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.

项目总结 暴露在环境和内源性因素中，这可能会对核造成DNA损伤 和线粒体基因组，代表了人类患癌症等重大疾病风险的80%-90%， 和退化性疾病。虽然到目前为止的大部分研究都是关于核DNA的，但它正在成为 越来越清楚的是，线粒体基因组的损伤在发病机制中起着关键作用 人类的一些重大疾病，特别是神经退行性疾病，以及衰老。这个 新兴的DNA加合物技术为全面评估加合物的整体提供了可能性 在基因组中。我们是第一个进行尿液DNA内收手术的人，这是一条重要的途径 简单地、非侵入性地评估人类人口中加合物的总数。DNA加合物的存在 尿液是核和线粒体基因组修复的结果，这导致产生 修饰的碱基和2‘-脱氧核糖核苷。然而，核能和核电的相对贡献 线粒体基因组到尿加合物的水平尚不清楚，细胞DNA加合物还有待应用 来区分核和线粒体DNA损伤。 我们建议使用DNA加合物来研究形成的加合物的光谱的形成和修复 在暴露于令人关注的关键环境制剂后，核和线粒体基因组中的突变。这将是 确定它们对损伤形成的相对敏感性，是否存在优先靶向一个基因组， 损伤持续的可能性，以及对尿加合物水平的潜在影响。这些发现是 这是母公司R01的组成部分，并将增强其结果。提升我们在这些领域的知识将呈现 多元化候选人获得世界级指导和前沿培训的关键机会 因此，他获得了执行DNA加合物提取和后续数据分析方面的专业知识。 在项目期间获得的指导、培训和专业知识将为应聘者提供必要的 职业发展经历，为健康相关研究的独立职业生涯做准备。 我们的假设是，外源性和内源性癌症风险因素部分地通过形成 DNA加合物。对这些加合物的评估有助于了解暴露的性质和大小，因此， 疾病风险。DNA加合物的应用将有助于检验这一假说，并最终可能 突出那些专门针对线粒体的环境制剂的性质，因此， 可能在线粒体功能障碍和疾病中起优先作用。