Myofibril disassembly during neonatal heart muscle cell proliferation

摘要 先天性心脏病是最常见的出生缺陷，通常与心肌缺陷有关， 导致心力衰竭目前，替代心肌细胞的唯一方法是通过心脏 移植再生疗法将改变先天性心脏病的治疗， 很多生命我们研究了心肌细胞增殖的机制，目的是增加这一进程 治疗上我们以前已经证明，细胞外因子可以用来刺激 心肌细胞增殖，导致心脏动物模型中心肌结构和功能的改善 失败这种创新方法的临床转化需要了解心肌细胞是如何 能够执行两个完全不同的任务：肌原纤维的收缩和细胞分裂。我们已经证明 在细胞分裂过程中，心肌细胞分裂它们的收缩器官，由肌原纤维组成，但详细的 机制不被理解。已经表明，肌原纤维的形成和心肌细胞胞质分裂是 由p38有丝分裂原活化蛋白激酶（MAPK）机制控制，但p38在 肌原纤维解体仍然未知。我们的初步数据表明，心肌细胞的细胞周期活动， 人类在婴儿中最高，这表明再生心肌细胞增殖可能是最有效的， 在这个年龄段受到刺激。因此，我们将在新生动物中进行研究。我们假设 增殖的新生心肌细胞中的肌原纤维分解是一个保守的多步骤过程， 这是由涉及p38 <$MAPK的机制控制，并与短暂的减少有关。 心肌细胞收缩功能在目标1中，我们将定义和描述拆卸过程。在 目的二，我们将修饰p38信号通路，并确定其对肌原纤维分解的影响。在目标3中，我们 确定肌原纤维分解对完整心脏中心肌细胞功能的影响。的结果 研究应该增加刺激心肌细胞的再生策略的转化潜力， 增殖

ABSTRACT Congenital heart disease, the most common birth defect, is frequently associated with deficient heart muscle, leading to heart failure. Currently, the only way to replace heart muscle cells, cardiomyocytes, is through heart transplantation. Regenerative therapies would transform the treatment of congenital heart disease and save many lives. We study the mechanisms of cardiomyocyte proliferation with the aim of increasing this process therapeutically. We have previously demonstrated that extracellular factors can be used to stimulate cardiomyocyte proliferation, leading to improved myocardial structure and function in animal models of heart failure. The clinical translation of this innovative approach requires understanding of how cardiomyocytes are able to perform two completely different tasks: contraction of myofibrils and cell division. We have shown that during cell division cardiomyocytes divide their contractile apparati, which consist of myofibrils, but the detailed mechanisms are not understood. It has been shown that myofibril formation and cardiomyocyte cytokinesis are controlled by mechanisms involving p38¿ mitogen-activated protein kinase (MAPK), but the role of p38¿ in myofibril disassembly remains unknown. Our preliminary data indicate that cardiomyocyte cell cycle activity in humans is highest in infants, suggesting that regenerative cardiomyocyte proliferation may be most effectively stimulated in this age group. We will therefore perform our investigations in neonatal animals. We hypothesize that myofibril disassembly in proliferating neonatal cardiomyocytes is a conserved, multi-step process that is controlled by a mechanism involving p38¿ MAPK and is associated with brief reduction of cardiomyocyte contractile function. In Aim 1 we will define and characterize the disassembly process. In Aim 2, we will modify p38 signaling and determine the effects on myofibril disassembly. In Aim 3, we will determine the effect of myofibril disassembly on cardiomyocyte function in the intact heart. The results of this research should increase the translational potential of regenerative strategies that stimulate cardiomyocyte proliferation.