% of the human risk of developing major diseases such as cancer, and degenerative diseases. While much of the research to date has been on nuclear DNA, it is becoming increasingly clear that damage to the mitochondrial genome, specifically, plays a critical role in the pathogenesis of a number of major human diseases, in particular, neurodegenerative diseases, together with aging. The emerging technique of DNA adductomics offers the potential to comprehensively assess the totality of adducts in the genome. We are the first to perform urinary DNA adductomics, which represents an important route to simply, and non-invasively, evaluate the totality of adducts in human populations. The presence of DNA adducts in urine is a consequence of repair of the nuclear and mitochondrial genomes, which results in the generation of modified nucleobases and 2’-deoxyribonucleosides. However, the relative contributions from the nuclear and mitochondrial genomes to urinary adduct levels is not clear, and cellular DNA adductomics has yet to be applied to discriminate between nuclear and mitochondrial DNA damage. We propose to use DNA adductomics to study the formation and repair of the spectra of adducts formed in the nuclear and mitochondrial genomes following exposure to key environmental agents of concern. This will determine their relative sensitivities to damage formation, whether there is preferential targeting of one genome, the likelihood of damage persistence, and potential contributions to urinary adduct levels. Such findings are integral to, and will enhance the results of, the parent R01. Advancing our knowledge in these areas will present pivotal opportunities for the diversity candidate to receive world-class mentoring, and training in a cutting-edge field, acquiring, as a result, expertise in both performing DNA adductomics, and the subsequent data analysis. The mentoring, training, and expertise acquired during the project will provide the candidate with the necessary career development experiences in preparation for an independent career in health-related research. Our hypothesis is that exogenous and endogenous cancer risk factors act, in part, through the formation of DNA adducts. Evaluation of these adducts informs on the nature and size of exposure, and, consequently, the disease risk. Application of DNA adductomics will facilitate testing this hypothesis, and ultimately, may highlight the nature of those environmental agents which target mitochondrial specifically, and are therefore, likely to have a preferential role in mitochondrial dysfunction and disease.

项目概要 暴露于环境和内源性物质，可能会导致核DNA损伤 和线粒体基因组，占人类患癌症等重大疾病风险的 80-90%， 虽然迄今为止大部分研究都是针对核 DNA，但它正在变得越来越重要。 越来越清楚的是，线粒体基因组的损伤在发病机制中发挥着关键作用 一些主要人类疾病，特别是神经退行性疾病以及衰老。 DNA 加合物组学的新兴技术提供了全面评估加合物总量的潜力 我们是第一个进行尿液 DNA 加合组学的人，这代表了一条重要的途径。 简单且非侵入性地评估人群中 DNA 加合物的总数。 尿液中的尿酸是细胞核和线粒体基因组修复的结果，从而导致产生 然而，修饰核碱基和 2'-脱氧核糖核苷的相对贡献。 线粒体基因组与尿加合物水平的关系尚不清楚，细胞DNA加合物组学尚未应用 区分核 DNA 损伤和线粒体 DNA 损伤。 我们建议使用DNA加合物组学来研究加合物光谱的形成和修复 暴露于关键环境因素后的核和线粒体基因组中。 确定它们对损伤形成的相对敏感性，是否优先靶向一个基因组， 损害持续的可能性以及对尿加合物水平的潜在贡献是。 母版 R01 的组成部分，并将增强母版 R01 的成果。 为多元化候选人提供接受世界一流指导和尖端培训的关键机会 因此，获得了执行 DNA 加合物组学和后续数据分析方面的专业知识。 项目期间获得的指导、培训和专业知识将为候选人提供必要的能力 为健康相关研究的独立职业做准备的职业发展经验。 我们的假设是，外源性和内源性癌症危险因素部分通过形成 DNA 加合物的评估可了解暴露的性质和大小，因此， DNA 加合组学的应用将有助于检验这一假设，并最终可能。 强调那些专门针对线粒体的环境剂的性质，因此， 可能在线粒体功能障碍和疾病中发挥优先作用。