Development of an integrated 4-organ animal model

综合四器官动物模型的开发

• 批准号: 9986123
• 负责人: James J Hickman
• 金额: $ 74.47万
• 依托单位: HESPEROS, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-17 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9986123
• 关键词: Acute; Adult; Animal Model; Animal Organ; Animal Sources; Animals; Archives; Biological Markers; Blood; Bolus Infusion; Cardiac; Cell Culture Techniques; Cells; Chemicals; Chronic; Clinical Data; Clinical Trials; Consumption; Development; Devices; Dose; Drug Compounding; Drug Kinetics; Drug or Chemical; Evaluation; Exposure to; Female; Goals; Health; Hour; Human; In Vitro; Laboratories; Lead; Liquid substance; Literature; Liver; Measurement; Mechanics; Metabolic; Microelectrodes; Microfluidics; Modeling; Monitor; Muscle; Myocardium; Nature; Neonatal; Neuraxis; Neurons; Organ; Organ Model; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phenotype; Physiological; Pre-Clinical Model; Publishing; Rattus; Reporting; Serum; Skeletal Muscle; System; Systems Development; Techniques; Testing; Tissue Model; Tissues; Toxicology; Work; animal data; base; body on a chip; body system; cantilever; cell type; clinical predictors; cost effective; drug metabolism; experience; experimental study; improved; in vitro Model; in vivo; induced pluripotent stem cell; innovation; interest; liver metabolism; male; microphysiology system; models and simulation; non-invasive monitor; nutrient metabolism; organ on a chip; pharmacokinetics and pharmacodynamics; response; shear stress; skills; species difference; success

Project Summary/Abstract We propose to construct multi organ microphysiological systems (“Body-on-a-Chip” or BoaCs) from human and rat cells to use as a basis to understand species differences in response to exposure to drugs or chemicals in this new platform. The results will then be compared to clinical data, where available, and to archived in vivo animal data. This work will directly test whether such in vitro models can accurately reproduce species differences in response to known drugs. A preclinical model based on human cells that can accurately predict human response should lead to better decisions on whether exposure to a chemical or chemical mixture will be harmful to humans. An advantage of this in vitro approach, compared to standard in vitro systems (e.g. such as multiwell plates), is that the tissues can exchange metabolites and the dose dynamics in the body of both parental compounds and metabolites are better represented than when a single cell type is exposed to a bolus dose. Also, by comparing acute to chronic effects it will enable prediction on clinical trial success as well for determining PK of the compounds. In addition, the comparison of animal cells derived from iPSCs will enable the assessment of whether they can be substituted for primary animal cells. If successful, this could lead to stable cell sources for the animal models and reduce the number of animals needed for these studies. For this proposal we will build upon a four-organ model we recently published in Nature Scientific Reports (Oleaga, et al. 2016) which included model tissues for the liver, cardiac, skeletal muscle, and neuronal compartments that correctly predicted clinical response to five compounds. To construct a well defined system we will use a common serum free medium which mimics key features of blood. Hickman has developed microelectrode arrays and cantilever systems that are integrated on chip that allow for noninvasive electronic and mechanical readouts for not only acute but also chronic tests as well. To improve operability and enable a low volume system for eventual metabolite evaluation, we will use a pumpless system (Sung, et al. 210) and self contained devices. We will also utilize microfluidic analytical components for rapid and sensitive biomarker assessment. However, the number of biomarkers to be monitored for cell health and function will be greatly reduced in our systems from use of the function readouts. The system will be modeled by simulation using CFD to establish acceptable ranges for consumption of nutrients and drug metabolism as well as shear stress and to predict drug concentration profiles in the system to also enable PK/PD prediction capabilities. We believe that this technique will lead to more accurate and cost-effective assessment of the efficacy and toxicological potential of drugs chemicals or chemical mixtures and this approach will have a major impact on improving human health.

项目摘要/摘要 我们建议从人类构建多有机微生物生理系统（“片上的身体”或BOAC） 和大鼠细胞用作理解对药物或化学物质暴露的物种差异的基础 在这个新平台中。然后将结果与可用的临床数据进行比较，并在体内存档 动物数据。这项工作将直接测试这种体外模型是否可以准确再现物种 对已知药物的响应差异。基于人类细胞的临床前模型，可以准确预测 人类反应应该可以更好地决定暴露于化学或化学混合物 对人类有害。与标准体外系统相比，这种体外方法的优点（例如 Multiwell板），是组织可以交换代谢物和两个父母体内的剂量动力学 与单个细胞类型暴露于推注剂量时相比，化合物和代谢产物更好地表示。 同样，通过将急性与慢性效应进行比较，它将对临床试验成功进行预测 化合物的PK。另外，从IPSC衍生的动物细胞的比较将使评估能够进行评估 是否可以代替原代动物细胞。如果成功，这可能会导致稳定的细胞源 对于动物模型并减少这些研究所需的动物数量。 对于此提案，我们将建立在我们最近在《自然科学报告》中发表的四项轨道模型的基础上 （Oleaga等人，2016年），其中包括肝脏，心脏，骨骼肌肉和神经元的模型组织 正确预测对五种化合物的临床反应的隔室。构建一个定义明确的系统 我们将使用一种常见的无血清培养基，该培养基模仿血液的关键特征。希克曼已经发展 集成在芯片上的微电极阵列和悬臂系统，该系统允许无创电子 和机械读数不仅是急性的，还可以进行慢性测试。改善运营并启用 最终代谢物评估的低容量系统，我们将使用Pumpless系统（Sung等，210）和自我 包含设备。 我们还将利用微流体分析成分进行快速和敏感的生物标志物评估。 但是，要监测细胞健康和功能的生物标志物数量将大大减少 使用功能读数的系统。该系统将通过使用CFD进行模拟来建立模型 可接受的营养素和药物代谢以及剪切应力的可接受范围并预测药物 系统中的浓度轮廓也可以启用PK/PD预测功能。我们相信这项技术 将导致对药物的有效性和毒理潜力的更准确和成本效益的评估 化学或化学混合物，这种方法将对改善人类健康产生重大影响。