Cardiac Pacemaker Development

心脏起搏器开发

• 批准号: 8237943
• 负责人: Takashi Mikawa
• 金额: $ 38.63万
• 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/8237943
• 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; 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

DESCRIPTION (provided by applicant): 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). PUBLIC HEALTH RELEVANCE: The cardiac pacemaker is essential for cardiac function and survival. Limited options of effective treatments contribute to the continued prevalence of arrhythmic heart disease. The proposed study will explore the molecular mechanisms that regulate the earliest developmental steps leading to the generation of this essential cardiac tissue and may provide a basis for future therapeutic approaches.

描述（由申请人提供）：Sinoatrial节点的心脏起搏器细胞对于产生有节奏的心跳至关重要。尽管这种专门的心脏细胞类型很重要，但对它们的本体发育或规范和分化机制知之甚少。我们的初步数据表明，尽管主要心脏管最初显示节奏的跳动，但其起搏的细胞并未区分到弦乐节点中。取而代之的是，起搏器前体来自中胚层后部到已知的心源场，并在心摇动过程中接管起搏功能。令人惊讶的是，起搏器前体中胚层可以在培养中分化，而无需任何其他周围的胚胎组织。它们显示出持续的节奏节拍率，以及对起搏器特异性离子通道阻滞剂的敏感性。此外，它们具有加快其他心肌细胞种群的能力。我们的全球RNA分析确定了在起搏器前体中表达的一组独特的WNT相关基因。这些令人惊讶的发现导致了三个中心假设：（1）起搏器前体是由特定的中胚层种群与心脏场分开的。 （2）在心管形成之前诱导起搏器细胞命运； （3）与心脏场抑制性WNT相关的信号传导在起搏器细胞规范过程中充当促进信号。我们将通过实验测试这些假设。该提案将提供第一基础，以识别起搏器前体的胚胎起源（AIM 1），特定的中胚层亚群进入起搏器细胞命运（AIM 2）的能力以及在短暂的时间窗口和胚胎中定义的位点指定和指导这种重要细胞类型的新型分子机制（AIM 2）。 公共卫生相关性：心脏起搏器对于心脏功能和生存至关重要。有效治疗的有限选择导致心律不齐心脏病的持续患病率。拟议的研究将探索调节最早的发育步骤的分子机制，从而导致这种基本心脏组织的产生，并可能为将来的治疗方法提供基础。