Characterizing the Mechanisms of Cardiac Recovery Following Treatment with Exosomes Secreted by iPS Derived Cardiomyocytes

表征 iPS 衍生心肌细胞分泌的外泌体治疗后心脏恢复的机制

• 批准号: 10399976
• 负责人: Bohao Liu
• 金额: $ 2.38万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399976
• 关键词: Academic Medical Centers; Address; Affect; Apoptosis; Award; Biological Response Modifier Therapy; Biology; Biomedical Engineering; Cardiac; Cardiac Myocytes; Cardiology; Cell Death; Cell Differentiation process; Cell Fraction; Cell Therapy; Cells; Clinic; Clinical; Computer Analysis; Development; EFRAC; Effectiveness; Faculty; Family; Fellowship; Future; Gene Expression; Goals; Heart; Heart Diseases; Heart Injuries; Heart Transplantation; Home; Hospitals; Human; Hydrogels; Hypoxia; Implant; Individual; Infarction; Injury; Kinetics; Laboratories; Mediating; Medicine; Mentors; Mentorship; MicroRNAs; Modeling; Molecular; Myocardial Infarction; Myocardial Ischemia; Myocardium; NUP214 gene; New York; Outcome; Pathway interactions; Patients; Phase; Physicians; Presbyterian Church; Prevention; Process; Rattus; Recovery; Recovery of Function; Research; Scientist; Technical Expertise; Time; Tissue Engineering; Training; Tumorigenicity; Undifferentiated; United States; Universities; base; cardiac repair; cell type; clinically significant; design; exosome; hospital bed; implantation; improved; in vitro Model; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; injured; intercellular communication; microvesicles; mortality; myocardial hypoxia; novel; pleiotropism; prevent; professor; response; treatment strategy

PROJECT SUMMARY / ABSTRACT Heart disease remains the leading cause of mortality worldwide with myocardial infarction (MI) affecting over 700,000 individuals annually in the United States alone. As standard therapies fail to recover the injured myocardium, any advances in the treatment of cardiac ischemia would have major clinical significance. Recently, cell-free biological therapies using cell-secreted exosomes have shown promise in achieving cardiac recovery. Exosomes contain sets of micro-RNAs (miRNAs) that they deliver to induce pleiotropic effects. As exosomes from different cell types carry different sets of miRNAs, some exosomes may have increased ability to recover the injured heart. In preliminary studies, I determined that exosomes from induced pluripotent stem cell derived cardiomyocytes (iCM-ex) were able to mediate recovery of the heart, resulting in improved ejection fraction and reduced infarct size after MI. An in-depth understanding of the cellular and molecular mechanisms behind iCM- ex induced cardiac recovery will be critical to further advance the utility of iCM-ex treatment. In pursuit of this goal, I propose the following aims: In Aim 1, I will investigate the ability of iCM-ex to deliver miRNAs that can directly alter gene expression and promote recovery in cardiomyocytes after hypoxic injury. I hypothesize that I will be able to identify a set of miRNAs delivered by iCM-exs to CMs that can directly regulate CM responses to hypoxia, protecting them from injury and preventing cell death. In Aim 2, I will determine how the timing of iCM-ex delivery after MI affects functional recovery. Based on how iCM-ex affect each phase of cardiac repair following MI, I hypothesize that I will be able to establish an iCM-ex treatment strategy that results in greater functional recovery. Overall, my proposed research is designed to advance the utility of iCM-ex treatment by identifying the key cellular and molecular mechanisms responsible for iCM-ex mediated cardiac recovery. I anticipate that this will allow for the future development of precisely controlled cell-free treatments that can be safely deployed in the clinic. This proposed project will be conducted in the lab of my sponsor, Dr. Gordana Vunjak-Novakovic, a University Professor on faculty at the Departments of Biomedical Engineering and Medicine at Columbia University. As part of a broader training plan for this fellowship, the execution of this project under her direct mentorship will allow me to expand and refine my technical skills in cardiac biology, computational analysis, and tissue engineering and to improve my ability to generate concrete hypotheses and formulate impactful projects. Additionally, my training plan includes substantial clinical training at the New York Presbyterian Hospital at the Columbia University Medical Center, a thousand-bed hospital home to the Vivian and Seymour Milstein Family Heart Center, one of the top hospitals in the field of cardiology. Together, this training plan will allow me to connect the laboratory bench to the patient bedside and benefit from an extensive network of dedicated scientific, clinical and professional mentors. If awarded, this fellowship will support my ultimate goal of developing into an independent and productive physician-scientist.

项目摘要 /摘要 心脏病仍然是全世界死亡的主要原因，并影响了心肌梗死（MI） 仅美国，每年有70万人。由于标准疗法未能恢复受伤 心肌，心脏缺血治疗的任何进步都将具有重要的临床意义。最近， 使用细胞分泌外泌体的无细胞生物疗法在实现心脏恢复方面已经有望。 外泌体包含以诱导多效效应提供的微RNA（miRNA）。作为外泌体 来自不同细胞类型的miRNA集合，一些外泌体可能具有增加的恢复能力 受伤的心。在初步研究中，我确定来自诱导多能干细胞的外泌体衍生 心肌细胞（ICM-EX）能够介导心脏的恢复，从而改善了射血分数和 MI后梗塞大小降低。深入了解ICM-背后的细胞和分子机制 EX诱导的心脏恢复对于进一步推进ICM-EX治疗的实用性至关重要。追求这个 目标，我提出以下目标：在AIM 1中，我将研究ICM-EX提供可以提供的miRNA的能力 直接改变基因表达并促进低氧损伤后心肌细胞的恢复。我假设这一点 我将能够确定ICM-EXS向CMS提供的一组miRNA，可以直接调节CM响应 缺氧，保护它们免受伤害并预防细胞死亡。在AIM 2中，我将确定如何定时 MI后的ICM-EX交付会影响功能恢复。根据ICM-EX如何影响心脏修复的每个阶段 在MI之后，我假设我将能够建立ICM-EX治疗策略，从而导致更大的 功能恢复。总体而言，我提出的研究旨在提高ICM-EX治疗的实用性 通过识别负责ICM-EX介导心脏的关键细胞和分子机制 恢复。我预计这将允许将来开发精确控制的无细胞治疗 可以安全部署在诊所中。这个建议的项目将在我的赞助商博士的实验室中进行。 Gordana Vunjak-Novakovic，生物医学工程系的大学教授 哥伦比亚大学的医学。作为该奖学金的更广泛培训计划的一部分，该项目的执行 在她的直接指导下，我可以扩展和完善我在心脏生物学方面的技术技能， 计算分析和组织工程，并提高我产生具体假设的能力和 制定有影响力的项目。此外，我的培训计划包括在纽约进行大量临床培训 哥伦比亚大学医学中心的长老会医院，一千张病床的住所 西摩·米尔斯坦（Seymour Milstein）家庭心脏中心是心脏病学领域的顶级医院之一。一起，这个 培训计划将使我能够将实验室长凳连接到患者的床边，并受益于 专门的科学，临床和专业导师的广泛网络。如果被授予，该奖学金将 支持我发展成独立和生产性医师科学家的最终目标。