Integration of Genomic Biomarkers with the devTOX Human Embryonic Stem Cells Scre
基因组生物标志物与 devTOX 人类胚胎干细胞 Scre 的整合
基本信息
- 批准号:8645338
- 负责人:
- 金额:$ 57.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-08-01 至 2015-11-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAdultAgingAnimal TestingAnimalsBiochemicalBioinformaticsBiologicalBiological AssayBiological MarkersBlindedCell physiologyChemical ExposureChemicalsCodeComputing MethodologiesCongenital AbnormalityDevelopmentEpigenetic ProcessEuropean UnionExposure toFunctional RNAFunctional disorderGene Expression ProfileGenesGenomeGenomicsHumanHuman DevelopmentIn VitroLate EffectsLeadLifeMessenger RNAMethodsMicroRNAsModelingMolecular ProfilingOrganismPathway interactionsPerinatal ExposurePharmaceutical PreparationsPharmacologic SubstancePhasePredictive ValueProceduresPropertyProteinsProtocols documentationPubertyQuality ControlRelianceSafetySmall Business Innovation Research GrantSpontaneous abortionStem cellsStimulusSystemSystems BiologyTeratogensTestingToxic effectToxicant exposureToxicogenomicsToxicologyTrainingValidationbasebiological systemscell typedaughter celldevelopmental toxicologyenvironmental chemicalepigenomehuman embryonic stem cellin vitro testinginnovationinstrumentationmetabolomicsnervous system disorderpredictive modelingprogramspublic health relevanceresponsescreeningtoxicanttranscriptomics
项目摘要
DESCRIPTION (provided by applicant): In utero exposure to environmental chemicals or drugs accounts for approximately 5% of all birth defects and can have an impact in adult life by disrupting the epigenetic developmental programs that are activated later in life (e.g., puberty, aging). The currently accepted regulatory test for identifying potential teratogens involves the use of thousands of animals, is costly, takes two years to complete, and shows poor concordance (~60%) for human teratogens. The recent European Union ban on animal testing makes the reliance on non-animal test systems more urgent. Human embryonic stem (hES) cells reflect a unique biological system that cannot be represented by any other cell type used in toxicology. This proposal is focused on developing and validating a rapid toxicogenomics-based signature profiling assay for seamless integration into the Stemina Biomarker Discovery devTOX(tm) metabolomics-based platform. The combined expertise at ILS and Stemina will enable an innovative "systems biology" approach to in vitro developmental toxicology screening in a human-relevant assay using the cell type at the origin of human development, the hES cell. We will identify a toxicogenomics-based signature profile built on the unique stem cell transcriptome response (protein coding mRNA and non-coding RNAs), and cellular response pathways to toxicant exposures, using bioinformatics-driven computational methods. Ultimately, this Phase II SBIR will result in the development, validation, and implementation of a medium throughput assay using transcriptome-based profiling with a high predictive value for potential developmental toxicants. This objective will be completed in three Specific Aims: Specific Aim 1: Conduct expression profiling of hES cells exposed to known/suspect teratogens and nonteratogens using a training set of 62 compounds to construct a predictive transcriptome-based signature of developmental toxicity; Specific Aim 2: Develop and implement bioassay standard operating procedures, quality control criteria, and validation of instrumentation and GLP-compliant protocols for the conduct of the devTOX(tm) assay integrated with transcriptomics; Specific Aim 3: Test the transcriptome-based signature derived from the training set with a blinded set of test articles using qRT-PCR assays for specific mRNAs, lncRNAs and miRNAs. This will allow development of a biologically relevant signature profile based on dysfunction of the highly regulated genome and epigenome circuitry that maintains stem cell functions.
描述(由申请人提供):在子宫内暴露于环境化学物质或药物约占所有出生缺陷的 5%,并且可能通过破坏生命后期激活的表观遗传发育程序(例如青春期、衰老)对成年生活产生影响。 )。目前公认的用于识别潜在致畸剂的监管测试需要使用数千只动物,成本高昂,需要两年才能完成,并且与人类致畸剂的一致性较差(~60%)。欧盟最近禁止动物测试,使得对非动物测试系统的依赖变得更加紧迫。人胚胎干 (hES) 细胞反映了一种独特的生物系统,无法用毒理学中使用的任何其他细胞类型来代表。该提案的重点是开发和验证基于毒物基因组学的快速特征分析测定,以便无缝集成到 Stemina Biomarker Discovery devTOX(tm) 基于代谢组学的平台中。 ILS 和 Stemina 的专业知识相结合,将采用创新的“系统生物学”方法,利用人类发育起源的细胞类型(hES 细胞)在人类相关测定中进行体外发育毒理学筛选。我们将使用生物信息学驱动的计算方法,确定基于毒物基因组学的特征谱,该特征谱建立在独特的干细胞转录组反应(蛋白质编码 mRNA 和非编码 RNA)以及对毒物暴露的细胞反应途径的基础上。最终,该 II 期 SBIR 将开发、验证和实施中等通量测定,使用基于转录组的分析,对潜在的发育毒物具有较高的预测价值。该目标将通过三个具体目标来完成: 具体目标 1:使用 62 种化合物的训练集对暴露于已知/可疑致畸剂和非致畸剂的 hES 细胞进行表达谱分析,以构建基于转录组的预测性发育毒性特征;具体目标 2:制定并实施生物测定标准操作程序、质量控制标准以及仪器验证和符合 GLP 的协议,以进行与转录组学相结合的 devTOX(tm) 测定;具体目标 3:使用特定 mRNA、lncRNA 和 miRNA 的 qRT-PCR 检测,通过一组盲法测试文章来测试源自训练集的基于转录组的特征。这将允许基于维持干细胞功能的高度调控的基因组和表观基因组电路的功能障碍来开发生物学相关的特征谱。
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('LESLIE RECIO', 18)}}的其他基金
Mutational profiling in human cells as an in vitro alternative to in vivo mutagenicity assessments
人体细胞突变分析作为体内致突变性评估的体外替代方案
- 批准号:
10696867 - 财政年份:2023
- 资助金额:
$ 57.37万 - 项目类别:
Mutational profiling in human cells as an in vitro alternative to in vivo mutagenicity assessments
人体细胞突变分析作为体内致突变性评估的体外替代方案
- 批准号:
10696867 - 财政年份:2023
- 资助金额:
$ 57.37万 - 项目类别:
GENETIC TOXICOLOGY SUPPORT FOR THE NTP AND THE NIEHS
NTP 和 NIEHS 的遗传毒理学支持
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10918014 - 财政年份:2020
- 资助金额:
$ 57.37万 - 项目类别:
Integration of Genomic Biomarkers with the devTOX Human Embryonic Stem Cells Scre
基因组生物标志物与 devTOX 人类胚胎干细胞 Scre 的整合
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8394684 - 财政年份:2012
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