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:
  • 金额:
    $ 22.47万
  • 依托单位:
  • 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

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).


项目成果

期刊论文数量(0)
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会议论文数量(0)
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Teresa Whei-Mei Fan其他文献

Teresa Whei-Mei Fan的其他文献

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{{ truncateString('Teresa Whei-Mei Fan', 18)}}的其他基金

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
  • 批准号:
    8927921
  • 财政年份:
    2015
  • 资助金额:
    $ 22.47万
  • 项目类别:
Integrated Chemoselective and Informatic Platform for Large-Scale Metabolomics
用于大规模代谢组学的集成化学选择性和信息平台
  • 批准号:
    8914844
  • 财政年份:
    2014
  • 资助金额:
    $ 22.47万
  • 项目类别:
Determining Tumor Metabolism and Biochemical Mechanism of beta-glucan Action in
确定肿瘤代谢和 β-葡聚糖作用的生化机制
  • 批准号:
    8744923
  • 财政年份:
    2014
  • 资助金额:
    $ 22.47万
  • 项目类别:
Integrated Chemoselective and Informatic Platform for Large-Scale Metabolomics
用于大规模代谢组学的集成化学选择性和信息平台
  • 批准号:
    8916721
  • 财政年份:
    2014
  • 资助金额:
    $ 22.47万
  • 项目类别:
Administration, Bioinformatics and Biostatistics Core
管理、生物信息学和生物统计学核心
  • 批准号:
    8744925
  • 财政年份:
    2014
  • 资助金额:
    $ 22.47万
  • 项目类别:
Systems Biochemistry in Lung Cancer: Toward a Mechanistic Understanding of NSCLC
肺癌的系统生物化学:了解非小细胞肺癌的机制
  • 批准号:
    9025455
  • 财政年份:
    2014
  • 资助金额:
    $ 22.47万
  • 项目类别:
Microenvironmental Nutrient Availability and Immunomodulation in Lung Cancer Cel
肺癌细胞的微环境营养素利用率和免疫调节
  • 批准号:
    8744921
  • 财政年份:
    2014
  • 资助金额:
    $ 22.47万
  • 项目类别:
Determining Molecular Mechanisms of NSCLC and Response to beta-glucan
确定 NSCLC 的分子机制和对 β-葡聚糖的反应
  • 批准号:
    8744924
  • 财政年份:
    2014
  • 资助金额:
    $ 22.47万
  • 项目类别:
Stable Isotope Resolved Metabolomics Analytical Shared Core
稳定同位素解析代谢组学分析共享核心
  • 批准号:
    8744926
  • 财政年份:
    2014
  • 资助金额:
    $ 22.47万
  • 项目类别:
Integrated Chemoselective and Informatic Platform for Large-Scale Metabolomics
用于大规模代谢组学的集成化学选择性和信息平台
  • 批准号:
    8687656
  • 财政年份:
    2014
  • 资助金额:
    $ 22.47万
  • 项目类别:

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