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: 8780671
• 负责人: Bernhard Kuhn
• 金额: $ 37.92万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8780671
• 关键词: Affect; Animal Model; Birth; Cardiac Myocytes; Cardiac development; 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; 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; cardiac regeneration; 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; pediatric patients; periostin; receptor; regenerative; regenerative therapy; time use; two-photon

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.

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并节省 许多人的生命。我们研究心肌细胞增殖的机制，旨在促进这一过程。 从治疗上讲。我们之前已经证明，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心肌结构和功能的改善 失败了。这一创新方法的临床翻译需要了解心肌细胞是如何 能够执行两种完全不同的任务：收缩肌原纤维和细胞分裂。我们已经证明了 在细胞分裂期间，心肌细胞分裂其由肌原纤维组成的收缩装置，但详细的 机制还不清楚。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p38？丝裂原活化蛋白激酶(MAPK)的机制控制，但p38？ 肌原纤维的解体仍不清楚。我们的初步数据表明，心肌细胞周期活动在 人类在婴儿中的比例最高，这表明再生性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，我们将在新生动物身上进行调查。我们假设 增殖中的新生心肌细胞肌原纤维的分解是一个保守的、多步骤的过程 这是由一种涉及p38？MAPK的机制控制的，并与短暂的 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……里面 目的2，我们将对p38信号进行修饰，并确定其对肌原纤维分解的影响。在《目标3》中，我们将 测定肌原纤维解离对完整心脏心肌细胞功能的影响。这样做的结果 研究应增加刺激心肌细胞的再生策略的翻译潜力 扩散。

项目成果

Mechanisms of Cardiomyocyte Proliferation and Differentiation in Development and Regeneration.

• DOI: 10.1007/s11886-017-0826-1
• 发表时间: 2017-02
• 期刊: Current cardiology reports
• 影响因子: 3.7
• 作者: Yester JW;Kühn B
• 通讯作者: Kühn B

Generation of Human Induced Pluripotent Stem Cells and Differentiation into Cardiomyocytes.

• DOI: 10.1007/978-1-0716-0668-1_10
• 发表时间: 2021
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Han L;Mich-Basso J;Kühn B
• 通讯作者: Kühn B

New mechanistic and therapeutic targets for pediatric heart failure: report from a National Heart, Lung, and Blood Institute working group.

• DOI: 10.1161/circulationaha.113.007980
• 发表时间: 2014-07-01
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Burns KM;Byrne BJ;Gelb BD;Kühn B;Leinwand LA;Mital S;Pearson GD;Rodefeld M;Rossano JW;Stauffer BL;Taylor MD;Towbin JA;Redington AN
• 通讯作者: Redington AN