Quantitative Adductomics Approaches for Assessing the Occurrence and Repair of DNA Adducts

用于评估 DNA 加合物的发生和修复的定量加合物组学方法

基本信息

批准号：
9389996
负责人：
Yinsheng Wang
金额：
$ 35.46万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-16 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9389996
关键词：
Acetylcysteine Affect Cancer Biology Coupled Cultured Cells Cytosine DNA DNA Adduction DNA Adducts DNA Damage DNA Repair DNA Repair Enzymes DNA biosynthesis DNA lesion DNA photoproducts Development Dilution Techniques Environmental Exposure Enzymes Epigenetic Process Etiology Excision Exposure to Family Gene Expression Regulation Genetic Fingerprintings Genetic Transcription Human Induced Mutation Lead Left Lipid Peroxidation Lipid Peroxides Malignant Neoplasms Mammalian Cell Measurement Mediating Metabolism Methods Methylation Modification Molecular Mus Mutagens Outcome Play Positioning Attribute Prevention Preventive Process Publishing Reactive Oxygen Species Research Risk Factors Role Skin Skin Cancer Skin Tissue Source Specimen Sunscreen Effect Sunscreening Agents Therapeutic Tissues Topical application UV induced Ultraviolet Rays Veins analytical method animal tissue base cancer chemoprevention cancer initiation cancer prevention cancer risk cancer therapy epigenetic regulation genetic information genetic manipulation human disease melanoma methyl group novel oxidation repaired skin cancer prevention stable isotope sunlight-induced ultraviolet irradiation

项目摘要

The long-term objective of this application is to discover and characterize the adductomics-based exposure indicators for the assessment of cancer risks and for cancer prevention. Endogenous metabolism and environmental exposure can both give rise to DNA damage. If left unrepaired, the resulting DNA adducts may compromise the flow of genetic information by inhibiting DNA replication and transcription and inducing mutations in these processes. In addition, the ultimate levels of DNA adducts accumulated in mammalian cells and tissues are the result of a dynamic interplay between DNA adduct formation and repair. Thus, it is important to establish a robust analytical method for the quantitative measurement of a broad range of DNA adducts that are implicated in the etiology for the development of cancer and other human diseases. Such a method will also enable the characterizations of the repair of DNA adducts, which may lead to the discovery of risk factors for cancer initiation and development, and guide the development of approaches for effective cancer chemoprevention. In this application, we propose to establish a DNA adductomic approach by employing and expanding our recently established LC-MS/MS methods for the quantification of DNA adducts induced by reactive oxygen species, DNA photoproducts arising from UV irradiation, and DNA epigenetic marks, which represent a substantial subset of the DNA adductome. We will then employ this adductomic approach for investigating the modulations of the levels of oxidatively induced DNA lesions and DNA epigenetic marks by DNA repair enzymes, for assessing the implications of DNA adducts in the etiology of melanoma development, and for evaluating the effects of sunscreen components on altering UV-induced DNA adduct formation. The proposed research will have a long- lasting impact on the fields of DNA damage repair and cancer biology by offering a facile adductomic platform for characterizing the risk factors and therapeutic/preventive approaches that modulate the formation and removal of DNA adducts.

该应用的长期目标是发现并表征基于加合组学的暴露癌症风险评估和癌症预防的指标。内源性代谢和环境暴露都会引起 DNA 损伤。如果不修复，产生的 DNA 加合物可能通过抑制 DNA 复制和转录以及诱导突变来损害遗传信息的流动在这些过程中。此外，哺乳动物细胞和组织中积累的 DNA 加合物的最终水平是 DNA 加合物形成和修复之间动态相互作用的结果。因此，重要的是建立一种稳健的分析方法，用于定量测量各种相关的 DNA 加合物癌症和其他人类疾病发展的病因学。这种方法也将使 DNA 加合物修复的特征，可能导致癌症发生的危险因素的发现和开发，并指导有效癌症化学预防方法的开发。在这个应用程序，我们建议通过采用和扩展我们最近的研究来建立 DNA 加合体方法建立了 LC-MS/MS 方法，用于定量由活性氧、DNA 诱导的 DNA 加合物紫外线照射产生的光产物和 DNA 表观遗传标记，代表了 DNA 的一个重要子集 DNA加合物。然后我们将采用这种内合方法来研究 DNA 修复酶氧化诱导的 DNA 损伤和 DNA 表观遗传标记的水平，用于评估 DNA 加合物在黑色素瘤发展病因学中的意义，以及评估防晒成分改变紫外线诱导的 DNA 加合物形成。拟议的研究将具有长期通过提供简便的内合体平台对 DNA 损伤修复和癌症生物学领域产生持久影响用于描述调节形成和形成的风险因素和治疗/预防方法去除DNA加合物。