Cardiac Pacemaker Development

心脏起搏器开发

• 批准号: 8585876
• 负责人: Takashi Mikawa
• 金额: $ 37.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-02 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8585876
• 关键词: Action Potentials; Arrhythmia; Artificial cardiac pacemaker; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Differentiation process; Cells; Characteristics; Collaborations; Data; Defect; Development; Embryo; Embryonic Development; Exhibits; Future; Generations; Genes; Growth; Heart; Heart Diseases; Human; Image; In Situ Hybridization; In Vitro; Ion Channel; Lateral; Lateral Mesoderm; Lead; Life; Location; Maps; Mediating; Mesoderm; Mesoderm Cell; Molecular; Monitor; Morbidity - disease rate; Optics; Pacemakers; Pathway interactions; Pattern; Physiological; Population; Prevalence; Production; Protocols documentation; RNA; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Sinoatrial Node; Site; Specific qualifier value; Staging; Techniques; Testing; Therapeutic; Time; Tissue Engineering; Tissues; Tube; Viral; abstracting; base; cardiogenesis; cell fate specification; cell type; effective therapy; embryo tissue; in vivo; ion channel blocker; mortality; nodal myocyte; novel; precursor cell; repaired; serial analysis of gene expression

Project Summary/Abstract Cardiac pacemaker cells of the Sinoatrial Node are essential for producing rhythmic heartbeats. Despite the importance of this specialized cardiac cell type, little is known about their ontogeny or mechanisms of specification and differentiation. Our preliminary data show that although the primary heart tube initially displays rhythmic beating, the cells pacing it do not differentiate into the Sinoatrial Node. Instead, pacemaker precursors arise from the mesoderm posterior to the known cardiogenic field and take over the pacing function during heart-looping. Surprisingly, the pacemaker precursor mesoderm can differentiate in culture without any other surrounding embryonic tissues. They display sustained rhythmic beat rates, and sensitivity to pacemaker cell specific ion channel blockers. Furthermore, they have the ability to pace other cardiomyocyte populations. Our global RNA profiling has identified a unique set of Wnt-related genes expressed in pacemaker precursors. These somewhat surprising findings lead to three central hypotheses: (1) the pacemaker precursors arise from a specific mesoderm population separate from the heart field; (2) pacemaker cell fate is induced prior to heart tube formation; and (3) Wnt-related signaling, which is inhibitory to the heart field, acts as a promoting signal during pacemaker cell specification. We will test these hypotheses experimentally. This proposal will provide the first basis for identifying the embryonic origin of pacemaker precursors (Aim 1), the ability of a specific mesoderm subpopulations to enter the pacemaker cell fate (Aim 2), and novel molecular mechanisms that specify and direct the differentiation this important cell type during a brief temporal window and at a defined site in the embryo (Aim 3).

项目总结/摘要 窦房结的心脏起搏细胞对于产生节律性心跳是必不可少的。尽管 这种特殊的心脏细胞类型的重要性，很少有人知道他们的个体发育或机制， 规格和差异化。 我们的初步数据显示，虽然初级心管最初显示有节奏的跳动， 起搏它不分化成窦房结。相反，起搏器前体来自中胚层， 在已知的心电场之后，并在心脏循环期间接管起搏功能。令人惊奇的是， 起搏器前体中胚层可以在没有任何其他周围胚胎的情况下在培养中分化， 组织中它们表现出持续的节律性搏动率，并对起搏细胞特异性离子通道敏感 阻滞剂。此外，它们还具有调节其他心肌细胞群的能力。我们的全球RNA分析 已经确定了一组独特的Wnt相关基因在起搏器前体中表达。 这些有些令人惊讶的发现导致了三个中心假设：（1）起搏器前体来自于 与心脏区域分离的特定中胚层群体;（2）起搏细胞命运在心脏区域之前被诱导。 管形成;和（3）Wnt相关信号，其对心脏场是抑制性的，充当促进信号 在起搏器细胞规格。我们将用实验来检验这些假设。 这一建议将为确定起搏器前体的胚胎起源提供第一个基础（目标1）， 特定中胚层亚群进入起搏细胞命运的能力（Aim 2），以及新的分子生物学。 在短暂的时间窗口内指定和指导这种重要细胞类型分化的机制 在胚胎中的一个确定的位置（目标3）。