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：
8927921
负责人：
Teresa Whei-Mei Fan
金额：
$ 18.81万
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 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8927921
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 Metabolism 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 RNA Sequences 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 next generation next generation sequencing oxidative DNA damage public health relevance 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（由适用提供）：尽管流行病学研究已将砷（AS）暴露与肺癌的风险增加相关，但砷暴露与肺癌发展有关的分子机制仍然很差。最近的文献已经实施了改变的线粒体（MT）代谢，氧化应激和DNA损伤作为致癌作用，但是这些过程及其相互作用的基础的生化失调尚不清楚。还不清楚模型系统中对AS的AS的理解是否可以转化为对人类癌症的床边理解。在此R21/R33提案中，该研究人员将通过采用综合``OMICS方法来解决这些问题，该方法使用稳定的同位素分辨的代谢组学（SIRM）来定义MT和细胞代谢网络，对增殖，REDOX稳态和氧化DNA损害的损害/修复的疾病/氧化损害/修复症状的疾病和CARTCINT和CARCINT（CARCINT）和CARCANTINCESS的氧化DNA损害响应和氧化型损害响应。这种方法将通过查询基因组，表观基因组学和转录组测序数据来揭示其失调（例如关键酶和相关调节蛋白）进一步测试（例如关键酶和相关调节蛋白）的途径。研究人员将在R21阶段以两个特定的目标（SA1和2）实现其目标，然后在R33期和SA1中实现SA3和4，以确定使用SIRR在转换的肺细胞中MT和细胞代谢网络是否以及如何改变MT和细胞代谢网络。转化后的肺细胞将在体外和小鼠异种移植物中使用SIRM进行研究。重编程的代谢网络将与从人体肺癌患者体内单独获取的代谢网络有关。 SA2）将ROS的产生，MT和核DNA损害/修复过程与AS转化的肺细胞中的代谢重编程联系起来。 SA1和2数据的相关性将使假设生成，以进一步测试SA3和4中的因果关系。 SA3）揭示了改变MT/细胞代谢网络，ROS产生和DNA损伤在AS诱导的时间依赖性过程中的因果关系。 SA4）要绘制相应的遗传，表观遗传和基因表达在转化的肺细胞中的变化，以进行假设检验作为作用。将获取并查询下一代序列数据，以了解与重编程的代谢网络，氧化还原平衡和DNA修复有关的关键基因的突变特征，表观遗传状态和mRNA表达。这些数据将有助于描述如何诱导的遗传或表观遗传病变导致代谢重编程，反之亦然。基因组，表观基因组学，转录组和代谢组学分析在模型肺细胞系统中的作用的整合应提供前所未有的详细见解，对线粒体中的代谢失调和DNA损伤，以及如何将它们与核DNA损伤链接到核DNA损伤和改变基因的表达。综合`omics信息将促进有关AS诱导的分子机制的全尺度验证研究由于暴露而引起的这种基本见解对人类肺癌的癌变和转化（例如发现机械和健壮的生物标志物模式）。