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）：用于评估药物和环境药物可能导致出生缺陷的潜力的当前测定涉及动物模型的使用。这些模型不仅昂贵且耗时，而且对人类数据的一致性也很差。 STEMINATM生物标志物发现（STEMINA）开发了一种筛选测定法，该测定法利用人类胚胎（HES）细胞和代谢组学来研究暴露于所有人类模型系统中测试化合物的HES细胞的分泌组，以识别具有致病潜力的化合物。综合实验室系统（ILS）和STEMINA已正式建立了合作伙伴关系，以推动DevToXTM（Stemina的基于干细胞的毒理学测试平台）。该SBIR将通过询问对毒物暴露的HES细胞的人类基因组和表观基因组的影响来加深和扩展独特的DevToXTM平台。毒性测试筛查的重点是对表观基因组的影响是基于毒性的筛查的方面，即在基于高含量细胞的毒性测定中实际上不存在少数例外。重点 该SBIR的作用是：1。进行时间课程和剂量反应研究，旨在评估已知和研究的表观遗传生物标志物，使用DevToxtM平台和2。将基于毒性的mRNA和miRNA生物标记物整合到DevToxtm平台上，以对基因组和毒素对基因组和epepepegemome的影响进行整合。具体目的1是评估与在细胞培养过程中保持HES细胞的自我更新和多能性相关的生物标志物基因和miRNA的稳定性。具体目标2评估参考化合物对HES细胞中基因组和表观基因组反应生物标志物的影响。具体目标3将测试DOW Chemical Company在DevToXTM中提供的10种盲化学物质，这些化学品与基因组和表观基因组反应生物标志物集成在一起，然后将结果与其他发育毒理学筛查的“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平台的预测性，从而增加了其作为预测潜在发展和生殖毒性的权重工具的使用。 公共卫生相关性：干细胞在人体自我更新的所有细胞中具有独特的能力，也就是说，它们可以保持原始的非专业状态。在正确的条件下，它们可以产生身体的专门细胞（分化），例如心脏，肝脏或胰腺。人类胚胎干细胞被开发为评估发育毒性的毒性测试平台。这些细胞提出了一个独特的模型系统，可以理解和评估环境药物和新药候选者的影响，以预测或预期人类的毒性。