Computational Modeling Core

药代动力学（PK）和药效学（PD）共同定义了从毒物暴露到药物代谢的连续体。 可能导致不良后果的生物扰动。毒理学越来越多地涉及计算 补充实验室研究的方法，并提供一个更综合，定量和机械 人类健康风险评估的基础。计算建模核心（CMC）将提供一套 计算能力，以支持生物医学和环境工程项目。中央军委 将：（一）开发二恶英和二恶英类化合物的生理学PK（PBPK）和PD模型，（二） 为高维组学研究提供面向项目的生物信息学支持，以及（iii）提供交叉- 接受过计算毒理学的专业训练模型开发将与实验室反复协调 项目开展的实验。之前CMC与密歇根州立大学（MSU）的互动 超级基金项目已经表明，这种迭代方法对于假设生成和评估是有效的。 在具体目标1（SA 1）中，我们将开发2，3，7，8-四氯二苯-对-二恶英（TCDD）的PBPK模型， 与超级基金场地相关的多氯二苯并对二恶英和呋喃。模型将包括 诱导肝脏CYP 1A 2作为二恶英结合蛋白和肝脏脂质蓄积， 预测游离PCDD/F浓度。该模型将支持项目3中的小鼠肝毒性研究 和项目5中活性炭处理土壤的多氯二苯并对二恶英/多氯二苯并呋喃生物利用度研究。人PBPK模型还将 开发用于帮助建立小鼠和人类之间的组织剂量等效性，用于项目3和 根据项目1和项目2的体外分析推断体内多氯二苯并对二恶英/多氯二苯并呋喃接触水平。在SA 2中，我们将 使用生物信息学工具从单个细胞中解析出芳烃受体（AHR）介导的细胞状态轨迹， 人CD 5 + B细胞（项目1）和小鼠肝细胞（项目3）的细胞RNA测序数据，并应用于 非线性动力学系统分析，以鉴定预测AHR介导的毒性发作的新型生物标志物。 我们还将确定AHR干扰的基因调控网络，以告知SA 3中的途径建模。在SA 3中， 项目1的动力学通路建模将解决AHR激活对PD-1抑制信号的影响 在CD 5 + B细胞中的转导途径。对于项目2，诱导肝脏甲状腺激素代谢的模型 将制定多氯二苯并对二恶英/多氯二苯并呋喃的风险评估标准，以支持人口健康风险评估。对于项目3，途径建模 将重点关注通过AHR介导的关键肝脏转录改变来破坏肝脏脂质代谢， 内切酶这些模型将支持非线性剂量反应的严格调查，并提供强有力的 支持机械驱动风险评估的研究基础。CMC还将支持项目4， 模拟维生素B12抢救和从头合成途径的细菌脱卤二恶英/Fs。在SA 4中， 与RETCC合作，举办了为期3天的PBPK建模课程和为期5天的计算系统课程 毒理学：建模和信息学将在每隔一年提供给SRP和风险评估社区。

Pharmacokinetics (PK) and pharmacodynamics (PD) together define the continuum from toxicant exposure to biological perturbations that can cause adverse outcomes. Toxicology increasingly involves computational approaches that complement laboratory studies and provide a more integrated, quantitative and mechanistic basis for human health risk assessment. The Computational Modeling Core (CMC) will provide a suite of computational capabilities to support both the Biomedical and Environmental Engineering Projects. The CMC will: (i) develop physiologically based PK (PBPK) and PD models of dioxins and dioxin-like compounds, (ii) provide Project-oriented bioinformatic support for high-dimensional omic studies, and (iii) provide cross- disciplinary training in computational toxicology. Model development will be coordinated iteratively with laboratory experiments carried out by the Projects. Prior CMC interactions with the Michigan State University (MSU) Superfund Projects have shown that this iterative approach is efficient for hypothesis generation and evaluation. In Specific Aim 1 (SA1) we will develop PBPK models for 2,3,7,8-tetrachlorodiben-p-dioxin (TCDD) and Superfund site-relevant polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs). The models will include induction of hepatic CYP1A2 as a dioxin-binding protein and liver lipid accumulation for more accurate predictions of free PCDD/F concentrations. The models will support hepatotoxicity studies in mice in Project 3 and PCDD/F bioavailability studies of activated carbon-treated soil in Project 5. Human PBPK models will also be developed to help establish tissue dose equivalency between mice and humans for Project 3 and for extrapolation of in vivo PCDD/F exposure levels based on in vitro assays in Projects 1 and 2. In SA2 we will use bioinformatic tools to parse out aryl hydrocarbon receptor (AHR)-mediated cell state trajectories from single- cell RNA sequencing data in human CD5+ B cells (Project 1) and mouse hepatocytes (Project 3), and apply nonlinear dynamical systems analysis to identify novel biomarkers predictive of onset of AHR-mediated toxicity. We will also identify AHR-perturbed gene regulatory networks to inform pathway modeling in SA3. In SA3, dynamical pathway modeling for Project 1 will address the effects of AHR activation on the PD-1 inhibitory signal transduction pathway in CD5+ B cells. For Project 2, a model of induction of hepatic thyroid hormone metabolism by PCDD/Fs will be developed to support population health risk assessment. For Project 3, pathway modeling will focus on disruption of hepatic lipid metabolism through AHR-mediated transcriptional alteration of key liver enzymes. These models will support rigorous investigation of nonlinear dose-responses and provide a strong foundation for research supporting mechanistically-driven risk assessment. CMC will also support Project 4 to model the vitamin B12 salvaging and de novo synthesis pathways in bacteria dehalogenating PCDD/Fs. In SA4, in collaboration with RETCC, a 3-day course on PBPK modeling and a 5-day course on Computational Systems Toxicology: Modeling and Informatics will be offered in alternate years to SRP and risk assessment communities.