A synergistic in vitro-in silico model of the placental barrier for predicting fetal exposure and toxicity of xenobiotic compounds

胎盘屏障的协同体外计算机模拟模型，用于预测胎儿的外源化合物暴露和毒性

• 批准号: 10698740
• 负责人: Carrie German
• 金额: $ 85.74万
• 依托单位: CFD RESEARCH CORPORATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698740
• 关键词: Acetaminophen; Active Biological Transport; Address; Anatomy; Antibodies; Automobile Driving; Biological; Biological Assay; Blood Vessels; Calcium; Cell Death; Cell Line; Cells; Cellular Morphology; Chemicals; Circulation; Computer Models; Data; Dependence; Development; Devices; Dextrans; Dimensions; Disadvantaged; Discipline of obstetrics; Drug Kinetics; Drug Prescriptions; Drug Transport; Endothelial Cells; Ethics; Evaluation; Exclusion; Exposure to; Fetus; Genetic; Genetic Complementation Test; Gestational Age; Goals; Guidelines; Health; Hormones; Human; Human Chorionic Gonadotropin; Human body; Immunoglobulin G; In Vitro; Inflammation; Inulin; Lipids; Literature; Maintenance; Maternal Exposure; Mediating; Medical; Medical center; Microfluidic Microchips; Microfluidics; Modeling; Morphology; Mothers; Nutrient; Organ; Palmitates; Perfusion; Permeability; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Physiology; Placenta; Placental Biology; Positioning Attribute; Pregnant Women; Property; Protocols documentation; Regulation; Reperfusion Therapy; Reporting; Research; Resolution; Role; Source; Standardization; Syncytiotrophoblast; System; Testing; Therapeutic; Third Pregnancy Trimester; Time; Toxic effect; Toxin; Vascular Endothelial Cell; Waste Products; Xenobiotics; barrier to testing; cell type; cytotrophoblast; design; effective therapy; ex vivo perfusion; experience; experimental study; fetal; hydrophilicity; improved; in silico; in vitro Model; in vivo; in vivo evaluation; inorganic phosphate; ionization; lipophilicity; multidisciplinary; multiplex assay; oxygen transport; passive transport; pharmacokinetic model; phase 1 study; predictive modeling; prenatal exposure; protein expression; prototype; success; tool; treatment strategy; trophoblast; uptake

The placenta is one of the least understood organs of the human body. Acting as a barrier between mother and fetus, the placenta mediates transport of oxygen, nutrients, fetal waste products and other compounds present in maternal circulation. Full term placental explants are currently the most widely used models for assessing transport and barrier function. Unfortunately, these models are dependent upon the availability of fresh placentas. There is a critical need for standardized tools that quantitatively assess placental barrier transport to enable prediction of maternal and fetal pharmacokinetics (PK) and placental and fetal toxicity. In Phase I, we developed and demonstrated a physiologically relevant, microfluidic model of the placental barrier, comprising the maternal vasculature, placenta and fetal vasculature. Immortalized cytotrophoblasts were differentiated in the device into syncytiotrophoblasts, as verified by extensive characterization. Barrier function in the model was demonstrated by showing size-dependent permeability of compounds across the device. In parallel, we developed and validated an in vitro model of the microfluidic device, as a first step toward development of a physiologically- based, high-resolution model of transplacental species transport. In Phase II, we will continue to develop and integrate our in vitro and in silico components of this tool kit. We will extend the microfluidic model to comprise primary cells (trophoblasts and endothelial cells) and determine morphological, genetic and phenotypic differences between it and the Phase I cell line-based model. Further, we will test transplacental transport for a panel of compounds including xenobiotics, endogenous molecules, lipids, antibodies and toxins, for thorough evaluation of barrier function and replication of species transport in vivo. In parallel, we will develop a physiologically-based (PB), high-resolution model of the placenta to support mechanistic modeling of transplacental species transport. This model will be integrated with maternal and fetal PBPK models to enable prediction of maternal and fetal PK. Data obtained from in vitro experiments will be used to characterize drug transport at the level of the whole placenta using the integrated toolkit. The computational model will account for passive and active transport. The development of this platform will aide in the prediction of chemicals’ negative health effects in humans and address key limitations of current in vitro barrier test systems. A multidisciplinary team with expertise in microfluidic cell-based assays and placental biology has been assembled for the successful completion of the proposed project. By providing a more realistic representation of the placental barrier both in vitro and in silico, the toolkit promises to establish a new paradigm for assessment of the placenta as a barrier.

胎盘是人体最不为人所知的器官之一，充当着人体之间的屏障。 母亲和胎儿，胎盘介导氧气、营养物质、胎儿废物和其他物质的运输 存在于母体循环中的化合物是目前使用最广泛的。 使用模型来评估运输和屏障功能不幸的是，这些模型是相互依赖的。 迫切需要能够定量分析的标准化工具。 评估胎盘屏障转运以预测母体和胎儿药代动力学 (PK) 和 在第一阶段，我们开发并证明了一种生理相关的、 胎盘屏障的微流体模型，包括母体脉管系统、胎盘和胎儿 永生化细胞滋养层在装置中分化为合体滋养层， 通过模型中的广泛表征验证了这一点。 同时，我们开发并验证了化合物在整个设备中的尺寸依赖性渗透性。 微流体装置的体外模型，作为开发生理学的第一步 在第二阶段，我们将继续基于高分辨率的经胎盘物种运输模型。 开发并集成该工具包的体外和计算机组件我们将扩展微流体。 模型包含原代细胞（滋养层细胞和内皮细胞）并确定形态、 它与基于 I 期细胞系的模型之间的遗传和表型差异。 测试一组化合物的经胎盘转运，包括外源性分子、 脂质、抗体和毒素，用于全面评估物种的屏障功能和复制 与此同时，我们将开发一个基于生理学（PB）的高分辨率模型。 胎盘支持跨胎盘物种运输的机械模型。 与母体和胎儿 PBPK 模型集成，以预测母体和胎儿 PK 数据。 从体外实验获得的结果将用于表征整体水平的药物转运 使用集成工具包的胎盘计算模型将考虑被动和主动。 该平台的开发将有助于预测化学品的负面健康状况。 对人类的影响并解决当前体外屏障测试系统的关键局限性。 拥有微流体细胞分析和胎盘生物学专业知识的团队已经组建 通过提供更真实的代表来成功完成拟议的项目。 该工具包有望在体外和计算机模拟中建立胎盘屏障的新范例 评估胎盘作为屏障的作用。