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确定人体对各种药物和环境化学品的反应。然后，可以使用提供该信息的设备或系统来制定可接受剂量和暴露的指南。目前预测体内人类对化学品反应的方法分为两个基本类别：非人类动物的体内工作和人类或非人类细胞和组织的体外工作。 动物研究可能是漫长和昂贵的，很难在很大范围内推断人类。使用单一类型的分离细胞的体外研究不允许组织之间的代谢物交换。 一种更现实的方法是构建微细胞培养模拟物（microCCA），其使用在互连室中培养的哺乳动物细胞来物理地代表基于生理学的药代动力学模型（PBPK）。 PBPK模型通过对化学品在相互连接的组织隔室中的吸附、分布、代谢和消除动力学进行建模，在数学上模拟动物/人体代谢。在之前的工作中，PI通过制造三腔和四腔microCCA设备来模拟肝脏、肺和脂肪，展示了“概念验证”。 拟议的工作将侧重于与microCCA操作相关的重大工程挑战，例如，GOALI活动的重点是开发一种microCCA和PBPK组合，可用于评估化学品作为抑制结肠癌多药耐药性（MDR）的潜在药剂。 PI将设计一个CCA系统，并将其转移至Gene Network Sciences，Inc.。(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将匹配以包括相同的器官/组织隔室，从而可以直接比较模拟与体外CCA的反应。 将筛选多种MDR抑制剂和化疗药物以治疗MDR结肠癌。 GNS将提供所有的建模专业知识，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.