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

[342985]舒勒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物质的反应。提供这些信息的设备或系统可用于制定可接受剂量和暴露的指导方针。目前预测人体对化学物质的体内反应的方法分为两大类：非人类动物的体内研究和人类或非人类细胞和组织的体外研究。动物研究可能耗时长、成本高，而且很难在大范围内推广到人类身上。使用单一类型的分离细胞的体外研究不允许在组织之间交换代谢物。一种更现实的方法是建立一个微细胞培养模拟物（microCCA），它使用在相互连接的腔室中培养的哺乳动物细胞来物理表征基于生理学的药物动力学模型（PBPK）。PBPK模型通过模拟化学物质在相互连接的组织隔间中的吸附、分布、代谢和消除动力学，在数学上模拟动物/人类的代谢。在之前的工作中，PI通过制造三室和四室微型cca设备来模拟肝脏，肺和脂肪，展示了“概念验证”。拟议的工作将集中在与microCCA操作相关的重大工程挑战上，例如，集成一个能够维持再循环流动的微泵，并用光学透明基板制造该设备，以便集成用于数据收集的传感器。GOALI活动的重点是开发一种微cca和PBPK组合，可用于评估化学物质作为抑制结肠癌多药耐药（MDR）的潜在药物。PI将设计一个CCA系统，该系统将转交给基因网络科学公司（GNS, Co-PI）。GNS已经构建了一个结肠癌细胞的生物学详细模型，该模型将被修改以纳入不同的多药耐药机制。PBPK和CCA将被匹配，包括相同的器官/组织区室，允许直接比较体外CCA的模拟反应。多种耐多药抑制剂和化疗药物将被筛选用于治疗耐多药结肠癌。GNS将提供所有建模专业知识，并与PI共享仿真和实验结果。

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.