Multimodality Molecular Imaging of Stem Cell Therapy for Ischemic Cardiomyopathy

项目摘要 接受这个新的和早期的研究者R 01赠款将帮助我完成我的过渡到一个独立的 他是一位医生兼科学家，运用先进的成像技术将新颖的治疗方法应用于临床。作为 作为一名心血管医学专家，我在多模态成像和干细胞生物学方面接受过广泛的培训， 在一个独特的位置，运用我的专业知识，以克服重要的障碍，继续阻碍例行 缺血性心脏病心脏干细胞再生治疗的临床实施。 缺血性心脏病引起的终末期心力衰竭仍然是一种毁灭性的疾病， mortality.据估计，每九个人中就有一个死于心力衰竭。虽然心脏干细胞疗法 已经成为修复或替换受损心肌的有希望的疗法，其由大的， 使用骨髓来源的干细胞的随机临床试验显示只有少数患者受益。 这些令人失望的结果引发了非信徒的批评，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，或者在它们到达之前死亡。 显著改善心脏功能。很明显，我们需要结合先进的成像技术 移植后干细胞的命运，以更好地理解为什么临床试验显示心脏 干细胞治疗只能使少数患者受益。 该提案的长期目标是将新技术应用于基因组编辑和多模态成像 在不久的将来促进人类干细胞的贩运。在本建议的目标1中，我们将使用新网站- 特定的基因组编辑技术（例如，CRISPR）引入人类报告基因，这可能是 免疫原性较低的人诱导多能干细胞（hiPSC）用于细胞运输。在目标2中，我们 从携带报告基因的iPSC（iPSC-CM）分化的移植心肌细胞， 用促存活剂预处理心肌梗死大鼠模型。我们将进行体内追踪 并将存活曲线与功能改善相关联。我们将使用分子成像技术， 以及转录、蛋白质组学和组织学分析，以更好地了解有助于 急性供体死亡，并确定给予佐剂是否可以改善细胞存活。在目标3中， 我们将确定目标2中确定的最佳辅助治疗是否也会改善细胞存活率。 缺血性心肌病的猪模型。我们将优化成像和治疗方案， 动物模型，这是在启动人类报告基因成像之前所必需的。这些信息 这些研究将为我们小组和其他人将心脏干细胞成像纳入临床研究奠定基础。 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.