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Mitochondrial Metabolic Reprogramming and DNA Damage in Arsenic Carcinogenesis

砷致癌过程中的线粒体代谢重编程和 DNA 损伤

基本信息

批准号：
9090111
负责人：
Teresa Whei-Mei Fan
金额：
$ 22.47万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9090111
关键词：
Acetylcysteine Address Adopted Arsenic Arsenites Biochemical Biochemical Pathway Biological Assay Biological Markers Biological Models Cancer Patient Cells Citric Acid Cycle Complex Coupled DNA DNA Damage DNA Repair Data Data Correlations Dependence Development Electron Transport Environmental Carcinogens Enzymes Epidemiologic Studies Epigenetic Process Epithelial Cells Equilibrium Etiology Event Fumarate Hydratase Future Gene Expression Gene Mutation Generations Genes Genetic Genomic DNA Genomics Genus Hippocampus Glucose Glutamine Goals Health Homeostasis Human In Vitro Kidney Knowledge Lead Lesion Link Literature Lung Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mammalian Cell Maps Measures Mediating Metabolic Mitochondria Mitochondrial DNA Modeling Molecular Mus Mutation Nuclear Oxidation-Reduction Oxidative Stress Pathway interactions Pattern Phase Poly(ADP-ribose) Polymerases Populations at Risk Preventive Process Production Protocols documentation RNA Research Personnel Respiration Risk Role Succinate Dehydrogenase System Testing Therapeutic Time Tracer Translating Translations Xenograft procedure arsenic-induced carcinogenesis base carcinogenesis cell transformation environmental carcinogenesis enzyme activity epigenomics genetic regulatory protein in vivo insight mRNA Expression metabolomics mitochondrial dysfunction mitochondrial metabolism next generation next generation sequencing oxidative DNA damage repaired respiratory response stable isotope transcriptome sequencing transcriptomics tumor validation studies

项目摘要

DESCRIPTION (provided by applicant): Although epidemiological studies have associated arsenic (As) exposures with increased risk of lung cancer, the molecular mechanisms involved in lung cancer development by arsenite exposure remain poorly defined. Recent literature has implicated altered mitochondrial (mt) metabolism, oxidative stress, and DNA damage in environmental As carcinogenesis, but the biochemical dysregulations that underlie these processes and their interactions are unknown. It is also unclear if benchside understanding of As carcinogenesis in model systems can be translated into bedside understanding of human cancer. In this R21/R33 proposal, this team of investigators will address these issues by adopting an integrated `omics approach that uses stable isotope-resolved metabolomics (SIRM) to define mt and cellular metabolic networks central to proliferation, redox homeostasis and oxidative DNA damage/repair response in lung cells, as perturbed by As transformation and carcinogenesis. This approach will reveal pathway changes for further testing on their dysregulations (e.g. key enzymes and related regulatory proteins) at the gene mutational, epigenetic, and transcriptional level by querying into genomic, epigenomic, and transcriptomic sequencing data. The investigators will fulfill their goal with two specific aims (SA1 & 2) in the R21 phase followed by SA3 & 4 in the R33 phase and SA1 to determine if and how mt and cellular metabolic networks are altered in As-transformed lung cells using SIRM. Transformed lung cells will be studied in vitro and in mouse xenografts using SIRM. The reprogrammed metabolic networks obtained will be related to those separately acquired in vivo from human lung cancer patients. SA2) to link ROS production, mt, and nuclear DNA damages/repair processes to metabolic reprogramming in As-transformed lung cells. Correlations of SA1&2 data will enable hypothesis generation for further testing of cause-and-effect relationships in SA3&4. SA3) to reveal cause-and-effect relations among altered Mt/cellular metabolic networks, ROS production, and DNA damage during As-induced transformation by their time-dependence. SA4) to map corresponding genetic, epigenetic and gene expression changes in As-transformed lung cells for hypothesis testing on As action. Next-generation sequence data will be acquired and queried for mutational signatures, epigenetic status, and mRNA expression of key genes involved in the reprogrammed metabolic networks, redox balance, and DNA repair. These data will help delineate how As-induced genetic or epigenetic lesions lead to metabolic reprogramming or vice versa. Such integration of genomic, epigenomic, transcriptomic, and metabolomics analysis of As action in model lung cell systems should provide unprecedentedly detailed insights into metabolic dysregulation and DNA damage in the mitochondria and how they may be linked to nuclear DNA damage and altered gene expression. The integrated `omics information will facilitate full-scale validation studies on the molecular mechanism for As-induced carcinogenesis and translation of such basic insights into human lung cancer resulting from As exposure (e.g. discovery of mechanistic and robust biomarker patterns).

描述（由申请人提供）：尽管流行病学研究表明砷（As）暴露与肺癌风险增加相关，但砷暴露导致肺癌发生的分子机制仍不明确。最近的文献表明，在环境致癌作用中，线粒体（mt）代谢、氧化应激和DNA损伤发生了改变，但这些过程及其相互作用的生化失调是未知的。目前还不清楚，如果benchside了解作为致癌模型系统可以转化为床旁了解人类癌症。在这个R21/R33提案中，这个研究小组将通过采用一种综合的“组学”方法来解决这些问题，该方法使用稳定的同位素分辨代谢组学（SIRM）来定义肺细胞中对增殖、氧化还原稳态和氧化性DNA损伤/修复反应至关重要的MT和细胞代谢网络，这些网络受到As转化和致癌作用的干扰。该方法将通过查询基因组、表观基因组和转录组测序数据，揭示途径变化，以进一步在基因突变、表观遗传和转录水平上测试其失调（例如关键酶和相关调控蛋白）。研究人员将在R21阶段完成两个特定目标（SA 1和2），然后在R33阶段完成SA 3和4，以及SA 1，以确定MT和细胞代谢网络是否以及如何使用SIRM在As转化的肺细胞中改变。将使用SIRM在体外和小鼠异种移植物中研究转化的肺细胞。获得的重编程代谢网络将与从人肺癌患者体内单独获得的代谢网络相关。SA 2）将ROS产生、mt和核DNA损伤/修复过程与AS转化的肺细胞中的代谢重编程联系起来。SA1&2数据的相关性将使假设生成能够进一步测试SA3&4中的因果关系。SA 3）揭示了As诱导转化过程中Mt/细胞代谢网络改变、ROS产生和DNA损伤之间的时间依赖性因果关系。SA 4）以绘制As转化的肺细胞中相应的遗传、表观遗传和基因表达变化，用于As作用的假设检验。将获得下一代序列数据，并查询突变特征、表观遗传状态和参与重编程代谢网络、氧化还原平衡和DNA修复的关键基因的mRNA表达。这些数据将有助于描述As诱导的遗传或表观遗传病变如何导致代谢重编程，反之亦然。这种整合的基因组学，表观基因组学，转录组学和代谢组学分析作为模型肺细胞系统中的作用，应该提供前所未有的详细的见解代谢失调和线粒体中的DNA损伤，以及它们如何可能与核DNA损伤和改变基因表达。整合的组学信息将有助于对As诱导的分子机制进行全面的验证研究致癌作用和翻译的基本见解人类肺癌造成的砷暴露（如发现机制和强大的生物标志物模式）。