Omics-Based Assays for Screening Chemical Toxicity Using Stem Cells

 描述(由申请人提供)：化学毒性的测试和建模发生了范式转变。目前的毒理学要求基于细胞(与基于动物)、基于证据和基于Omics的分析。间充质干细胞(MSC)在骨、软骨、肌肉等多种组织的维持和修复中发挥重要作用。在循环血液中也可以发现间充质干细胞，并参与伤口愈合过程。因此，MSC可以说是化学毒理学中最具生理学相关性的成体干细胞之一。为了响应RFA-ES-15-006，Neomeics Inc.提出了这个SBIR第二阶段项目，以完成其产品的开发，即基于OMICS的高通量检测，以评估化学毒物对干细胞增殖和分化的影响。第二阶段项目是建立在我们第一阶段项目产生的非常有希望的结果的基础上。在第一阶段，我们已经展示了一个强大和通用的两阶段工作流程，用于基于Omics的高通量使用人类MSCs进行化学毒性筛选。我们还发现了几条途径和网络，用于从机制上了解间充质干细胞的化学毒性。在第二阶段，我们将利用Tox21 10k文库扩大对MSCs的毒性测试，开发Omics芯片并验证其在基于Omics的化学毒性测试中的应用，并提供一个工具包来筛选化学毒物对细胞分化的影响。一旦开发出来，我们的平台和解决方案可以用于其他类型干细胞的化学毒性研究，如ESCs和IPSCs，帮助确定深入毒理学评估的化学品的优先顺序，甚至帮助开发新的干预战略，以减轻化学毒性，从而促进公众健康。

 DESCRIPTION (provided by applicant): There is a paradigm shift in testing and modeling of chemical toxicity. Current toxicology calls for cell-based (vs. animal-based), evidence-based, and Omics-based assays. Mesenchymal stem cells (MSC) play important roles in the maintenance and repair of various tissues, including bone, cartilage, and muscle. MSCs are also found in circulating blood and participate in the wound-healing process. Therefore, MSC is arguably one of the most physiologically relevant adult stem cells for chemical toxicology. In response to RFA-ES-15-006, Newomics Inc. proposes this SBIR Phase II project to complete development of its product, high-throughput Omics-based assays to evaluate the effects of chemical toxicants on proliferation and differentiation of stem cells. The Phase II project is buil upon the extremely promising results generated from our Phase I project. In Phase I, we have demonstrated a robust and universal two-stage workflow for Omics-based and high-throughput screening of chemical toxicity using human MSCs. We have also discovered several pathways and networks for mechanistic understanding of chemical toxicity on MSCs. In Phase II, we will scale up our toxicity assays for MSCs using the Tox21 10k library, develop Omics-chips and validate their applications in Omics-based assays for chemical toxicity, and provide a toolkit for screening the effects of chemical toxicants on cell differentiation. Once developed, our platforms and solutions may be utilized for chemical toxicity studies of other types of stem cells such as ESCs and iPSCs, to help prioritize chemicals for in-depth toxicological evaluation, and to even help develop new intervention strategies for mitigating chemical toxicity, thereby contributing to public health.