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大需求。我们建议通过使用精确控制的人工基质制剂来建立病变心脏组织的体外模型。本项目的主要目的是利用患者特异性的人诱导多能干细胞(HIPS)来源的心肌细胞(HIPS-CMS)群体重建人心肌组织的合成模型，建立人心肌组织的体外模型。对于这一应用，我们选择关注一种“特定于患者”的疾病--长QT间期综合征(LQTS)，作为我们的方法和工作流程原则证明的基础。QT间期延长是心脏复极的电学表现，是心律失常和猝死的主要原因。因此，LQTS患者特有的心脏组织生理功能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。我们提出了以下旨在生成人类心脏3D组织模型的细节。目的1.优化定向分化方法以获得一致的高产量(&gt；75%)人CMS群体，该群体来自健康髋关节或携带LQTS基因突变的HIPS细胞，LQTS是一种潜在的致命突变。目的2.构建精确定义的3D丝状基质，将健康HIPS-CMS的结构组织成人体心脏组织的3D体外模型。通过检查模型的电气和机械活动来评估模型的功能行为。目的3.将LQTS-HIPS-CMS的结构组织成人体心肌的三维体外模型。通过检测“病变组织”模型的电和机械活性以及对药物的反应来评估该模型的功能行为。(摘要结束)

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)