GOAL: Development of a Cell Culture Analog Device to Assess MultiDrug Resistant Suppressors

改善人类健康的一个关键因素是决定人体对各种药物和环境化学品的反应。然后，可以使用提供这一信息的设备或系统来制定可接受剂量和暴露的指导方针。目前预测体内人类对化学物质反应的方法可分为两大类：体内研究非人类动物，以及体外研究人类或非人类细胞和组织。动物研究可能既冗长又昂贵，而且很难在很大范围内推算到人类身上。在使用单一类型的分离细胞的体外研究中，不允许组织之间的代谢物交换。一种更现实的方法是建立一个微型细胞培养模拟物(MicroCCA)，它使用在相互连接的房间中培养的哺乳动物细胞来物理地表示基于生理的药动模型(PBPK)。PBPK模型通过模拟化学物质在相互连接的组织间隔中的吸附、分布、代谢和消除动力学来数学模拟动物/人类的新陈代谢。在之前的工作中，PI通过制造三腔和四腔的微CCA设备来模拟肝脏、肺和脂肪，展示了“概念证明”。拟议的工作将集中在与微CCA操作相关的重大工程挑战上，例如，集成能够维持循环流动的微泵，以及利用光学透明的衬底制造设备，以便集成用于数据收集的传感器。目标活动集中于开发微CCA和PBPK的组合，该组合可用于评估化学物质作为潜在的药物来抑制结肠癌的多药耐药(MDR)。PI将设计一个CCA系统，该系统将被转移到基因网络科学公司(GNS，Co-PI)。GNS已经构建了一个详细的结肠癌细胞生物学模型，该模型将进行修改，以纳入不同的多药耐药机制。PBPK和CCA将被匹配，以包括相同的器官/组织隔室，从而允许模拟与体外CCA的反应进行直接比较。将筛选多种耐多药抑制药和化疗药物来治疗多药耐药结肠癌。GNS将提供所有建模专业知识，并与PI共享模拟和实验结果。

0342985ShulerA key factor in improving human health is determining the response of the human body to various pharmaceutical and environmental chemicals. A device or system to provide this information can then be used to formulate guidelines for acceptable doses and exposure. Current approaches to predicting in vivo human response to chemicals fall into two basic categories: in vivo work with non-human animals and in vitro work with human or non-human cells and tissues. Animal studies may be lengthy and expensive and difficult to extrapolate to humans over a wide range. In vitro studies using isolated cells of a single type do not allow for exchange of metabolites between tissues. A more realistic approach is to build a micro cell culture analog (microCCA) that uses mammalian cells cultured in interconnected chambers to physically represent a physiologically based pharmokinetic model (PBPK). PBPK models mathematically simulate animal/human metabolism by modeling the adsorption, distribution, metabolism, and elimination kinetics of a chemical in interconnected tissue compartments. In prior work, the PI demonstrated "proof of concept" through fabrication of three and four chamber microCCA devices to model liver, lung and fat. The proposed work will focus on significant engineering challenges related to the operation of the microCCA, e.g., integrating a micropump capable of maintaining recirculating flow and fabricating the device from an optically clear substrate in order to integrate sensors for data collection.The GOALI activities are focused on developing a microCCA and PBPK combination that can be used to assess chemicals as potential agents to suppress multidrug resistance (MDR) in colon cancer. The PI will design a CCA system that will be transferred to Gene Network Sciences, Inc. (GNS, Co-PI). GNS has constructed a biologically detailed model of a colon cancer cell that will be modified to incorporate different mechanisms of multidrug resistance. The PBPK and CCA will be matched to include the same organ/tissue compartments allowing direct comparisons of simulation to responses of the in vitro CCA. A large variety of MDR suppressors and chemotherapeutics will be screened to treat MDR colon cancer. GNS will provide all of the modeling expertise and share both simulation and experimental results with the PI.