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子潜在的导致出生缺陷的分析涉及动物模型的使用。这些模型不仅成本高、耗时长，而且与人类数据的一致性也很差。Stemina生物标志物发现（Stemina）开发了一种筛选试验，利用人类胚胎干细胞（hES）细胞和代谢组学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，以识别具有致畸潜力的化合物。近日，集成实验室系统公司（ILS）与Stemina公司正式建立合作伙伴关系，共同推进Stemina公司基于干细胞的毒理学测试平台devTOXTM。该SBIR将通过询问毒物暴露对人类基因组和hES细胞表观基因组的影响来深化和扩展独特的devTOXTM平台。毒性测试筛选侧重于对表观基因组的影响，这是基于毒性筛选的一个方面，除了少数例外，在高含量的基于细胞的毒性分析中几乎不存在。重点