Quantitative analysis of damage to the nucleotide pool
核苷酸库损伤的定量分析
基本信息
- 批准号:8638724
- 负责人:
- 金额:$ 19.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-11-20 至 2015-10-31
- 项目状态:已结题
- 来源:
- 关键词:8-hydroxyguanosineAddressAdenineAffectAnabolismAnionsAntibioticsApplications GrantsAreaAttentionBiochemicalBiomedical ResearchCell DeathCell modelCellsCellular StressChromatographyCoupledDNADNA DamageDNA Repair EnzymesDataDeaminationDefectDeoxyribonucleotidesDevelopmentEnsureEnzymesEscherichia coliExploratory/Developmental GrantFutureGeneticGenetic VariationGoalsGuanineHealthHereditary DiseaseHumanHuman GeneticsHydrogen PeroxideHygieneHypoxanthinesInflammationKnockout MiceLesionLipid PeroxidationLiquid ChromatographyMammalian CellMass Spectrum AnalysisMetabolic PathwayMethodsModelingMono-SMorphologic artifactsMutagenesisNucleic AcidsNucleotidesOxidative StressPathologyPolymerasePopulationProtein DephosphorylationPurine NucleotidesRNAReactionRoleSolventsSourceSystemTechnologyTestingToxic effectToxicogeneticsWalkersXanthinesadductanalytical methodanticancer researchcell killingchemical carcinogenesiscytotoxicexperiencehuman diseasehuman tissueinorganic phosphatemetabolomicsmutantnew technologynucleotide metabolismoxidationphosphatase inhibitorpublic health relevancepurine metabolismpyrophosphatasetoxicant
项目摘要
Project Summary/Abstract
The goal of these R21 Exploratory/Developmental studies is to develop a sensitive metabolomic platform to
quantify damaged components of the nucleotide pool as a source of DNA and RNA damage. While toxic and
mutagenic lesions arise in nucleic acids by direct reaction with environmental and endogenous toxicants,
incorporation of damaged ribo- and 2-deoxyribonucleotides into DNA and RNA represents a potentially
important source of genetic and cellular toxicity. The impact of the nucleotide pool has long been suspected
from studies of highly conserved pool sanitizing enzymes, such as the pyrophosphatases that target damaged
and non-canonical (d)NTP. The loss of these enzymes leads to increased levels of DNA damage. In spite of
this evidence, there have been few quantitative studies of nucleotide pool damage due to a lack of analytical
methods. To address this problem, we will develop a specific, sensitive and precise analytical method to
quantify damaged nucleotide mono-, di- and tri-phosphates in the nucleotide pool. Following development with
standards, the method will applied to two cellular models of genetic pathology and chemical carcinogenesis in
humans: defects in purine nucleotide metabolism and oxidative stress. We recently discovered that defects in
purine nucleotide metabolic pathways cause up to 600-fold increases in hypoxanthine, but not xanthine, into
both DNA and RNA, presumably due to imbalances in guanine (G) and adenine (A) precursors in the
nucleotide pool. The second application, which poses a greater challenge in terms of sensitivity, addresses
oxidation of purine nucleotides in cells subjected to oxidative stress. These applications allow us to test and
optimize the analytical platform for future studies in mammalian cells and human tissues, in which we address
the full range of genotoxic and cytotoxic nucleotide pool damage from endogenous and environmental sources.
Furthermore, both the results obtained and the novel technologies developed will find broad application in a
variety of areas of biomedical research, including antibiotic development, genetic toxicology, inflammation and
oxidative stress, and, at a systems level, any of the dozens of hereditary disorders of purine nucleotide
metabolism.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Peter C Dedon其他文献
The Spectrum of 8-oxoguanine Oxidation Products is both Sequence and Oxidant Dependent
- DOI:
10.1016/j.freeradbiomed.2010.10.477 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
- 作者:
Kok Seong Lim;Liang Cui;Koli Taghizadeh;John S Wishnok;Vladimir Shafirovich;Nicholas E Geacintov;Steven R Tannenbaum;Peter C Dedon - 通讯作者:
Peter C Dedon
Peter C Dedon的其他文献
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{{ truncateString('Peter C Dedon', 18)}}的其他基金
13th International Workshop on Radiation Damage to DNA
第13届DNA辐射损伤国际研讨会
- 批准号:
8720445 - 财政年份:2014
- 资助金额:
$ 19.5万 - 项目类别:
Sulfur DNA modifications in gut microbes confer resistance to oxidative stress
肠道微生物中的硫 DNA 修饰赋予其对氧化应激的抵抗力
- 批准号:
8751068 - 财政年份:2014
- 资助金额:
$ 19.5万 - 项目类别:
Sulfur DNA modifications in gut microbes confer resistance to oxidative stress
肠道微生物中的硫 DNA 修饰赋予其对氧化应激的抵抗力
- 批准号:
8898718 - 财政年份:2014
- 资助金额:
$ 19.5万 - 项目类别:
DNA and protein reactions of NO', ONOO-, and reactive species produced by phagocy
NO、ONOO- 和吞噬产生的反应性物质的 DNA 和蛋白质反应
- 批准号:
7514461 - 财政年份:2009
- 资助金额:
$ 19.5万 - 项目类别:
Chemistry and Biology of Deoxyribose Oxidation in DNA
DNA 脱氧核糖氧化的化学和生物学
- 批准号:
7911253 - 财政年份:2009
- 资助金额:
$ 19.5万 - 项目类别:
Complex modifications of tRNA: regulatory roles and crosstalk with DNA metabolism
tRNA 的复杂修饰:调节作用以及与 DNA 代谢的串扰
- 批准号:
9134775 - 财政年份:2006
- 资助金额:
$ 19.5万 - 项目类别:
Complex modifications of tRNA: regulatory roles and crosstalk with DNA metabolism
tRNA 的复杂修饰:调节作用以及与 DNA 代谢的串扰
- 批准号:
8884789 - 财政年份:2006
- 资助金额:
$ 19.5万 - 项目类别:
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