Toxicology in the 21st Century Program (Tox21) - Genomic Toxicology

Tox21计划是环境保护局(EPA)、食品和药物管理局(FDA)、国家环境健康科学研究所(NIEHS)的国家毒理学计划(NTP)和NCATS为推进体外毒理学测试而进行的多机构合作努力。Tox21计划由三个NCATS团队组成：系统毒理学、基因组毒理学和计算毒理学。基因组毒理学小组开发改进的人类细胞培养模型和方法，以阐明毒理学和人类疾病。例如，我们验证了IPSC衍生的内皮细胞模型，根据基因表达谱和细胞因子谱显示它对烟草烟雾的反应非常像原代内皮细胞。(朱等人，2020)这个内皮细胞模型也被用来解释吸烟、病毒感染或其他血管毒物是如何导致心脏病发作的。这项工作还展示了一种信息学方法来识别控制转录反应的转录因子。在过去的一年里，我们还开发了永生化肾足细胞培养模型，以阐明糖尿病肾病和狼疮性肾炎等肾脏疾病的发生机制。将SV40大T基因导入原代细胞，并改进培养条件，建立了永生化足细胞系。我们还通过鉴定几个生物标志物改进了我们的LUHMES永生化人多巴胺能神经元模型。这些生物标记物对不同的神经毒物做出反应(童等人提交)，特别是那些损害神经元易感性途径、铁运输和氧化应激的生物标记物(通2018)因此，这些生物标记物将有助于筛选化学库以识别可能导致帕金森氏病或其他神经退行性疾病的神经退行性毒物。

The Tox21 Program is a multiagency collaborative effort among the Environmental Protection Agency (EPA), Food and Drug Administration (FDA), the National Toxicology Program (NTP) at the National Institute of Environmental Health Sciences (NIEHS), and NCATS to advance in vitro toxicological testing. The Tox21 Program is comprised of three NCATS teams: Systems Toxicology, Genomic Toxicology, and Computational Toxicology. The Genomic Toxicology group develops improved human cell culture models and methods to illuminate toxicology and human diseases. For example, we validated an iPSC-derived endothelial cell model by showing it responds to tobacco smoke very much like primary endothelial cells according to gene expression profiles and cytokine profiles.(Chu et al, 2020) This endothelial cell model is also being used to elucidate how smoking, viral infection, or other vascular toxicants lead to heart attack. This work also demonstrated an informatic method to identify transcription factors that govern transcriptional responses. Over the past year, we also developed an immortalized kidney podocyte culture model to illuminate how kidney diseases arise, such as diabetic nephropathy and lupus nephritis. Immortalized podocyte cell lines were established by introducing the SV40 Large T gene into primary cells, and improving culture conditions. We also improved our LUHMES immortalized human dopaminergic neuron model by characterizing several biomarkers. These biomarkers respond to diverse neurotoxicants (Tong et al., submitted), particularly those that impair characteristic neuronal susceptibility pathways, iron transport and oxidative stress (Tong 2018) Thus, these biomarkers will facilitate screening chemical libraries to identify neurodegenerative toxicants that may cause Parkinsons disease or other neurodegenerative diseases.