Disease Specific Cardiac Tissue Models

描述（由申请人提供）： 心血管疾病的治疗是全球医学界尚未满足的重要需求。我们建议通过使用精确控制的人工基质制剂来开发患病心脏组织的体外模型。本项目的主要目的是建立一个体外模型的人心脏组织的基础上重建的合成模型的人心室心肌与人口的患者特异性人类诱导多能干细胞（hiPS）细胞衍生的心肌细胞（hiPS-CM）。对于该应用，我们选择专注于单一的“患者特异性”疾病，长QT综合征（LQTS），作为我们的方法和工作流程的原理证明的基础。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。因此，心脏组织的LQTS“患者特异性”生理功能3D模型将是理解、研究和开发治疗心律失常和其他心血管疾病的新策略的重大进步。我们提出了以下细节，旨在生成人体心脏3D组织模型。目标1。优化定向分化方法，以获得来源于健康hiPS或携带LQTS基因突变（一种潜在致死突变）的hiPS细胞的一致高产（>75%）人CM群体。目标二。制造精确定义的3D丝状基质，将健康hiPS-CM的结构组织成人体心脏组织的3D体外模型。通过检查其电和机械活动来评估模型的功能行为。目标3。将LQTS-hiPS-CM的结构组织成人心肌的3D体外模型。通过检查“病变组织”模型的电和机械活动以及对药理学试剂的反应，评估其功能行为。(End摘要）

DESCRIPTION (provided by applicant): Treatments for cardiovascular diseases are significant unmet needs in the global medical community. We propose to develop in vitro models of diseased cardiac tissues by using precisely controlled artificial matrix preparations. The principal objective of this project is to establish an in vitro model of human cardiac tissue based on the reconstitution of synthetic models of the human ventricular myocardium with populations of patient specific human induced pluripotent stem (hiPS) cell-derived cardiomyocytes (hiPS-CMs). For this application we have chosen to focus on a single "patient-specific" disease, long QT syndrome (LQTS), as a basis for proof-of-principle of our methodology and workflow. Prolongation of the QT interval, the electrical manifestation of cardiac ventricular repolarization, is a major cause of cardiac arrhythmias and sudden death. Thus a LQTS "patient-specific" physiologically functioning 3D model of heart tissue would be a significant advancement for understanding, studying, and developing new strategies for treating cardiac arrhythmias and other cardiovascular diseases. We propose the following specifics aims to generate a human cardiac 3D tissue model. Aim 1. To optimize a directed differentiation method to obtain a consistent high yield (>75%) population of human CMs derived from either healthy hiPS or hiPS cells harboring gene mutations of LQTS, a potentially lethal mutation. Aim 2. To fabricate precisely defined 3D filamentous matrices that organize the structure of healthy hiPS-CMs into a 3D in vitro model of the human cardiac tissue. To assess the functional behavior of the model by examining its electrical and mechanical activity. Aim 3. To organize the structure of LQTS-hiPS-CMs into a 3D in vitro model of the human myocardium. To assess the functional behavior of the "diseased tissue" model by examining its electrical and mechanical activity, and response to pharmacological agents. (End of Abstract)