Development of a DNA Adductome Database

DNA 加合物数据库的开发

• 批准号: 10023262
• 负责人: Scott J Walmsley
• 金额: $ 7.57万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-24 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023262
• 关键词: Biological; Biological Assay; Biological Monitoring; Cell division; Chemical Agents; Chemicals; Cohort Studies; Collaborations; Collection; Communities; Computer software; Consensus; Custom; DNA; DNA Adduction; DNA Adducts; DNA Damage; DNA Databases; DNA Library; DNA Modification Process; DNA analysis; Data; Databases; Deoxyribonucleosides; Development; Diet; Disease; Disease Outcome; Eating; Environment; Evaluation; Exposure to; Genome; Goals; Hazardous Chemicals; Heterogeneity; Human; Human Genome; Hybrids; Individual; Induced Mutation; International; Ions; Laboratories; Lead; Letters; Libraries; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Meat; Metadata; Mutagens; Neurodegenerative Disorders; North America; Oxidative Stress; Pathogenesis; Pharmaceutical Preparations; Play; Prevention; Process; Proteomics; Public Health; RNA; Reactive Oxygen Species; Research; Resolution; Ribonucleosides; Risk Assessment; Role; Scanning; Scientist; Smoking; Source; Structure; Techniques; Technology; Therapeutic; Toxic Environmental Substances; Urine; Vendor; adduct; base; computerized data processing; cooking; data mining; disorder prevention; disorder risk; environmental mutagens; exposed human population; human disease; improved; instrumentation; lifestyle factors; mass spectrometer; member; metabolomics; novel; nucleobase; open source; programs; repository; time of flight mass spectrometry; tool; toxicant

Abstract/Summary The frequent exposure to chemicals in the environment, diet, endogenous electrophiles, and reactive oxygen species leads to the chemical modification of DNA, resulting in the formation of DNA adducts. Some DNA adducts can induce mutations during cell division, and when occurring in critical regions of the genome, can lead to disease, including cancer. The targeted analysis of DNA adducts over the past 30 years has revealed that the human genome contains a wide array of DNA adducts, many of which are attributed to life-style factors, such as smoking, the eating of well-done cooked meats, or through oxidative stress. With the advancement of high- resolution mass spectrometry instrumentation and new scanning technologies, untargeted “omics” approaches have become available to simultaneously screen for multiple DNA adducts in a single assay. However, the development of this emerging field of DNA adductomics is hindered by the lack of a publicly available mass spectral database for DNA adduct identification and characterization. Our goal is to curate and develop a comprehensive database of DNA adducts standards, obtained from international collaborators and commercial sources. The database will be freely available and searchable by the public. In Aim 1, we will establish an extensive collection of DNA adduct standards, via our domestic and international collaborations and commercial sources. We will prioritize 2'-deoxyribonucleoside and nucleobase adducts formed from environmental and dietary toxicants, and endogenous electrophiles, but also acquire modified RNA adduct standards from the emerging field of RNA adductomics. We will collect high-resolution mass spectra of these adduct standards via two commonly used mass spectrometer platforms, Orbitrap MS and Q-TOF MS. Spectra of MS, MS2 and MS3 will be acquired at various collision energies to characterize adduct structures. In Aim 2, we will develop an automated workflow to process MS2 and MS3 data to rapidly curate the spectra of individual DNA adducts with annotation, which can be submitted to a repository using commonly available software. The resulting spectral library will be freely available for download in common formats for characterization of DNA adductome profiles by members of the research community. The successful establishment of a validated DNA adduct mass spectral database in a searchable, reference library is critical for the comprehensive analysis of DNA adductome profiles from cellular DNA, urine, and other biological matrices. This database will facilitate the usage of DNA adductomics in human cohort studies and advance our understanding of the relationships between external and internal exposures and disease risk.

摘要/摘要 经常暴露于环境中的化学物质，饮食，内源性电力和活性氧气 物种导致DNA的化学修饰，从而形成DNA加合物。一些DNA 加合物可以在细胞分裂期间诱导突变，并且在基因组的临界区域发生时，可以引导 疾病，包括癌症。在过去30年中，对DNA加合物的有针对性分析表明 人基因组包含多种DNA加合物，其中许多归因于生活方式的因素，例如 吸烟，煮熟的煮熟的肉或通过氧化压力。随着高级的发展 分辨率质谱仪器和新的扫描技术，不受靶向的“ OMICS”方法 可以同时筛选单个测定中的多个DNA加合物。但是， 缺乏公开可用的质量，阻碍了这种新兴DNA加成学领域的发展 用于DNA加合物识别和表征的光谱数据库。我们的目标是策划和发展 从国际合作者和商业广告获得的DNA加合物标准的综合数据库 来源。该数据库将由公众免费提供并可以搜索。 在AIM 1中，我们将通过我们的国内和国际建立广泛的DNA加合物标准集合 合作和商业资料。我们将优先考虑2'-脱氧核糖核苷和核碱化合物 由环境和饮食有毒物质以及内源性电力组成，但也获得了改良的RNA RNA加合体的新兴领域的加合标准标准。我们将收集高分辨率的质谱 通过两个常用的质谱仪平台Orbitrap MS和Q-TOF MS，这些加合物标准标准。 MS，MS2和MS3的光谱将在各种碰撞能量中获取，以表征加合物结构。 在AIM 2中，我们将开发一个自动化工作流以处理MS2和MS3数据以迅速策划的光谱 带有注释的单个DNA加合物，可以使用常用 软件。由此产生的光谱库将免费下载以通用格式 研究界成员对DNA的添加曲线表征。 在可搜索的参考中成功建立了经过验证的DNA加合物质谱数据库 库对于对细胞DNA，尿液和其他的DNA添加体谱的全面分析至关重要 生物矩阵。该数据库将促进人类队列研究中DNA加合物学的使用和 促进我们对外部和内部暴露与疾病风险之间关系的理解。