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

项目摘要 暴露于环境和内源性因子，可诱导细胞核和细胞核的DNA损伤， 和线粒体基因组，代表了80-90%的人类患癌症等重大疾病的风险， 和退行性疾病。虽然迄今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， 一些主要的人类疾病，特别是神经退行性疾病，以及衰老。的 一种新兴的DNA加合物组学技术提供了全面评估加合物总体的可能性 在基因组中。我们是第一个进行尿DNA内收管切开术的人，这是一条重要的途径， 简单地，非侵入性地，评估人群中加合物的总量。DNA加合物的存在 尿中的蛋白质是细胞核和线粒体基因组修复的结果，这导致产生 修饰的核碱基和2 ′-脱氧核糖核苷。然而，核武器和 线粒体基因组与尿加合物水平的关系尚不清楚，细胞DNA加合物组学尚未得到应用 区分核和线粒体DNA损伤。 我们建议使用DNA加合物组学来研究所形成的加合物的光谱的形成和修复 在暴露于令人关切的关键环境因子后，细胞核和线粒体基因组中的基因突变。这将 确定它们对损伤形成的相对敏感性，是否存在一个基因组的优先靶向， 损害持续性的可能性，以及对尿加合物水平的潜在贡献。这些发现 集成到父R 01中，并将增强父R 01的结果。推进我们在这些领域的知识将提出 多元化候选人获得世界级指导和尖端培训的关键机会 因此，获得了执行DNA内收切开术和后续数据分析的专业知识。 在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 职业发展经验，为独立从事健康相关研究做准备。 我们的假设是，外源性和内源性癌症风险因素的作用，部分是通过形成 DNA加合物对这些加合物的评价可告知暴露的性质和大小，因此， 疾病风险。DNA内收体学的应用将有助于验证这一假设，并最终可能 强调了那些专门针对线粒体的环境因子的性质，因此， 可能在线粒体功能障碍和疾病中具有优先作用。

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.