Project 5: Development and Applications of Integrated in Vitro and Cell-Based
项目5:体外集成和细胞基础的开发与应用
基本信息
- 批准号:7936573
- 负责人:
- 金额:$ 54.15万
- 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:2010-04-15 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimal ModelArsenicArsenicalsArsenitesB-LymphocytesBindingBiochemicalBiologicalBiological AssayBiological MarkersBiological PreservationCalcium/calmodulin-dependent protein kinaseCardiovascular DiseasesCell Culture TechniquesCell LineCell physiologyCellsChemicalsComplexComplex MixturesDetectionDevelopmentDioxinsEndocrine DisruptorsEnvironmental MonitoringEnzymesEventExposure toFlame RetardantsGene ExpressionGenerationsGenetic TranscriptionGoalsGrowthHazardous ChemicalsHazardous Waste SitesHumanIn VitroIndividualInflammationKnowledgeLOX geneLigandsLinkLipidsMediatingModelingMolecularNeuronsNuclear ReceptorsOxidative StressPainPlasmaPoisonProductionProteinsProteomicsReceptor SignalingRecombinantsRelative (related person)Reporter GenesRyR2RyanodineRyanodine Receptor Calcium Release ChannelRyanodine ReceptorsSamplingScreening procedureSeriesSignal PathwaySignal TransductionSignal Transduction PathwaySite-Directed MutagenesisStem cellsStructure-Activity RelationshipSulfhydryl CompoundsSuperfundSystemTestingToxic effectToxicant exposureTriclosanXenobioticsantimicrobialantimicrobial drugarachidonatebaseenzyme activityhigh throughput screeninghuman FRAP1 proteinimprovedin vitro Bioassayin vivoinhibitor/antagonistkeratinocytenanoparticleneuronal growthnovelrapid detectionreceptorresponsesmall molecule librariessteroid hormonesuperfund chemicaltoxicant
项目摘要
Hazardous waste sites contain complex mixtures of a wide variety of toxic chemicals. Unfortunately, development of rapid and inexpensive detection of specific chemicals or chemical classes in environmental and biological samples has been hampered by the lack of specific bioassay/biomarker systems. Accordingly, the overall goals of this project are to develop and validate a series of mechanistically-based cell and in vitro bioassays/biomarkers with applications to chemical detection and screening. Since effective
development and application of bioassays/biomarkers is greatly facilitated by an understanding of the specific responses of cell to a given toxicant(s), each of the four proposed approaches will exploit information derived from analysis of the mechanisms by which selected chemicals affect cellular receptors, signal transduction pathways and/or cellular/enzyme functions. In Aim 1, stably transfected cell lines will be developed as bioassays for ultra-low levels of dioxin-like or steroid hormone-like chemicals with the induction of receptor-dependent reporter gene expression. Chemical-specific recombinant AhRs will be generated to improve both cell and in vitro AhR based bioassay systems. In Aim 2, human keratinocytes will be used to examine specific intracellular proteomic changes that occur in response to exposure to arsenicals and to identify potential biomarkers specifically altered by these chemicals. In Aim 3, high throughput in vitro and cell-based bioassays will be used to examine the influence of Superfund chemicals on the production of regulatory lipids controlling cardiovascular diseases, inflammation and pajn. In Aim 4, structure activity relationships will be established for a series of brominated flame retardants and their metabolites and the antimicrobial agent triclosan for their ability to alter ryanodine receptor signaling functions and the resulting impact on neuron growth and plasticity. In the final Aim, integrated bioassay/biomarkers will be used to identify and characterize the biochemical and toxicological effects of individual chemicals and complex mixtures of chemicals.
危险废物场含有各种有毒化学品的复杂混合物。不幸的是,环境和生物样品中特定化学品或化学类别的快速和廉价检测的发展受到缺乏特定生物测定/生物标志物系统的阻碍。因此,本项目的总体目标是开发和验证一系列基于机械的细胞和体外生物测定/生物标志物,并应用于化学检测和筛选。因为有效
生物测定/生物标记物的开发和应用通过理解细胞对给定毒物的特异性反应而得到极大的促进,所提出的四种方法中的每一种都将利用从所选化学物质影响细胞受体、信号转导途径和/或细胞/酶功能的机制的分析中得到的信息。在目标1中,稳定转染的细胞系将被开发为用于超低水平的二恶英样或类固醇激素样化学物质的生物测定,并诱导受体依赖性报告基因表达。将产生化学特异性重组AhR以改进基于细胞和体外AhR的生物测定系统。在目标2中,人类角质形成细胞将用于检查特定的细胞内蛋白质组学变化,发生在暴露于砷,并确定潜在的生物标志物,特别是改变这些化学品。在目标3中,将使用高通量体外和基于细胞的生物测定来检查Superfund化学品对控制心血管疾病、炎症和pajn的调节脂质的产生的影响。在目标4中,将建立一系列溴化阻燃剂及其代谢物和抗菌剂三氯生的构效关系,以改变兰尼碱受体信号传导功能及其对神经元生长和可塑性的影响。在最终目标中,综合生物测定/生物标志物将用于识别和表征单个化学品和化学品复杂混合物的生化和毒理学效应。
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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BRUCE D HAMMOCK其他文献
BRUCE D HAMMOCK的其他文献
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{{ truncateString('BRUCE D HAMMOCK', 18)}}的其他基金
Soluble epoxide hydrolase and epoxide fatty acid involvement in corneal injury after ammonia exposure: Mechanisms of injury and potential therapeutics using sEH inhibitors and biostable EpFA mimics.
可溶性环氧化物水解酶和环氧化物脂肪酸参与氨暴露后角膜损伤:损伤机制和使用 sEH 抑制剂和生物稳定 EpFA 模拟物的潜在治疗方法。
- 批准号:
10708436 - 财政年份:2023
- 资助金额:
$ 54.15万 - 项目类别:
Bioactive lipids as effectors and indicators of the deleterious effects of environmental exposure on chronic diseases
生物活性脂质作为环境暴露对慢性疾病有害影响的效应物和指标
- 批准号:
10400036 - 财政年份:2019
- 资助金额:
$ 54.15万 - 项目类别:
Bioactive lipids as effectors and indicators of the deleterious effects of environmental exposure on chronic diseases
生物活性脂质作为环境暴露对慢性疾病有害影响的效应物和指标
- 批准号:
10615675 - 财政年份:2019
- 资助金额:
$ 54.15万 - 项目类别:
Bioactive lipids as effectors and indicators of the deleterious effects of environmental exposure on chronic diseases
生物活性脂质作为环境暴露对慢性疾病有害影响的效应物和指标
- 批准号:
10153794 - 财政年份:2019
- 资助金额:
$ 54.15万 - 项目类别:
Clinical Paths for Soluble Epoxide Hydrolase Inhibitors at Experimental Biology 2018
2018 年实验生物学中可溶性环氧化物水解酶抑制剂的临床路径
- 批准号:
9544621 - 财政年份:2018
- 资助金额:
$ 54.15万 - 项目类别:
Role of Epoxygenated Fatty Acids in Modulating Pain
环氧化脂肪酸在调节疼痛中的作用
- 批准号:
8446055 - 财政年份:2013
- 资助金额:
$ 54.15万 - 项目类别:
Role of Epoxygenated Fatty Acids in Modulating Pain
环氧化脂肪酸在调节疼痛中的作用
- 批准号:
8619587 - 财政年份:2013
- 资助金额:
$ 54.15万 - 项目类别:
METHODS MONITOR TOXIC SUBSTAN AND/OR INDICATORS OF PRESENCE IN HUMANS&OTHER SPE
监测人类体内有毒物质和/或存在指标的方法
- 批准号:
8362756 - 财政年份:2011
- 资助金额:
$ 54.15万 - 项目类别:
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