Multimodality Molecular Imaging of Stem Cell Therapy for Ischemic Cardiomyopathy

干细胞治疗缺血性心肌病的多模态分子成像

基本信息

批准号：
10456522
负责人：
Patricia Kim Phuong Nguyen
金额：
$ 3.09万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456522
关键词：
Acute Adjuvant Adjuvant Therapy Animal Model Animals Apoptosis Area Biological Assay Bone Marrow CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiovascular Physiology Cardiovascular system Cell Death Cell Line Cell Survival Cell Transplantation Cell physiology Cells Cessation of life Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Disease EFRAC Ensure Environment Foundations Future Generations Genetic Transcription Goals Grant Heart Heart failure Histologic Human Hypoxia Image Imaging Techniques Imaging technology Individual Infarction Inflammation Integrase Legitimacy Medicine Mitochondria Modeling Morbidity - disease rate Multimodal Imaging Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Natural regeneration Oncogenic Patients Physicians Positioning Attribute Proteomics Randomized Randomized Clinical Trials Rattus Regenerative Medicine Reporter Genes Research Personnel Risk Role Safety Science Scientist Site Specialist Techniques Technology Therapeutic Effect Thymidine Kinase Training Translating Transplantation Treatment Protocols Viral base career cellular imaging clinical application clinical implementation clinical translation comparative efficacy design experience functional improvement genome editing heart function immunogenic immunogenicity improved in vivo induced pluripotent stem cell induced pluripotent stem cell technology injured ischemic cardiomyopathy member molecular imaging mortality multidisciplinary multimodality novel novel strategies novel therapeutics porcine model pre-clinical preclinical study prevent regenerative therapy repaired site-specific integration stem cell biology stem cell fate stem cell therapy stem cells tissue repair trafficking vector

项目摘要

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.

项目摘要收到这个新的和早期的调查员R01赠款将帮助我完成过渡到独立的过渡应用高级成像技术将新颖疗法转化为床边的医师科学家。作为心血管医学专家，通过多模式成像和干细胞生物学进行广泛培训，我是在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的缺血性心脏病的临床实施。缺血性心脏病的终阶段心力衰竭仍然是一种毁灭性疾病，发病率高和死亡。据估计，九分之九的死亡是由心力衰竭导致的。虽然心脏干细胞疗法已成为一种有前途的疗法，用于修复或替换受损的心肌，这是由大型，由大的疗法使用骨髓衍生的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激发了非信徒的批评，即这些细胞无法再生心。但是，这些细胞可能永远不会到达受伤的心肌或死亡。显着改善心脏功能。显然，我们需要合并高级成像技术来可视化移植后干细胞命运，以更好地了解为什么临床试验表明心脏干细胞疗法仅受益于少数患者。该提案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促进人类的干细胞贩运。在本提案的目标1中，我们将使用新颖的站点 - 特定的基因组编辑技术（例如CRISPR）引入人类记者基因，这可能是较少的免疫原性进入人类诱导的多能干细胞（HIPSC）进行细胞运输。在AIM 2中，我们将带有和不带有报告基因的IPSC（IPSC-CMS）的移植心肌细胞与IPSC（IPSC-CMS）区分开用促生存药预先治疗梗死大鼠模型。我们将在体内跟踪细胞存活和与功能改善相关的生存曲线。我们将使用分子成像为以及转录，蛋白质组学和组织学测定法，以更好地了解有助于急性供体死亡，并确定辅助剂的给药是否可以改善细胞存活。在AIM 3中，我们将确定AIM 2中确定的最佳辅助治疗是否还会改善细胞存活缺血性心肌病的猪模型。我们将优化这个大型的成像和处理方案动物模型，这是在人类启动记者基因成像之前所必需的。这些信息研究将为我们的小组和其他人奠定基础，以将心脏干细胞成像纳入临床试验。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Single-Cell Transcriptional Profiling Reveals Sex and Age Diversity of Gene Expression in Mouse Endothelial Cells.

DOI：
10.3389/fgene.2021.590377
发表时间：
2021
期刊：
Frontiers in genetics
影响因子：
3.7
作者：
Huang X;Shen W;Veizades S;Liang G;Sayed N;Nguyen PK
通讯作者：
Nguyen PK

Risk prediction for abdominal aortic aneurysm: One size does not necessarily fit all.

腹主动脉瘤的风险预测：一刀切不一定适合所有人。

DOI：
10.1007/s12350-021-02680-0
发表时间：
2023
期刊：
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology
影响因子：
0
作者：
Sokol,Jan;Nguyen,PatriciaK
通讯作者：
Nguyen,PatriciaK

Coronary artery calcification: More than meets the eye.