Project 1: Genotoxic & Cell Signaling Pathways of As in Mammalian Cells
项目1:基因毒性
基本信息
- 批准号:7609036
- 负责人:
- 金额:$ 21.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-04-04 至 2011-03-31
- 项目状态:已结题
- 来源:
- 关键词:ATP Synthesis PathwayAddressAffectApoptosisApoptoticArsenicArsenicalsArsenitesBase PairingBiological AssayBladderCell Death InductionCellsChromosome abnormalityDNA ProbesDataDoctor of PhilosophyDoseEnvironmental CarcinogensExposure toFluorescent ProbesFundingGenesGoalsGrantHamstersHumanHybridsIn VitroIncidenceInduced MutationKidneyL CellsLabelLinkLiverLungMalignant NeoplasmsMammalian CellMediatingMelanoma CellMembrane PotentialsMitochondriaMitochondrial DNAMutagenesisMutagensMutationNuclearNucleotidesOxygenPlayPolymerase Chain ReactionPreventionRadioReactive Nitrogen SpeciesRespiratory ChainRestriction Fragment Length Polymorphism AnalysisRoleSamplingSeriesSignal PathwaySignal TransductionSkinSkin CancerSouthern BlottingTimeWater Supplycarcinogenicitycytochrome c oxidasedaygenotoxicityhuman diseasein vivomelanocytemitochondrial DNA mutationmitochondrial genomemitochondrial membraneresponsesodium arsenite
项目摘要
Arsenic is an important environmental carcinogen that affects millions of people worldwide through
contaminated water supplies. Although arsenic induces various human cancers including skin, lung, bladder,
kidney and liver, the carcinogenic mechanism remains unknown. With the funding support of this grant, the
applicant has shown, for the first time, that arsenic is a potent gene and chromosomal mutagen in
mammalian cells and induces mostly multilocus deletions. These findings provide the first direct link between
chromosomal abnormalities that have frequently been demonstrated in vitro and carcinogenicity in vivo.
Furthermore, our recent data have shown that mitochondria are a primary target in mediating arsenicinduced
genotoxicity. The overall goal of this application is to elucidate the contribution of mitochondrial DNA
mutations and cell signaling pathways in mediating the genotoxicity and apoptosis of arsenic in mammalian
cells. To achieve this goal, a series of eight inter-related specific aims are proposed to address the four
testable hypotheses. The human-hamster hybrid (A-L) cell assay will be used to ascertain the role of
mitochondrial DNA mutations and mitochondrial functions in modulating arsenic (sodium arsenite and
methylated arsenic species) induced mutations at the CD59 locus. Since mitochondrial damage is often
associated with induction of cell death, human melanocytes and melanoma cells will be used to define the
cell signaling pathways involved in mediating arsenic-induced apoptosis. There is a profound necessity to
develop effective treatment strategy for this often fatal cancer. Furthermore, there is considerable interaction,
both conceptually and in shared materials, between this project and that of Projects 2, 3 and 4. A better
understanding of the genotoxic and apoptotic mechanisms of arsenic will provide better interventional
approach both in the treatment and prevention of arsenic-induced human diseases.
砷是一种重要的环境致癌物,通过以下方式影响全世界数百万人
受污染的水源。尽管砷会诱发多种人类癌症,包括皮肤癌、肺癌、膀胱癌、
肾和肝,致癌机制尚不清楚。在本次补助金的资助下,
申请人首次证明砷是一种有效的基因和染色体诱变剂
哺乳动物细胞并诱导大部分多位点缺失。这些发现首次提供了两者之间的直接联系
体外经常证实的染色体异常和体内致癌性。
此外,我们最近的数据表明线粒体是介导砷诱导的主要目标
遗传毒性。该应用的总体目标是阐明线粒体 DNA 的贡献
突变和细胞信号通路介导砷对哺乳动物的遗传毒性和细胞凋亡
细胞。为了实现这一目标,提出了一系列八个相互关联的具体目标来解决四个问题
可检验的假设。人仓鼠杂交 (A-L) 细胞测定将用于确定
线粒体 DNA 突变和线粒体在调节砷(亚砷酸钠和
甲基化砷)诱导 CD59 位点突变。由于线粒体损伤常常
与诱导细胞死亡相关,人类黑色素细胞和黑色素瘤细胞将被用来定义
细胞信号通路参与介导砷诱导的细胞凋亡。存在着深刻的必要性
为这种通常致命的癌症制定有效的治疗策略。此外,还有相当多的互动,
该项目与项目 2、3 和 4 的项目在概念上和共享材料上都存在差异。
了解砷的基因毒性和细胞凋亡机制将提供更好的干预措施
治疗和预防砷引起的人类疾病的方法。
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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Tom K. Hei其他文献
Lowering iron level protects against bone loss in focally irradiated and contralateral femurs through distinct mechanisms
降低铁水平可通过不同的机制防止局部照射和对侧股骨的骨质流失
- DOI:
- 发表时间:
2018 - 期刊:
- 影响因子:4.1
- 作者:
Jian Zhang;Lijun Zheng;Ziyang Wang;Hailong Pei;Wentao Hu;Jin Nie;Peng Shang;Bingyan Li;Tom K. Hei;Guangming Zhou - 通讯作者:
Guangming Zhou
Characterization of ataxia telangiectasia fibroblasts with extended life-span through telomerase expression
通过端粒酶表达延长寿命的共济失调毛细血管扩张成纤维细胞的特征
- DOI:
10.1038/sj.onc.1204072 - 发表时间:
2001-01-18 - 期刊:
- 影响因子:8
- 作者:
Lauren D Wood;Tanya L Halvorsen;S. Dhar;Joseph A Baur;R. Pandita;W. Wright;M. Hande;G. Calaf;Tom K. Hei;F. Levine;Jerry W. Shay;Jean JY Wang;T. Pandita - 通讯作者:
T. Pandita
Differential effects of p53 on bystander phenotypes induced by gamma ray and high LET heavy ion radiation
p53 对伽马射线和高 LET 重离子辐射诱导的旁观者表型的不同影响
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:2.5
- 作者:
Yoshiya Furusawa;Tom K. Hei;Bingrong Dang;Chunlin Shao - 通讯作者:
Chunlin Shao
The differential role of human macrophage in triggering secondary bystander effects after either gamma-ray or carbon beam irradiation
人类巨噬细胞在伽马射线或碳束照射后触发次级旁观者效应中的不同作用
- DOI:
10.1109/msp.2014.2326181 - 发表时间:
2015 - 期刊:
- 影响因子:9.7
- 作者:
Wenjian Li;Yukio Uchihori;Tom K. Hei;Chunlin Shao - 通讯作者:
Chunlin Shao
Genotoxic damage in non-irradiated cells: contribution from the bystander effect.
未照射细胞的基因毒性损伤:旁观者效应的贡献。
- DOI:
10.1093/oxfordjournals.rpd.a006769 - 发表时间:
2002-06-01 - 期刊:
- 影响因子:1
- 作者:
Hongning Zhou;G. R;ers;ers;M. Suzuki;C. Waldren;Tom K. Hei - 通讯作者:
Tom K. Hei
Tom K. Hei的其他文献
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{{ truncateString('Tom K. Hei', 18)}}的其他基金
Project 1: Genotoxic & Cell Signaling Pathways of As in Mammalian Cells
项目1:基因毒性
- 批准号:
8065864 - 财政年份:2010
- 资助金额:
$ 21.99万 - 项目类别:
Project 1: Genotoxic & Cell Signaling Pathways of As in Mammalian Cells
项目1:基因毒性
- 批准号:
7550964 - 财政年份:2007
- 资助金额:
$ 21.99万 - 项目类别:
Project 1: Genotoxic & Cell Signaling Pathways of As in Mammalian Cells
项目1:基因毒性
- 批准号:
7089753 - 财政年份:2006
- 资助金额:
$ 21.99万 - 项目类别:
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