Hypoxia and Epigenetic Mechanisms for Toxicity
缺氧和毒性的表观遗传机制
基本信息
- 批准号:7249502
- 负责人:
- 金额:$ 32.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-07-19 至 2009-06-30
- 项目状态:已结题
- 来源:
- 关键词:ARNT geneARNT2 geneAddressAdultAffectAnimalsApoptoticBiochemicalBiological AssayBiologyCancer BiologyCaspaseCell LineCell SurvivalCellsCobaltConditionDataDevelopmentEmbryoEnd PointEnvironmentEnzymatic BiochemistryEnzymesEpigenetic ProcessEssential GenesExposure toFamilyFertilizersFlow CytometryGene TargetingGenesGenetic TranscriptionGrowthHistopathologyHydroxylationHypoxiaHypoxia Inducible FactorIn VitroIndustrial WasteInjuryInorganic ChemistryKnockout MiceLeadLentivirus VectorLinkLungMalignant NeoplasmsManganeseMeasurementMediatingMediator of activation proteinMetal exposureMetalsMixed Function OxygenasesMusNickelOntologyOrganismOxygenOxygen measurement, partial pressure, arterialPathway interactionsPharmacology and ToxicologyPhysiologyPlayProcessProcollagen-Proline DioxygenaseProductionProteinsPublicationsRNA InterferenceResearchResearch PersonnelRoleSignal PathwaySignal TransductionSmall Interfering RNAStandards of Weights and MeasuresStreamSystemTissuesToxic effectTransfectionbasecellular engineeringcopingdivalent metalfunctional genomicshypoxia inducible factor 1in vivoinhibitor/antagonistinterestoncologyprogramsrecombinaseresearch studyresponsesensortranscription factor
项目摘要
DESCRIPTION (provided by applicant): Exposure to ferrous-like metals lead to multiple toxic endpoints, including lung and erythropoietic abnormalities, and cancer. Many different mechanisms have been proposed to explain the toxicity of ferrous-like metals. Our preliminary data and recent publications suggest that the hypoxia signaling system may play a role in metal induced injury. The ability to sense and cope with low oxygen tension, or hypoxia, is critical to normal physiology and several pathological conditions. Organisms have developed a mechanism of coping with hypoxia and central to this process are the hypoxia inducible factors (HIFs). HIFs are inducible transcription factors that regulate the expression of a battery of genes essential to dealing with a hypoxic environment. These hypoxia responsive genes are also affected by ferrous-like metals, such as cobalt and nickel. Recently, a family of prolyl hydroxylases was identified that act as oxygen sensors for the HIF proteins. These enzymes can be inhibited by ferrous-like metals and offer a link between hypoxia and metal exposure. This intersection has led us to the following hypothesis: HIF mediated transcription is necessary for cellular damage and lung toxicity caused by exposure to ferrous-like metals. To address this hypothesis five specific aims are proposed: 1) Create and characterize ARNT deficient cells. 2) Characterize the role of HIF signaling in metal induced toxicity with HIF deficient cell lines. 3) Determine whether metal induced toxicity is dependent upon stabilization of the HIFs through inhibition of prolyl. hydroxylation. 4) Determine the role of HIF regulated genes in mediating metal induced toxicity using RNAi. 5) Determine whether HIF mediated signaling is necessary for metal induced lung toxicity using HIF1 n and ARNT conditional null mice. The completion of the proposed research will increase our understanding of the signaling mechanism used by ferrous-like metals. The studies will link ferrous-like metals to the hypoxia response pathway and its down-stream target genes. The proposal will create a set of cell lines that will have broad interest in several fields, including oncology, toxicology, and pharmacology. In addition, the understanding we gain about hypoxia and HIF mediated signaling will have benefits to developmental and cancer biology. Finally, these studies will elucidate the role of hypoxia signaling in metal induced toxicity in vitro and in vivo.
描述(由申请人提供):暴露于亚铁类金属导致多种毒性终点,包括肺和红细胞生成异常以及癌症。 人们提出了许多不同的机制来解释类铁金属的毒性。 我们的初步数据和最近的出版物表明,缺氧信号系统可能在金属诱导的损伤中发挥作用。感知和科普低氧张力或缺氧的能力对正常生理和几种病理状况至关重要。生物体已经开发出应对缺氧的机制,并且该过程的核心是缺氧诱导因子(HIF)。 HIF是可诱导的转录因子,其调节处理低氧环境所必需的一系列基因的表达。这些缺氧反应基因也受到铁类金属的影响,如钴和镍。最近,脯氨酰羟化酶家族被鉴定为HIF蛋白的氧传感器。这些酶可以被类亚铁金属抑制,并提供缺氧和金属暴露之间的联系。 这种交叉导致了我们以下的假设:HIF介导的转录是必要的细胞损伤和肺毒性所造成的暴露于亚铁类金属。 为了解决这一假设,提出了五个具体的目标:1)创建和表征ARNT缺陷细胞。2)用HIF缺陷细胞系表征HIF信号传导在金属诱导的毒性中的作用。 3)确定金属诱导的毒性是否依赖于通过抑制脯氨酰稳定HIF。羟基化 4)使用RNAi确定HIF调节基因在介导金属诱导的毒性中的作用。 5)使用HIF 1 n和ARNT条件无效小鼠确定HIF介导的信号传导是否是金属诱导的肺毒性所必需的。 这项研究的完成将增加我们对类铁金属所使用的信号机制的理解。 这些研究将把类铁金属与缺氧反应途径及其下游靶基因联系起来。 该提案将创建一组细胞系,这些细胞系将在包括肿瘤学,毒理学和药理学在内的几个领域产生广泛的兴趣。 此外,我们对缺氧和HIF介导的信号传导的理解将有利于发育和癌症生物学。 最后,这些研究将阐明缺氧信号在体外和体内金属诱导的毒性中的作用。
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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{{ truncateString('JOHN J LAPRES', 18)}}的其他基金
A Proteomic Analysis of the AHR signaling Network
AHR 信号网络的蛋白质组学分析
- 批准号:
7064102 - 财政年份:2006
- 资助金额:
$ 32.09万 - 项目类别:
Multidisciplinary Training in Environmental Toxicology
环境毒理学多学科培训
- 批准号:
9307838 - 财政年份:1989
- 资助金额:
$ 32.09万 - 项目类别:
Multidisciplinary Training in Environmental Toxicology
环境毒理学多学科培训
- 批准号:
10659034 - 财政年份:1989
- 资助金额:
$ 32.09万 - 项目类别: