Altering Cardiac Cell Fate for Heart Repair

改变心肌细胞命运以修复心脏

• 批准号: 10328550
• 负责人: Li Qian
• 金额: $ 92.81万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-13 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328550
• 关键词: Acute myocardial infarction; Cardiac; Cardiac Myocytes; Cardiovascular Physiologic Processes; Cells; Cicatrix; Development; Disease; Doctor of Philosophy; Fibroblasts; Funding; GATA4 gene; Grant; Heart; Heart Diseases; Heart Injuries; Heart failure; Human; Impairment; Knowledge; Laboratories; Mechanics; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardium; National Heart, Lung, and Blood Institute; Natural regeneration; Pathologic Processes; Patients; Post-Transcriptional Regulation; Postdoctoral Fellow; Pump; System; Time; Tissues; Training; Transcriptional Regulation; cardiac repair; clinical application; epigenetic regulation; functional improvement; improved; in vivo; in vivo evaluation; insight; mathematical model; mortality; multiple omics; novel; novel therapeutics; public health relevance; regeneration potential; response to injury; stem cell biology; transcription factor

Abstract Direct cardiac reprogramming holds great promise as a novel therapy for heart failure, a common and morbid disease that is usually caused by irreversible loss of massive functional cardiomyocytes. By leveraging the knowledge in developmental and stem cell biology gained during my PhD and postdoc training, in 2012 I demonstrated that in a murine acute myocardial infarction model, delivery of three transcription factors, Gata4, Mef2c and Tbx5 (GMT) converted cardiac fibroblasts (CFs) into functional induced cardiomyocytes (iCMs) that integrated electrically and mechanically with surrounding myocardium, resulting in functional improvement and scar size reduction. These findings suggest that iCM reprogramming is an effective means of regenerating heart tissue in vivo for human patients with heart disease. However, because relatively little was known about the factors that allow CFs to be reprogrammed, the applicability of cardiac reprogramming was limited to the context in which it had been attempted at that time. Since my independence, my own laboratory has established robust murine and human iCM reprogramming systems. By using these systems, we obtained novel insights into the transcriptional, post-transcriptional and epigenetic regulation of both murine iCM (supported by R01HL128331 as ESI) and human iCM reprogramming (supported by R01HL144551), and concomitantly improved the quality and yield of iCMs. This R35 EIA application is an extension to these two currently funded NHLBI R01 grants to further unravel the molecular mechanisms underlying iCM conversion, to test in vivo iCM reprogramming in non- acutely injured hearts and to exploit the latest single cell multi-omics and mathematical modeling for optimized and individualized reprogramming. Successful completion of this proposal will help to move direct cardiac reprogramming closer to its clinical application, provide new insights into molecular mechanisms underlying cardiac cell fate determination, and open new opportunities for the field to leverage the models and platforms we will develop here to study other cardiovascular physiological and pathological processes.

抽象的 直接心脏重编程具有巨大的希望，作为一种新的心力衰竭疗法，一种常见和病态 通常是由于不可逆转的大量功能性心肌细胞引起的疾病。通过利用 在我的博士和博士后培训期间获得的发育和干细胞生物学知识，2012年I 证明在鼠急性心肌梗死模型中，三个转录因子GATA4， MEF2C和TBX5（GMT）转​​化为功能诱导的心肌细胞（ICMS）的心脏成纤维细胞（CFS） 电气和机械地与周围心肌进行了机械整合，从而实现了功能的改进和 疤痕尺寸减小。这些发现表明，ICM重编程是再生心脏的有效手段 人体疾病患者的体内组织。但是，因为关于 可以重新编程CF的因素，心脏重编程的适用性仅限于环境 当时尝试过的。自从我独立以来，我自己的实验室已经建立了强大的 鼠和人类ICM重编程系统。通过使用这些系统，我们获得了对 两种鼠ICM的转录，转录后和表观遗传调节（由R01HL128331支持 如ESI）和人类ICM重编程（由R01HL144551支持），并随之提高了质量 和ICM的产量。此R35 EIA应用程序是对当前资助的NHLBI R01赠款的扩展 进一步阐明ICM转化率的分子机制，以测试非 - 在非 - 重新编程中 急性伤害的心脏，并利用最新的单细胞多词和数学建模进行优化 和个性化的重编程。成功完成此建议将有助于移动直接心脏 重新编程更接近其临床应用，为分子机制提供新的见解 心脏细胞命运的确定，并为该领域开辟了新的机会，以利用模型和平台 我们将在这里发展以研究其他心血管生理和病理过程。