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始内皮细胞。(Chu等人，2020)该内皮细胞模型还与NIEHS心血管计划合作用于阐明环境毒物和药物如何导致血管毒性和心脏病发作。方法：我们开发并申请了一项高通量方法的专利申请，该方法利用多重基因表达筛选化学文库，称为APLS。(Gerhold等人)US#63/196,438)与R.Huang Group一起，我们还开发了一种适用于公众访问的起点算法(POD)，以分析浓度反应转录数据，以识别剂量反应基因以及每个基因的浓度受治疗上调或下调的情况。在过去的两年里，我们开发了永生化肾足细胞培养(再生)模型，以阐明肾脏如何适应肾小球毒性和疾病，如糖尿病肾病和狼疮性肾炎。我们还通过表征包括铁代谢和氧化应激在内的几个生物标记物和神经元易感性途径，完善了我们的LUHMES永生化人类多巴胺能神经元模型(通2018)该模型将使筛选化学资料库能够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 in collaboration with the NIEHS Cardiovascular Program to elucidate how environmental toxicants and drugs cause vascular toxicity and heart attacks. Methods: We developed and filed a patent application on a high-throughput method to screen chemical libraries using multiplex gene expression, called APLS. (Gerhold et al. US #63/196,438) With R. Huangs Group we also developed a Point of Departure algorithm (POD) for public access to analyze concentration-response transcriptomic data to identify dose-responsive genes and the concentration where each is up- or down-regulated by a treatment. Over the past two years, we developed an immortalized kidney podocyte culture (regeneration) model to illuminate how kidneys adapt to glomerular toxicities and disease such as diabetic nephropathy and lupus nephritis. We also refined our LUHMES immortalized human dopaminergic neuron model by characterizing several biomarkers and neuronal susceptibility pathways including, iron metabolism and oxidative stress (Tong 2018) This model will enable screening chemical libraries to identify neurodegenerative toxicants that may cause Parkinsons disease or other neurodegenerative diseases.