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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).