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.
首席调查员/项目主任(最后、第一、中间):格罗尔曼,Arthur P
描述:项目2
马兜铃酸(AA)是马兜铃亚科植物的主要成分,是一种有效的
人体肾毒素和致癌物质。其毒性作用主要针对肾近端小管,
它会导致细胞损伤,导致皮质小管间质纤维化,最终导致慢性肾功能衰竭。这个
这种肾病的病理机制已明确,但对其生化机制却知之甚少。
AA发挥其肾毒性作用或如何促进器官特异性致癌。我们假设AA
和/或其代谢物之一通过两个独立和不同的细胞机制起作用,即:(A)
转运蛋白介导的肾近端小管细胞的浓度和代谢,在那里毒素诱导
肾小管损伤;以及(B)通过与DMA反应生成DA-和DG-AA加合物,从而启动肾小管肿瘤的改变。
尿路上皮细胞。一系列实验模型,包括全动物、灌流肾、离体肾
近端小管和细胞培养将被用来确定肾脏处理再生障碍性贫血和
氨基酸代谢转化的生化途径(S)。我们将利用自然发生的
对AA毒性敏感或耐药的小鼠品系以确定与相关过程相关的过程
敏感度。分离的灌流大鼠肾脏,分离的小鼠和人肾的近端小管,
和细胞培养模型,将被用来检查AA及其代谢物
通过近端小管运输并在近端小管中发挥毒性作用,重点是确定
肾毒性反应中的线粒体和氧化损伤。近端小管参与的通路
AA在通过上皮向间充质转化诱导肾小管间质纤维化中的反应
人输尿管上皮细胞对AA的反应与DMA损伤和癌变有关,将是
通过基因芯片表达谱和蛋白质组学分析进行研究。AA-DNA的形成和修复
加合物将在体内用AA肾病的小鼠模型进行探索,并在体外用分离的小鼠和
人肾小管和人输尿管上皮细胞培养,重点是确定机制
与再生障碍性贫血、肾脏和遗传毒性有关。最后,我们将确定参与激活和
AA及其代谢物的解毒作用,认为遗传多态可能会使某些
AA肾病和/或尿路上皮细胞癌的个体通过改变这些基因的表达或功能
酵素。
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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