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

目标：开发细胞培养模拟装置来评估多重耐药抑制剂

• 批准号: 0342985
• 负责人: Michael Shuler
• 金额: --
• 依托单位: Cornell University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2006-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0342985&HistoricalAwards=false
• 关键词: GOAL; Development; Cell; Culture; Analog

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.

0342985Shulera改善人类健康的关键因素是确定人体对各种药物和环境化学物质的反应。然后可以使用设备或系统来提供可接受剂量和暴露的指南。当前预测体内人类对化学物质反应的方法分为两个基本类别：体内与非人类动物一起工作，并在体外与人或非人类或非人类细胞和组织一起工作。 动物研究可能是漫长而昂贵的，难以推断在广泛范围内的人类。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构建一种微细胞培养类似物（MicroCCA），该微细胞培养类似物（Microcca）使用在互连室中培养的哺乳动物细胞在物理上代表基于生理的药物动力学模型（PBPK）。 PBPK通过对互连组织隔室中化学物质的吸附，分布，代谢和消除动力学进行建模，从而模拟了数学模拟动物/人类代谢。在先前的工作中，PI通过制造三个和四个腔室微量糖设备来模拟肝脏，肺和脂肪，证明了“概念证明”。 拟议的工作将集中于与MicroCCA的运行相关的重大工程挑战，例如，集成了能够维持循环流并从光学清晰的基板制造设备以集成传感器以集成数据收集的微型量。在开发一种微C和PBPK组合时，该组合可用于评估化学物质作为抑制结肠癌中多药耐药性（MDR）的潜在药物。 PI将设计一个CCA系统，该系统将转移到Gene Network Sciences，Inc。（GNS，Co-Pi）。 GNS构建了结肠癌细胞的生物详细模型，该模型将进行修改，以结合多药耐药的不同机制。 PBPK和CCA将匹配，以包括相同的器官/组织室，可以直接比较模拟与体外CCA的响应。 将筛选大量的MDR抑制剂和化学治疗剂以治疗MDR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。