Disease-Specific Integrated Microphysiological Human Tissue Models

疾病特异性综合微生理人体组织模型

• 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
• 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

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）：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依赖于非人类动物模型。这种低效过程中的一个根本问题是，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。患者特异性人诱导多能干细胞（hiPS）的发现为开发用于高含量药物筛选和患者特异性药物的体外疾病特异性模型组织创造了机会。该提案的主要里程碑是基于人心肌和肝脏的微生理学模型建立人心脏和肝脏组织的整合体外模型，其中正常和患者特异性hiPS细胞群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通常与这些器官之一的毒性有关。对于这个UH2应用程序，我们选择关注长QT综合征，作为我们方法原理验证的基础。QT间期延长是心脏心室复极的电表现，是心律失常和猝死的主要原因。我们的模型将允许人类心脏组织的受控制造，以研究新型微流体系统中健康和患病的功能。我们计划将患病的心脏组织模型与“健康”的肝脏模型集成在微流体平台上，然后使用该设备作为原理验证系统来筛选“治疗”LQTS的药物。由于心脏和肝脏模型将被整合，我们可以筛选药物的直接和脱靶毒性 在肝脏上。在UH2阶段结束时，我们预计我们的平台将易于适应设计变更，并能够与UH3阶段竞争团队开发的其他生理系统集成。