Primate Heart Regeneration

灵长类动物心脏再生

• 批准号: 9101271
• 负责人: Charles E Murry
• 金额: $ 87.13万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9101271
• 关键词: Address; Adult; Animal Model; Animals; Architecture; Arrhythmia; Biosensing Techniques; Blood flow; Cardiac; Cardiac Myocytes; Catheters; Cell Culture Techniques; Cell Death; Cell Proliferation; Cells; Cessation of life; Clinical Trials; Coronary; Coronary Circulation; Coupled; Coupling; Dose; Electric Stimulation; Electrocardiogram; Electrophysiology (science); Ferritin; Foundations; Goals; Heart; Heart Transplantation; Histologic; Histology; Human; Hypertrophy; Hypoxia; Image; Imaging Techniques; Immune response; In Situ; Infarction; Injection of therapeutic agent; Ischemia; Left ventricular structure; MRI Scans; Macaca; Macaca nemestrina; Magnetic Resonance Imaging; Maps; Modeling; Monitor; Morphology; Mus; Myocardial Infarction; Myocardial dysfunction; Myocardium; Pacemakers; Patients; Pluripotent Stem Cells; Population; Population Dynamics; Positron-Emission Tomography; Predisposition; Primates; Pump; Research; Structure; System; Technology; Telemetry; Testing; Time; Tissues; Translating; Transplantation; Treatment Efficacy; Vascularization; Ventricular; Ventricular Arrhythmia; Ventricular Dysfunction; Ventricular Function; Work; angiogenesis; arterial remodeling; base; cardiac regeneration; clinically relevant; density; design; graft healing; heart rhythm; human embryonic stem cell; improved; insight; instrument; microangiography; molecular imaging; nonhuman primate; overexpression; prevent; programs; public health relevance; repaired; research study; response; voltage

 DESCRIPTION (provided by applicant): The long term goal of these studies is to develop a heart regeneration strategy that can be translated to humans. Our current focus is in human pluripotent stem cells, and more specifically, in human embryonic stem cell-derived cardiomyocytes (hESC-CMs). Building on 15 years' work in cell culture and small animals, we recently showed that hESC-CMs can be produced at a scale and purity that permit testing in the animal most likely to predict the human response: the non-human primate Macaca nemestrina. The hESC-CMs can generate grafts that average 40% of infarct size, and they electromechanically couple, beat in sync with the macaque heart and mature to adult size by 3 months. This proposal addresses the next-level challenges. Aim 1 is a pivotal efficacy study that will determine if hESC-CMs enhance contractile function in the infarcted macaque heart. Three doses of human cardiomyocytes will be tested, and ventricular structure and function will be determined by MRI. Aim 2 addresses the genesis of ventricular arrhythmias identified in our recent study. In addition to monitoring heart rhythm by telemetry, we will perform serial catheter-based mapping of the engrafted (3 cell doses) and sham-engrafted primate heart, generating activation maps that will classify arrhythmias as resulting from reentry or ectopic pacemakers. Programmed electrical stimulation will assess susceptibility to induced arrhythmias. In combination with Aim 1, these studies will determine if there is a dose of cardiomyocytes that enhances function without arrhythmias. Aim 3 uses molecular imaging techniques to assess graft population dynamics, tracking the waves of cell death and proliferation after transplantation. We also address the key question of graft vascularization, testing the hypothesis that grafts induce host coronary arterial remodeling and that, despite this response, that grafts are chronically underperfused. These experiments will provide the foundation for a planned clinical trial of heart repair and provide mechanistic insights not possible in human patients.

 描述（由申请人提供）：这些研究的长期目标是开发一种可以应用于人类的心脏再生策略，我们目前的重点是人类多能干细胞，更具体地说，是人类胚胎干细胞衍生的心肌细胞。 (hESC-CM) 基于 15 年在细胞培养和小动物方面的工作，我们最近表明，hESC-CM 的生产规模和纯度可以允许在最有可能预测人类的动物中进行测试。回应：非人类灵长类猕猴 Nemestrina 可以生成平均梗塞大小 40% 的移植物，并且它们通过机电耦合，与猕猴心脏同步跳动，并在 3 个月内成熟到成年大小。目标 1 是一项关键功效研究，将确定 hESC-CM 是否会增强梗死猕猴心脏的收缩功能。进行测试，心室结构和功能将通过 MRI 确定。目标 2 解决了我们最近研究中发现的室性心律失常的起源。除了通过遥测监测心律外，我们还将对植入的 (3) 进行连续导管测绘。细胞剂量）和假移植灵长类动物心脏，生成激活图，将心律失常分类为折返或异位起搏器引起的心律失常，从而评估敏感性。与目标 1 相结合，这些研究将确定是否有一定剂量的心肌细胞可以增强功能而不会导致心律失常。目标 3 使用分子成像技术来评估移植物群体动态，跟踪移植后的细胞死亡和增殖波。我们还解决了移植物血管化的关键问题，测试了移植物诱导宿主冠状动脉重塑的假设，并且尽管存在这种反应，移植物仍长期灌注不足。这些实验将为以下研究奠定基础。一项计划中的心脏修复临床试验，并提供在人类患者中不可能实现的机制见解。