PROJECT 2- MOLECULAR & CELLULAR MECHANISMS AAs
项目 2-分子
基本信息
- 批准号:8069936
- 负责人:
- 金额:$ 43.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-05-05 至 2012-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimalsAristolochiaAristolochic AcidsAttentionBiochemicalBiochemical PathwayBiochemical ProcessCarcinogensCell Culture TechniquesCellsChronic Kidney FailureDNADNA AdductsDNA DamageDrug Metabolic DetoxicationEnzyme GeneEnzymesEpithelialExperimental ModelsFibrosisGene ExpressionGenesGenetic PolymorphismHumanIn VitroIndividualInjuryKidneyKidney DiseasesMalignant NeoplasmsMediatingMesenchymalMetabolicMetabolismMitochondriaModelingMolecularMolecular ProfilingMouse StrainsMusNephrotoxicOrganPathologyPathway interactionsPlant ComponentsPredispositionPrincipal InvestigatorProcessProteomicsProximal Kidney TubulesRattusReactionRelative (related person)Renal tubule structureResistanceRodentRoleToxic effectToxinTubular formationUrinary tractUrothelial Celladductaristolochic acid IIcarcinogenesiscell injuryepithelial to mesenchymal transitiongenotoxicityin vivokidney cellmouse modelneoplasticprogramsrepairedresponse
项目摘要
Principal Investigator/Program Director (Last, First, Middle): Grollman, Arthur P
DESCRIPTION: PROJECT 2
Aristolochic acid (AA), the principal component of plants belonging to the genus Aristolochiae, is a potent
human nephrotoxin and carcinogen. Its toxic effects are targeted primarily to the renal proximal tubule where
it causes cellular injury leading to cortical tubulointerstitial fibrosis, and ultimately, chronic renal failure. The
pathology of this nephropathy is well defined but little is known about the biochemical mechanisms by which
AA exerts its nephrotoxic action or how it promotes organ specific carcinogenesis. We hypothesize that AA
and/or one of its metabolites act through two separate and distinct cellular mechanisms; namely, (a)
transporter-mediated concentration and metabolism in renal proximal tubule cells, where the toxin induces
tubular injury; and (b) by reacting with DMAto form dA- and dG-AA adducts that initiate neoplastic change in
urothelial cells. A spectrum of experimental models including whole animal, perfused kidney, isolated renal
proximal tubules, and cell culture will be used to identify mechanisms for renal handling of AA and the
biochemical pathways used for AA metabolic transformation(s). We will take advantage of naturally occurring
mouse strains that are sensitive or resistant to AA toxicity to identify processes associated with relative
susceptibility. Isolated perfused rat kidneys, renal proximal tubules isolated from mouse and human kidney,
and cell culture models, will be used to examine mechanisms by which AA and its metabolites are
transported by, and exert their toxic effects, in the proximal tubule, with a focus on defining the roles of
mitochondria and oxidative injury in the nephrotoxic response. Pathways involved in the proximal tubule
response to AA in induction of tubulointerstitial fibrosis through epithelial-to-mesenchymal transition, and in
the human ureteric urothelial cell response to AA as it relates to DMA damage and carcinogenesis, will be
studied by gene array expression profiling and proteomics analysis. The formation and repair of AA-DNA
adducts will be explored in vivo with mouse models of AA nephropathy, and in vitro with isolated mouse and
human tubules, and human ureteric urothelial cell cultures, with an emphasis on defining mechanisms
related to AA nephro- and genotoxicity. Finally, we will identify genes and enzymes involved in activation and
detoxification of AA and its metabolites, with the thought that genetic polymorphisms may predispose certain
individuals to AA nephropathy and/or urothelial cell cancer by altering the expression or function of these
enzymes.
首席研究员/项目主管(最后、第一、中):Grollman, Arthur P
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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SHINYA SHIBUTANI其他文献
SHINYA SHIBUTANI的其他文献
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{{ truncateString('SHINYA SHIBUTANI', 18)}}的其他基金
Genotoxicity of Estrogen Compounds in Endocrine Therapy
内分泌治疗中雌激素化合物的遗传毒性
- 批准号:
7106592 - 财政年份:2005
- 资助金额:
$ 43.8万 - 项目类别:
Genotoxicity of Estrogen Compounds in Endocrine Therapy
内分泌治疗中雌激素化合物的遗传毒性
- 批准号:
7409606 - 财政年份:2005
- 资助金额:
$ 43.8万 - 项目类别:
Genotoxicity of Estrogen Compounds in Endocrine Therapy
内分泌治疗中雌激素化合物的遗传毒性
- 批准号:
7232070 - 财政年份:2005
- 资助金额:
$ 43.8万 - 项目类别:
Genotoxicity of Estrogen Compounds in Endocrine Therapy
内分泌治疗中雌激素化合物的遗传毒性
- 批准号:
6917467 - 财政年份:2005
- 资助金额:
$ 43.8万 - 项目类别:
Genotoxicity of Estrogen Compounds in Endocrine Therapy
内分泌治疗中雌激素化合物的遗传毒性
- 批准号:
7618442 - 财政年份:2005
- 资助金额:
$ 43.8万 - 项目类别:
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