Myofibril disassembly during neonatal heart muscle cell proliferation

新生儿心肌细胞增殖过程中的肌原纤维解体

• 批准号: 8386967
• 负责人: Bernhard Kuhn
• 金额: $ 41.41万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-20 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386967
• 关键词: Affect; Animal Model; Birth; Cardiac; Cardiac Myocytes; Cell Cycle; Cell Proliferation; Cell division; Cell model; Child; Childhood; Clinical; Complication; Congenital Abnormality; Conserved Sequence; Cytokinesis; Cytoskeleton; Data; Development; Gene Silencing; Goals; Heart; Heart Transplantation; Heart failure; Human; Immunofluorescence Microscopy; In Vitro; Infant; Investigation; MAPK14 gene; Microscopy; Mitogen-Activated Protein Kinase Kinases; Mitogens; Mitotic spindle; Molecular Models; Myocardial; Myocardium; Myofibrils; Natural regeneration; Neonatal; Newborn Animals; Patients; Peptides; Phase; Photons; Problem Solving; Process; Proliferating; Pump; Regulation; Reporter; Research; Role; Sarcomeres; Scientific Advances and Accomplishments; Signal Transduction; Structure; Therapeutic; Time; Translations; Video Microscopy; Work; age group; base; congenital heart disorder; design; extracellular; heart function; human MAPK14 protein; improved; in vivo; inhibitor/antagonist; innovation; insight; mitogen-activated protein kinase p38; molecular modeling; nuclear division; outcome forecast; periostin; receptor; regenerative; regenerative therapy; time use

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.

抽象的 先天性心脏病是最常见的先天缺陷，经常与心脏不足有关， 导致心力衰竭。当前，替换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 许多生命。我们研究心肌细胞增殖的机制，目的是增加此过程 在治疗上。我们以前已经证明，细胞外因子可用于刺激 心肌细胞增殖，导致心脏动物模型的心肌结构和功能改善 失败。这种创新方法的临床翻译需要了解心肌细胞的方式 我们已经表明 在细胞分裂期间，心肌细胞将其收缩设备划分，该设备由肌原纤维组成，但详细 机制尚不理解。已经表明，肌原纤维形成和心肌细胞细胞因子是 受涉及p38？有丝分裂原激活蛋白激酶（MAPK）的机制控制，但p38在 肌原纤维拆卸仍然未知。我们的初步数据表明心肌细胞细胞周期活性 婴儿在婴儿中的最高 在这个年龄段刺激。因此，我们将在新生动物中进行调查。我们假设 在新生儿心肌细胞增殖时，肌原纤维分解是一个保守的多步骤过程 这是由涉及p38 p38的机制控制的，与短暂降低有关 心肌细胞收缩功能。在AIM 1中，我们将定义和表征拆卸过程。在 AIM 2，我们将修改P38信号传导，并确定对肌原纤维拆卸的影响。在AIM 3中，我们将 确定肌原纤维拆卸对完整心脏中心肌细胞功能的影响。结果的结果 研究应增加刺激心肌细胞的再生策略的翻译潜力 增殖。