Disease-Specific Integrated Microphysiological Human Tissue Models

描述（由申请人提供）：药物开发受到高失败率的阻碍，这归因于在安全性和有效性测试期间使用的非人类动物模型的依赖。这种低效过程的一个根本问题是，非人类动物模型既不能充分代表人类生物学，也不能概括人类疾病状态。患者特异性人类诱导多能干细胞（hiPS）细胞的发现为开发体外疾病特异性模型组织创造了机会，可用于高含量药物筛选和患者特异性药物。本研究的主要里程碑是在人类心肌和肝脏微生理模型的基础上，利用正常和患者特异性的hiPS细胞群体分化为心肌细胞或肝细胞，建立人类心脏和肝脏组织的体外综合模型。我们选择心脏和肝脏作为模型系统，因为候选药物的失败通常与其中一个器官的毒性有关。对于这个UH2应用，我们选择把重点放在长QT综合征上，作为我们方法原理验证的基础。QT间期延长是心室复极的电学表现，是心律失常和猝死的主要原因。我们的模型将允许控制制造人类心脏组织，以研究新型微流体系统中健康和患病的功能。我们计划将患病心脏组织模型与“健康”肝脏模型结合在微流控平台上，然后将该设备作为原理验证系统，筛选“治疗”LQTS的药物。随着心脏和肝脏模型的整合，我们可以同时筛选药物的直接毒性和脱靶毒性

DESCRIPTION (provided by applicant): Drug development is hampered by high failure rates attributed to the reliance on non-human animal models employed during safety and efficacy testing. A fundamental problem in this inefficient process is that non- human animal models neither adequately represent human biology nor recapitulate human disease states. The discovery of patient-specific human induced pluripotent stem (hiPS) cells creates the opportunity to develop in vitro disease-specific model tissues to be used for high content drug screening and patient specific medicine. The principal milestone of this proposal is to establish integrated in vitro models of human cardiac and liver tissue based on microphysiological models of human myocardium and liver with populations of normal and patient-specific hiPS cells differentiated into cardiomyocytes or hepatocytes. We chose the heart and liver as model systems, since failure of candidate drugs is most often associated with toxicity of one of these organs. For this UH2 application we have chosen to focus on long QT syndrome as a basis for proof-of-principle of our methodology. Prolongation of the QT interval, the electrical manifestation of cardiac ventricular repolarization, is a major cause of cardiac arrhythmias and sudden death. Our model will allow for controlled fabrication of human cardiac tissue to study the function of healthy and diseased within novel microfluidic systems. We plan to integrate the diseased cardiac tissue model with a "healthy" liver model on a microfluidic platform, and then use this device as proof-of-principle system to screen drugs to "treat" the LQTS. As the heart and liver models will be integrated, we can screen for both direct and off-target toxicity of drugs on the liver. At the end of the UH2 phase, we anticipate our platform will be easily adaptable to design changes and able to integrate with other physiological systems developed by competing groups during the UH3 phase.