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

• 批准号: 8394684
• 负责人: LESLIE RECIO
• 金额: $ 14.99万
• 依托单位: INTEGRATED LABORATORY SYSTEMS, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394684
• 关键词: Animal Model; Biological Assay; Biological Markers; Biological Models; Blinded; Cell Culture Techniques; Cell physiology; Cells; Chemicals; Congenital Abnormality; DNA Methylation; Data; Development; Dose; Embryo; Epigenetic Process; Gene Expression; Gene Expression Profiling; Genes; Genome; Genome Stability; Genomics; Growth; Heart; Housing; Human; Human Genome; Human body; In Vitro; Laboratories; Liver; Messenger RNA; MicroRNAs; Modeling; Pancreas; Pharmaceutical Preparations; Phase; Play; Reporting; Risk Assessment; Rodent; Role; Safety; Sampling; Screening procedure; Small Business Innovation Research Grant; Stem cells; System; Technology Transfer; Test Result; Testing; Time; Toxic effect; Toxicant exposure; Toxicity Tests; Toxicogenomics; Toxicology; Training; Untranslated RNA; Weight; Zebrafish; base; design; developmental toxicology; drug candidate; environmental agent; epigenomics; high throughput screening; histone modification; human data; human embryonic stem cell; human stem cells; metabolomics; neuronal cell body; pluripotency; reproductive development; response; self-renewal; stem; tool; toxicant

DESCRIPTION (provided by applicant): Current assays employed to assess the potential of drugs and environmental agents for their potential to cause birth defects involve the use of animal models. Not only are these models costly and time consuming, but they also have poor concordance to human data. SteminaTM Biomarker Discovery (Stemina) has developed a screening assay that utilizes human embryonic stem (hES) cells and metabolomics to study the secretome of hES cells exposed to test compounds in an all human model system to identify compounds with teratogenic potential. Integrated Laboratory Systems (ILS) and Stemina have formalized a partnership to advance devTOXTM, Stemina's stem cell-based toxicology testing platform. This SBIR will deepen and extend the unique devTOXTM platform by interrogating impact on the human genome and epigenome of hES cells from toxicant exposures. Toxicity testing screens focused on effects to the epigenome are aspect of toxicity based screening that with a few exceptions is virtually absent in high content cellular based toxicity assays. The focus of this SBIR is to: 1. conduct time course and dose-response studies directed at evaluating known and investigative epigenetic biomarkers indicative of aberrant hES cell function using the devTOXTM platform and 2. integrate toxicogenomics-based mRNA and miRNA biomarkers to the devTOXTM platform to assess the impact of toxicants on the genome and epigenome in three specific aims. Specific Aim 1 is to assess stability of biomarker genes and miRNAS associated with maintaining self- renewal and pluripotency of hES cells during cell culture expansion. Specific aim 2 Assess the impact of a reference set of test compounds on genomic and epigenomic response biomarkers in hES cells. Specific aim 3 will test 10 blinded chemicals provided by DOW Chemical Company in DevTOXTM integrated with genomic and epigenomic response biomarkers, then compare results to Dow "in-house" test results from other developmental toxicology screens. We anticipate that the integration of the gene expression and epigenomic profiling with the devTOXTM will increase the predictivity of the devTOXTM platform increasing its use as a weight- of-evidence tool in predicting potential development and reproductive toxicity. PUBLIC HEALTH RELEVANCE: Stem cells have the unique ability among all of the cells of the human body of self- renewal, that is, they can remain in a primitive unspecialized state. Under the right conditions, they can give rise to specialized cells of the body (differentiation) like th heart, liver, or pancreas. Human embryonic stem cells are being developed as a toxicity testing platform for the assessment of developmental toxicity. These cells present a unique model system to understand and assess the effects of environmental agents and new drug candidates to predict or anticipate toxicity in humans.

描述（由申请人提供）：目前用于评估药物和环境因素导致出生缺陷的可能性的测定涉及动物模型的使用。这些模型不仅成本高昂且耗时，而且与人类数据的一致性也很差。 SteminaTM Biomarker Discovery (Stemina) 开发了一种筛选方法，利用人胚胎干 (hES) 细胞和代谢组学来研究在全人类模型系统中暴露于测试化合物的 hES 细胞的分泌组，以识别具有致畸潜力的化合物。 Integrated Laboratory Systems (ILS) 和 Stemina 已正式建立合作伙伴关系，以推进 Stemina 基于干细胞的毒理学测试平台 devTOXTM。该 SBIR 将通过探究有毒物质暴露对人类基因组和 hES 细胞表观基因组的影响，深化和扩展独特的 devTOXTM 平台。毒性测试筛选侧重于对表观基因组的影响，是基于毒性的筛选的一个方面，除了少数例外，在高含量细胞毒性测定中几乎不存在。焦点 该 SBIR 的目的是： 1. 使用 devTOXTM 平台进行时程和剂量反应研究，旨在评估指示异常 hES 细胞功能的已知和研究性表观遗传生物标志物，以及 2. 将基于毒物基因组学的 mRNA 和 miRNA 生物标志物整合到 devTOXTM 平台，以从三个具体目标评估有毒物质对基因组和表观基因组的影响。具体目标 1 是评估与细胞培养扩增过程中维持 hES 细胞自我更新和多能性相关的生物标志物基因和 miRNAS 的稳定性。具体目标 2 评估测试化合物参考集对 hES 细胞基因组和表观基因组反应生物标志物的影响。具体目标 3 将在与基因组和表观基因组反应生物标志物集成的 DevTOXTM 中测试陶氏化学公司提供的 10 种盲化化学品，然后将结果与来自其他发育毒理学筛选的陶氏“内部”测试结果进行比较。我们预计，基因表达和表观基因组分析与 devTOXTM 的整合将提高 devTOXTM 平台的预测能力，增加其作为证据权重工具在预测潜在发育和生殖毒性方面的用途。 公共健康相关性：干细胞具有人体所有细胞中独特的自我更新能力，即它们可以保持原始的非特化状态。在适当的条件下，它们可以产生身体的特殊细胞（分化），如心脏、肝脏或胰腺。人类胚胎干细胞正在被开发为用于评估发育毒性的毒性测试平台。这些细胞提供了一个独特的模型系统，可以理解和评估环境因素和新候选药物的影响，从而预测或预测对人类的毒性。