Myofibril disassembly during neonatal heart muscle cell proliferation

描述(由首席调查员提供)：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心脏移植。再生疗法将改变先天性心脏病的治疗方法，拯救许多人的生命。我们研究心肌细胞增殖的机制，以期在治疗上促进这一过程。我们先前已经证明，细胞外因子可以刺激心肌细胞的增殖，从而改善心力衰竭动物模型的心肌结构和功能。这一创新方法的临床翻译需要了解心肌细胞如何能够执行两种完全不同的任务：收缩肌原纤维和细胞分裂。我们已经证明，在细胞分裂过程中，心肌细胞分裂其由肌原纤维组成的收缩装置，但其详细机制尚不清楚。已有研究表明，肌原纤维的形成和心肌细胞胞质分裂受涉及p381丝裂原活化蛋白激酶(MAPK)的机制控制，但p381在肌原纤维分解中的作用尚不清楚。我们的初步数据表明，人类的心肌细胞周期活动在婴儿中最高，这表明再生心肌细胞的增殖可能在这个年龄段得到最有效的刺激。因此，我们将在新生动物身上进行调查。我们假设，在增殖的新生心肌细胞中，肌原纤维的分解是一个保守的、多步骤的过程，受涉及p381MAPK的机制控制，并与心肌细胞收缩功能的短暂降低有关。在目标1中，我们将定义和描述拆卸过程。在目标2中，我们将修改p38信号并确定其对肌原纤维分解的影响。在目标3中，我们将确定肌原纤维解离对完整心脏心肌细胞功能的影响。这项研究的结果应该会增加刺激心肌细胞增殖的再生策略的翻译潜力。 公共卫生相关性：先天性心脏病是最常见的出生缺陷，经常与心肌缺陷有关，导致心力衰竭。目前，替代心肌细胞的唯一方法是心脏移植。这项拟议的研究将为再生疗法治疗先天性心脏病患者提供科学依据。这些新疗法应该会改善许多因先天性心脏病而患有心力衰竭的患者的生活。

DESCRIPTION (provided by Principal Investigator): 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 p381 mitogen-activated protein kinase (MAPK), but the role of p381 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 p381 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. PUBLIC HEALTH RELEVANCE: 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. The proposed research will advance the scientific basis for regenerative therapies to treat patients with congenital heart disease. These new therapies should improve the lives of many patients who have heart failure as a complication of congenital heart disease.