Multimodality Molecular Imaging of Stem Cell Therapy for Ischemic Cardiomyopathy

项目摘要 获得这份新早期调查员R01奖金将帮助我完成向独立调查人员的过渡 内科医生-科学家，他应用先进的成像技术将新的治疗方法转化到床边。作为一名 心血管医学专家，在多模式成像和干细胞生物学方面接受过广泛的培训，我是 在一个独特的位置上，运用我的专业知识来克服继续阻碍日常工作的重要障碍 心脏干细胞再生治疗缺血性心脏病的临床应用。 缺血性心脏病所致的终末期心力衰竭仍然是一种高发病率和高发病率的破坏性疾病。 死亡率。据估计，每九个人中就有一个死于心力衰竭。虽然心脏干细胞治疗 已成为修复或替代受损心肌的一种有前途的治疗方法，其结果是 使用骨髓干细胞的随机临床试验表明，只有少数患者受益。 这些令人失望的结果引发了非信仰者的批评，他们认为这些细胞不能再生 心。然而，这些细胞可能永远不会到达受损的心肌，或者在到达之前死亡。 显著改善心脏功能。显然，我们需要结合先进的成像技术来可视化 干细胞移植后的命运，以更好地了解为什么临床试验表明心脏 干细胞疗法只使少数患者受益。 这项提议的长期目标是将新技术应用于基因组编辑和多模式成像 在不久的将来为人体干细胞贩运提供便利。在这项提案的目标1中，我们将使用新的地点- 引入人类报告基因的特定基因组编辑技术(例如，CRISPR)，这可能是 免疫原性较低，转化为人类诱导的多能干细胞(HiPSCs)进行细胞运输。在目标2中，我们将 携带报告基因的IPSCs分化的心肌移植细胞(IPSC-CMS) 在大鼠心肌梗死模型中使用促存活药物进行预治疗。我们将进行活体追踪 并将存活曲线与功能改善相关联。我们将使用分子成像作为 以及转录、蛋白质组学和组织学分析，以更好地了解 急性供者死亡，并确定给予佐剂是否可以提高细胞存活率。在《目标3》中， 我们将确定在Aim 2中确定的最好的辅助治疗是否也将改善细胞存活 猪缺血性心肌病模型。我们将优化成像和治疗方案，在这个大型 动物模型，这在启动人类报告基因成像之前是必要的。来自这些的信息 这些研究将为我们小组和其他人将心脏干细胞成像技术应用于临床奠定基础 审判。

PROJECT ABSTRACT Receiving this New and Early Investigator R01 grant will help me complete my transition into an independent physician-scientist who applies advanced imaging technology to translate novel therapy to the bedside. As a cardiovascular medicine specialist with extensive training in multi-modality imaging and stem cell biology, I am in a unique position to apply my expertise to overcome important hurdles that continue to hinder the routine clinical implementation of cardiac stem cell regenerative therapy for ischemic heart disease. End-stage heart failure from ischemic heart disease remains a devastating disease with high morbidity and mortality. It is estimated that one in nine death results from heart failure. Although cardiac stem cell therapy has emerged as a promising therapy to repair or replace the damaged myocardium, results from large, randomized clinical trials using bone marrow derived stem cells have shown that only a few patients benefit. These disappointing results have fueled criticism from nonbelievers that these cells cannot regenerate the heart. It is possible, however, that these cells never reach the injured myocardium or die before they can significantly improve heart function. Clearly, we need to incorporate advanced imaging techniques to visualize stem cell fate after transplantation to gain a better understanding of why clinical trials have shown that cardiac stem cell therapy benefits only a few patients. The long-term goal of this proposal is to apply novel techniques in genome editing and multi-modality imaging to facilitate stem cell trafficking in humans in the near future. In Aim 1 of this proposal, we will use novel site- specific genome editing techniques (e.g., CRISPR) to introduce a human reporter gene, which is potentially less immunogenic, into human induced pluripotent stem cells (hiPSCs) for cell trafficking. In Aim 2, we will transplant cardiomyocytes differentiated from iPSCs (iPSC-CMs) carrying the reporter gene with and without pre-treatment with pro-survival agents into a rat model of myocardia infarction. We will perform in vivo tracking of cell survival and correlate survival curves with functional improvement. We will use molecular imaging as well as transcriptional, proteomic, and histological assays to better understand the mechanisms contributing to acute donor death and determine if the administration of adjuvant agents can improve cell survival. In Aim 3, we will determine whether the best adjuvant therapy identified in Aim 2 will also improve cell survival in a porcine model of ischemic cardiomyopathy. We will optimize imaging and treatment protocols in this large animal model, which is necessary before initiating reporter gene imaging in humans. Information from these studies will lay the foundation for our group and others to incorporate cardiac stem cell imaging into clinical trials.