A Targeted DNA Adductomics Approach for Analyzing > 100 DNA Adducts

用于分析 > 100 个 DNA 加合物的靶向 DNA 加合物组学方法

基本信息

批准号：
10371133
负责人：
Yinsheng Wang
金额：
$ 34.99万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10371133
关键词：
Acute Air Air Pollution Alkylating Agents Biochemical Genetics Biological Biological Assay Biological Markers Cell Respiration Chemicals Communities DNA DNA Adduction DNA Adducts DNA Damage DNA Repair DNA Repair Gene DNA analysis DNA biosynthesis DNA lesion Deoxyribonucleosides Deoxyribose Development Environmental Exposure Environmental Pollutants Enzymes Exposure to Genetic Transcription Grant Health Human Individual Ions Knowledge Laboratories Libraries Liquid Chromatography Mass Spectrum Analysis Measurement Metabolism Methods Monitor Mus Mutagens Outcome Oxidative Stress Oxygenases Particulate Matter Peptides Protein Analysis Proteomics Reaction Research Risk Running Sampling Schedule Signal Transduction Source Structure of parenchyma of lung Time Tissues alpha ketoglutarate analytical method crosslink experience exposed human population fine particles genetic approach genetic information genetic manipulation genotoxicity high throughput analysis improved insight interest novel public health relevance repaired tandem mass spectrometry

项目摘要

ABSTRACT Endogenous metabolism and environmental exposure can give rise to DNA adduct formation. Robust measurement of the levels of DNA adducts can offer important knowledge for understanding the mechanisms of DNA repair and allow for assessment of human exposure to genotoxic chemicals. We reason that a scheduled selected-reaction monitoring (SRM) method for DNA adduct analysis will facilitate high-throughput analysis of the DNA adductome. The long-term objective of this application is to develop a targeted DNA adductomic assay for assessing quantitatively the DNA adducts induced by various endogenous and exogenous sources of DNA damaging agents, and to employ the method for monitoring human exposure to complicated environmental pollutants and for investigating DNA repair. The proposed research is organized into three Specific Aims. In Aim #1, we will establish an SRM library for targeted quantitative measurement of the DNA adductome. In Aim 2, we will profile comprehensively the DNA adductome in lung tissues of mice exposed to particulate matter air pollution. In Aim 3, we will assess the oxidative metabolism and repair of alkylated DNA lesions by Fe2+- and 2- oxoglutarate-dependent oxygenases. The outcome of the proposed research will provide the scientific community with a high-throughput platform that allows for monitoring the DNA adductome and will afford novel insights about the repair of alkylated DNA lesions.

抽象的内源代谢和环境暴露会导致DNA加合物的形成。强壮的 DNA加合物水平的测量可以提供重要的知识，以了解 DNA修复并允许评估人类对遗传毒性化学物质的暴露。我们认为是计划的用于DNA加合分析的选定反应监测方法（SRM）方法将有助于高通量分析 DNA加合物。该应用的长期目的是开发靶向的DNA加合体测定用于定量评估由DNA的各种内源和外源性来源诱导的DNA加合物损害代理，并采用监测人类暴露于复杂环境的方法污染物和研究DNA修复。拟议的研究分为三个特定目标。目标＃1，我们将建立一个SRM库，用于针对DNA加合体的靶向定量测量。在AIM 2中，我们将全面介绍暴露于颗粒物空气的小鼠的肺组织中的DNA加合体污染。在AIM 3中，我们将评估Fe2+ - 和2-的氧化代谢和烷基化DNA病变的修复氧气依赖性氧酶。拟议研究的结果将提供科学具有高通量平台的社区，可以监视DNA加合物，并负担得起新颖关于修复烷基化DNA病变的见解。