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

项目摘要/摘要： 药物发现和开发受到高失败率的阻碍，归因于对非人类的依赖 在安全性和有效性测试中使用的动物模型。即使药物获得批准，也有越来越多的人 担心癌症化疗药物通过未知的机制导致心脏毒性，使其难以 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可供使用的组织和器官的体外人体模型 用于高含量药物筛选和患者特效药。我们设想了这个装置和干细胞 本申请中提出的组合将产生体外微生理系统(MPS)，该系统 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。具体来说， 一种具有生理功能的心脏组织体外模型(例如，MPS)将是一个重要的 了解心脏毒性(如化疗)，研究疾病机制，以及 开发治疗心脏病的新策略。作为我们的方法和方法的原则证明的基础 工作流，我们选择集中在最常见的心肌病的说明性形式上，例如 肥厚型心肌病(HCM)和扩张型心肌病(DCM)。这项提议的主要目标是 基于人体心脏几何模型建立体外人心脏MPS模型 具有正常、基因工程和疾病特异性HIPS细胞分化群体的心肌 转化为心肌细胞(HIPS-CMS)。我们计划在HCM和DCM系中评估化疗的毒性 目前市场上的化合物，FDA批准，并已知会导致轻微或可逆的心脏 在某些人群中存在毒性。这项提议的一个关键优势是，一旦我们用以下标准校准了我们的MPS 等基因HIPS-CMS，然后我们将继续检测不同类型心肌病患者的HIPS-CMS 背景，作为利用我们的MPS推进个性化医疗目标的一步。这种比较是 关键，因为具有不同遗传背景的患者来源的iPS系对 生理学，所以很难知道我们心脏MPS的反应改变是由于疾病还是正常 变种。为了实现我们的目标，我们提出了三个具体目标。如果我们成功地完成了我们的 特异性靶点，那么我们的人体外心脏组织MPS可能成为筛选的有力工具 化疗药物候选治疗，并减少药物发现的时间和成本 周而复始。

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.