Disease-Specific Integrated Microphysiological Human Tissue Models

疾病特异性综合微生理人体组织模型

基本信息

批准号：
8768902
负责人：
KEVIN Edward HEALY
金额：
$ 82.99万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-24 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8768902
关键词：
Address Animal Model Arrhythmia Behavior Biological Models Blood Vessels Cardiac Cardiac Myocytes Cardiovascular Diseases Cells Communities Complex Devices Disease Drug Kinetics Drug toxicity Extracellular Matrix Failure Functional disorder Gene Mutation Genetic Heart Heart Diseases Hepatocyte Hereditary Disease Hip region structure Human Human Biology In Vitro Life Liver Liver diseases Long QT Syndrome Marketing Medicine Metabolism Methodology Methods Microfluidics Modeling Mutation Myocardium Organ Patients Pharmaceutical Preparations Pharmacodynamics Phase Physiological Population Positioning Attribute Preclinical Drug Evaluation Process Reliance Research Safety Structure Sudden Death System Tissue Engineering Tissue Model Tissues Toxic effect Toxicology Ventricular base cost cost effective design drug candidate drug development drug discovery drug metabolism efficacy testing human disease human tissue in vitro Model induced pluripotent stem cell novel reconstitution response safety testing scaffold screening stem theories

项目摘要

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.

描述（由申请人提供）：由于对安全性和有效性测试期间采用的非人类动物模型的依赖，药物开发受到阻碍。在这个效率低下的过程中，一个基本问题是，非人类动物模型既没有充分代表人类生物学，也没有概括人类疾病状态。发现特异性人类诱导多能茎（臀部）细胞的发现创造了开发体外疾病特异性模型组织的机会，用于高素质药物筛查和特定于患者的药物。该提案的主要里程碑是基于人类心肌和肝脏的微生物生理模型，建立人类心脏和肝组织的体外模型，具有正常和患者特异性髋关节细胞的群体，分化为心肌细胞或肝细胞。我们选择心脏和肝脏作为模型系统，因为候选药物的失败最常与其中一种器官的毒性有关。对于此UH2应用，我们选择将重点放在长QT综合征上，以此作为我们方法论的原则证明的基础。 QT间隔的延长，心脏心室复极化的电体现是心律不齐和猝死的主要原因。我们的模型将使人体心脏组织的受控制造能够研究新型微流体系统中健康和患病的功能。我们计划将患病的心脏组织模型与微流体平台上的“健康”肝模型相结合，然后将该设备用作原理系统，以筛选药物“治疗” LQT。随着心脏和肝模型的整合，我们可以筛选出药物的直接和非目标毒性在肝脏上。在UH2阶段结束时，我们预计我们的平台将很容易适应设计变化，并能够与UH3阶段竞争小组开发的其他生理系统集成。