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，我们正在与NIEHS心血管健康效果创新团队合作，评估12种可疑心血管毒物对心脏和血管系统的不良影响。方法：我的实验室正在使用原代人内皮细胞模型和共培养血管模型来阐明环境毒物和药物如何通过影响血管衰竭模式而导致血管毒性和心脏病发作。血管衰竭模式包括血管活性紊乱、凝血、炎症和动脉粥样硬化。我的实验室正在使用细胞毒性分析、细胞因子谱分析和转录组学结合出发点(POD)分析来表征这些反应机制。童志斌博士在我的实验室中继续推进神经毒性研究，他发表了我们的LUHMES永生化人类多巴胺能神经元模型，该模型特别容易受到铁链细胞死亡以及谷胱甘肽代谢和铁代谢的干扰(童某，2022)。为了筛选这些神经元缺陷的文库，我们设计了LUHMES MT1G：：荧光素酶报告细胞系，并在1536孔微孔板上建立了3D培养格式。该模型将使筛选化学库能够识别可能导致帕金森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 are collaborating with the NIEHS Cardiovascular Health Effects Innovation Team to evaluate twelve suspected cardiovascular toxicants for adverse effects on heart and vasculature. Methods: My lab is using primary human endothelial cell models and co-culture vascular models to elucidate how environmental toxicants and drugs cause vascular toxicity and heart attacks through impacts on vascular failure modes. Vascular failure modes include perturbations of vasoactivity, coagulation, inflammation, and atherosclerosis. My lab is characterizing these response mechanisms using cytotoxicity assays, cytokine profiling and transcriptomics coupled with Point of Departure (POD) analyses. Dr. Zhi-Bin Tong continues to advance neurotoxicity studies in my lab by publishing that our LUHMES immortalized human dopaminergic neuron model is uniquely vulnerable to ferroptotic cell death as well as perturbations to glutathione metabolism and iron metabolism (Tong 2022). In order to screen libraries for these neuronal vulnerabilities we engineered a LUHMES MT1G::Luciferase reporter cell line and established a 3D culture format in 1536 well microplates. This model will enable screening chemical libraries to identify neurodegenerative toxicants that may cause Parkinsons disease or other neurodegenerative diseases.