Human heart-on-a-chip for screening cardiomyopathy and chemotherapeutic cardiotoxicity

用于筛查心肌病和化疗心脏毒性的人类心脏芯片

• 批准号: 9240184
• 负责人: KEVIN Edward HEALY
• 金额: $ 59.23万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240184
• 关键词: Affect; Animal Model; BAG3 gene; Biological Models; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cell Differentiation process; Cells; Clinical; Clinical Medicine; Communities; Complex; Coupling; Devices; Dilated Cardiomyopathy; Dimensions; Disease; Drug Costs; Drug usage; FDA approved; Failure; Functional disorder; Genes; Genetic; Genetic Engineering; Genome engineering; Goals; Heart; Heart Diseases; Human; Hypertrophic Cardiomyopathy; In Vitro; Malignant Neoplasms; Measures; Medicine; Methodology; Microfluidics; Modeling; Mutation; Myocardium; Organ; Organ Model; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Physiology; Population; Preclinical Drug Evaluation; Protein Isoforms; Standardization; Stem cells; Structure; Symptoms; System; Testing; Time; Tissue Engineering; Tissue Model; Tissues; Toxic effect; Training; Variant; Ventricular; base; chemotherapy; cost; cost effective; disease mechanisms study; drug candidate; drug development; drug discovery; efficacy testing; geometric structure; human disease; improved; in vitro Model; induced pluripotent stem cell; innovation; myosin-binding protein C; novel therapeutics; personalized medicine; response; safety testing; screening; stem; tool

Project Summary/Abstract: Drug discovery and development are hampered by high failure rates attributed to the reliance on non-human animal models employed during safety and efficacy testing. Even when drugs are approved there is a growing concern that cancer chemotherapeutics result in cardiotoxicity via unknown mechanisms, making it difficult to predict which patients will be affected. The discovery of human induced pluripotent stem (hiPS) cells has enabled the tissue engineering community to develop in vitro human models of tissues and organs to be used for high content drug screening and patient specific medicine. We envisage the device and stem cell combinations proposed in this application will result in an in vitro microphysiological system (MPS) that significantly reduces the cost of bringing a new drug candidate to market while improving efficacy. Specifically, a physiologically functioning iPS-derived in vitro model of cardiac tissue (e.g., MPS) would be a significant advancement for understanding cardiotoxicity (e.g., with chemotherapy), studying disease mechanisms, and developing new strategies to treat cardiac diseases. As a basis for proof-of-principle of our methodology and workflow, we have chosen to focus on illustrative forms of the most common cardiomyopathies, such as hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). The principal goal of this proposal is to establish an in vitro human cardiac MPS model based on geometric models of human ventricular myocardium with populations of normal, genetically engineered, and disease specific hiPS cells differentiated into cardiac myocytes (hiPS-CMs). We plan to assess in HCM and DCM lines the toxicity of chemotherapeutic compounds that are currently on the market, FDA approved, and are known to cause mild or reversible cardiac toxicity in some populations. A key strength of this proposal is that once we have calibrated our MPS with isogenic hiPS-CMs, then we will proceed to testing hiPS-CMs from cardiomyopathy patients with diverse backgrounds, as a step to using our MPS to advance the goals of personalized medicine. This comparison is critical, as patient-derived iPS lines that have different genetic backgrounds have unknown effects on physiology, so it is difficult to know if an altered response in our cardiac MPS is due to the disease, or normal variation. We have proposed three specific aims to achieve our goals. If we are successful in completing our Specific Aims, then our human in vitro MPS of cardiac tissue could be a powerful tool for screening chemotherapeutic drug candidates for treatment, and reduce both the time and cost of the drug discovery cycle.

项目概要/摘要： 药物发现和开发受到高失败率的阻碍，这归因于对非人类药物的依赖。 在安全性和有效性测试期间使用的动物模型。即使药物获得批准， 关注癌症化疗药物通过未知机制导致心脏毒性，使得难以 预测哪些患者会受到影响。人类诱导多能干细胞（hiPS）的发现， 使组织工程界能够开发出体外人体组织和器官模型， 用于高含量药物筛选和患者特异性药物。我们设想这个装置和干细胞 本申请中提出的组合将产生体外微生理系统（MPS）， 显著降低了将新候选药物推向市场的成本，同时提高了疗效。具体而言， 心脏组织的生理功能iPS衍生的体外模型（例如，MPS）将是一个重要的 理解心脏毒性的进展（例如，化疗），研究疾病机制，以及 开发治疗心脏病的新策略。作为我们方法论的原理证明的基础， 工作流程，我们选择集中在最常见的心肌病的说明性形式，如 肥厚型心肌病（HCM）和扩张型心肌病（DCM）。这项建议的主要目的是 在人心室肌几何模型的基础上建立离体人心脏MPS模型 具有分化的正常、基因工程和疾病特异性hiPS细胞群的心肌 进入心肌细胞（hiPS-CM）。我们计划在HCM和DCM细胞系中评估化疗药物的毒性， 目前市场上的FDA批准的化合物，已知可引起轻度或可逆的心脏病， 在某些人群中的毒性。这一建议的一个关键优势是，一旦我们校准了MPS， 因此，我们将继续测试来自具有不同基因的心肌病患者的hiPS-CM， 背景，作为使用我们的MPS推进个性化医疗目标的一步。这种比较是 关键的，因为具有不同遗传背景的患者来源的iPS系对 因此，很难知道我们的心脏MPS反应的改变是由于疾病还是正常的 变化量我们提出了三个具体目标来实现我们的目标。如果我们成功地完成了我们的 具体的目的，那么我们的人类体外心脏组织MPS可以成为筛选的有力工具 化疗药物候选治疗，并减少了药物发现的时间和成本 周期