Regulatory Mechanisms of Myocardial Reprogramming in Zebrafish

心肌细胞经历广泛的生理和病理刺激，这些刺激可以影响其功能。 细胞状态虽然心肌细胞肥大和增生是众所周知的适应性心脏细胞 在这种反应中，一些心肌细胞也保留了重新编程的能力（即心脏可塑性），以改变 它们的分化状态和身份以适应压力。例如，心肌细胞去分化是一种 心力衰竭期间适应不良反应的组成部分; Ebstein氏病中右心室的一部分 异常，这是暴露于改变血流动力学力量，成为“心房化”;和两个心肌细胞去， 分化和转分化在一定条件下调节心脏再生。因此， 心脏“适应性细胞重编程”不仅在病理情况下起作用，而且在有益的情况下起作用。 然而，尽管心脏重编程在调节对刺激的适应性反应中的重要性， 了解控制心肌细胞可塑性的内在过程和 激活心脏重编程以改变心肌细胞分化状态和细胞特性仍然有待于 要充分阐明。因此，这些拟议研究的总体目标是阐明潜在的 机制1）控制心肌细胞可塑性，2）激活心肌细胞在可塑性中的重编程， 心肌细胞和3）调节这些心肌细胞的重编程。这些心脏的结果 重编程研究不仅能阐明心肌细胞如何适应（或不适应） 在体内响应细胞应激的重编程，而且还提供了如何指导哺乳动物 将来自各种细胞来源的细胞（即成纤维细胞、多能干细胞、心脏祖细胞）转化为功能性细胞， 用于人类心脏疾病建模和细胞中治疗筛选的心室和心房心肌细胞 培养系统以及用于人类心脏再生疗法。

Cardiomyocytes experience a wide range of physiologic and pathologic stimuli, which can influence their cellular state. Although cardiomyocyte hypertrophy and hyperplasia are well known adaptive cardiac cellular responses, some cardiomyocytes also retain the capacity to reprogram (i.e. cardiac plasticity) in order to alter their differentiation state and identity to adapt to stress. For instance, cardiomyocyte de-differentiation is a component of the maladaptive response during heart failure; a portion of the right ventricle in Ebstein's anomaly, which is exposed to altered hemodynamic forces, becomes “atrialized”; and both cardiomyocyte de- differentiation and trans-differentiation regulate cardiac regeneration under certain conditions. Thus, this cardiac “adaptive cellular reprogramming” can act in not only pathologic but also beneficial circumstances. However, despite the importance of cardiac reprogramming in regulating adaptive responses to stimuli, our understanding of the intrinsic processes that control cardiomyocyte plasticity and the external cues that activate cardiac reprogramming to modify cardiomyocyte differentiation states and cell identities remains yet to be fully elucidated. Thus, the overall goals of these proposed studies are to illuminate the underlying mechanisms that 1) control cardiomyocyte plasticity, 2) activate cardiomyocyte reprogramming in plastic cardiomyocytes and 3) regulate the reprogramming of these cardiomyocytes. The results of these cardiac reprogramming studies will not only illuminate how cardiomyocytes may adaptively (or maladaptively) reprogram in response to cellular stress in vivo but also provide further insight into how to direct mammalian cells from various cell sources (i.e. fibroblasts, pluripotent stem cells, cardiac progenitor 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.