Regulatory Mechanisms of Cardiomyocyte Lineage Specification

项目摘要： 包括心力衰竭和心房颤动在内的成人心脏病是老年人发病率和死亡率的主要原因。 美国和发达国家。尽管人类多能干细胞或其他心脏祖细胞 细胞有很大的潜力来治疗这些疾病，完全分化成成熟的功能性心室或 用于心室心肌再生疗法以治疗心力衰竭的心房心肌细胞，用于建模 在人类心室和心房心脏疾病的培养皿中，或用于治疗药物的筛选一直是一个主要的 在生物医学领域实现这些可能性的瓶颈。因此，我们建议解决这一关键问题， 通过发现介导重编程的细胞和分子机制， 将心肌细胞分化为功能性心室和心房谱系。为此，我们将询问基因 斑马鱼心脏重编程过程中控制心肌细胞谱系特化的调控网络 然后应用这些知识来识别指导心脏再生的关键心脏重编程因子。 人多能干细胞向心室和心房心肌细胞的分化。总体而言，这些 拟议中的心肌重编程研究可能为解决长期存在的问题提供新的方法， 如何将细胞定向为功能性心室和心房心肌细胞，用于人类心脏病建模 和细胞培养系统中的治疗筛选以及用于人类心脏再生疗法。

Project Summary: Adult heart disease including heart failure and atrial fibrillation are leading causes of morbidity and mortality in the United States and developed world. Although human pluripotent stem cells or other cardiac progenitor cells have great potential to treat these diseases, fully differentiating them into mature functional ventricular or atrial cardiomyocytes for ventricular myocardial regenerative therapies to treat heart failure, for modeling human ventricular and atrial cardiac diseases in a dish, or for therapeutic drug screening has remained a major bottleneck in the biomedical field for realizing these possibilities. Thus, we propose to address this crucial issue through discovering the cellular and molecular mechanisms that mediate the reprogramming of cardiomyocytes into functional ventricular and atrial lineages. Toward this end, we will interrogate the gene regulatory networks that control cardiomyocyte lineage specification during zebrafish cardiac reprogramming and regeneration and then apply this knowledge to identify key cardiac reprogramming factors that guide the differentiation of human pluripotent stem cells into ventricular and atrial cardiomyocytes. Overall, these proposed myocardial reprogramming studies may provide new approaches to address the long-standing issue of how to direct cells into functional ventricular and atrial cardiomyocytes for human cardiac disease modeling and therapeutic screening in cell culture systems as well as for human cardiac regenerative therapies.