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.

项目摘要 暴露于环境和内源性药物，这可能会诱导DNA损伤 线粒体基因组占患有主要疾病（例如癌症）的人类风险的80-90％，例如 和退化性疾病。尽管迄今为止的大部分研究都在核DNA上，但它正在变得 越来越清楚的是，对线粒体基因组的损害，特别是在发病机理中起着关键作用 许多主要的人类疾病，特别是神经退行性疾病，以及衰老。这 DNA加合体的新兴技术提供了全面评估加合物总数的潜力 在基因组中。我们是第一个执行尿液DNA加成学的人，这代表了一条重要的途径 简单而非侵入性地评估人类种群中的加合物的总体。 DNA加合物的存在 在尿液中是修复核和线粒体基因组的结果，这导致产生 修饰的核碱基和2'-脱氧核糖核苷。但是，核和 线粒体基因组对尿中加合物水平尚不清楚，并且尚未应用细胞DNA加合体。 区分核和线粒体DNA损伤。 我们建议使用DNA加合物学来研究形成的加合物光谱的形成和修复 在暴露于关键关注的关键环境药物后的核和线粒体基因组中。这会 确定它们对损伤形成的相对敏感性，是否有一个基因组的首选靶向， 损伤持久性的可能性以及对尿中加合物水平的潜在贡献。这样的发现是 与母体R01的结果不可或缺的组成部分。在这些领域中促进我们的知识将提供 多样性候选人接受世界一流的心理和培训的关键机会 因此，在执行DNA添加剂和随后的数据分析方面，获得了专家。 项目期间获得的心理，培训和专业知识将为候选人提供必要的 职业发展经验，为与健康有关的研究做准备独立职业。 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作用 DNA加合物。评估这些加合物有关暴露性质和大小的信息，因此 疾病风险。 DNA加成学的应用将有助于检验这一假设，最终可能 强调特定针对线粒体的环境药物的性质，因此是 可能在线粒体功能障碍和疾病中具有首选作用。