Regulation of cardiac pacemaker cell cyotarchitecture

摘要： 心脏的节律性跳动是由窦房结起搏细胞发出的电脉冲控制的 （件）。SA结功能障碍在广泛的人类心脏疾病中表现出来，并且是目前最主要的心脏疾病。 手术植入机械起搏装置的原因。无论病因或发病年龄， 触发SA结功能障碍的细胞缺陷知之甚少，突出了迫切需要定义SA结功能障碍。 支持和维持PC电活动的细胞、分子和微环境相互作用。的 这一建议的重要意义在于，PC具有独特的能力，可以有节奏地启动电脉冲， 理论上应该抑制其活性的离子条件。越来越明显的是， 细胞结构特征，包括缺乏高电导的闰盘和小细胞大小，赋予 保护PC免受离子抑制的生电特性。PC细胞结构失调， 因此代表了对电功能障碍和心律失常的显著脆弱性。目前，几乎 关于PC细胞结构的调节和/或维持是未知的。的长期目标 这一建议是为了解决目前知识中的这一根本性差距， 最初形成PC功能所需的表型特征。我们的假设是 形成SA结内存在的微环境条件抑制粘附连接的形成， 反过来，促进支持PC兴奋性的细胞属性（即小尺寸和差的电耦合）。这 假设将在三个具体目标中进行测试，这些目标将确定SA节点微环境是否控制 细胞结构（目的1），确定粘附连接形成的丧失是否调节PC大小/电活性 (Aim 2），并确定PC表型的上游分子调控因子（目的3）。通过定义事件， 模式PC细胞结构这一建议将创建一个新的全面的和机制的PC模型 发展此外，通过定义模式和维持PC表型的条件，这些研究将 揭示可能在青少年和/或成年SA结功能障碍病例中被破坏的途径，以及 建立基本的细胞生物学范式，需要作为基于细胞的治疗方法， 对心律失常的校正继续向前发展。

Abstract: Rhythmic beating of the heart is controlled by electrical impulses initiated by sinoatrial (SA) node pacemaker cells (PCs). SA node dysfunction manifests across a broad range of human cardiac disease and is currently the leading cause for the surgical implantation of mechanical pacing devices. Regardless etiology or age of presentation, the cellular defects that trigger SA node dysfunction are poorly understood, highlighting the urgent need to define the cellular, molecular, and microenvironmental interactions that support and sustain PCs electrical activity. Of significant interest to this proposal, PCs have the unique capacity to rhythmically initiate electrical impulse under ionic conditions that should theoretically suppress their activity. It is becoming increasingly apparent that specific cytoarchitectural features including the lack of high-conductance intercalated disks and small cell size, confer electrogenic characteristics that protect PCs from ionic suppression. Dysregulation of PC cytoarchitecture, therefore, represents a significant vulnerability to electrical dysfunction and cardiac arrhythmia. Currently, almost nothing is known regarding the regulation and/or maintenance of PC cytoarchitecture. The long-term objectives of this proposal are to address this fundamental gap in current knowledge by defining the developmental events that initially pattern the phenotypic features required for PC function. Our overall working hypothesis is that unique microenvironmental conditions present within the forming SA node suppress adherens junction formation which, in turn, promotes the cellular attributes that support PC excitability (i.e. small size and poor electrical coupling). This hypothesis will be tested in three specific aims that will define whether the SA node microenvironment controls cytoarchitecture (Aim 1), establish whether loss of adherens junction formation regulates PC size/electrical activity (Aim 2), and identify the upstream molecular regulators of the PC phenotype (Aim 3). By defining the events that pattern PC cytoarchitecture this proposal will create a new comprehensive and mechanistic model of PC development. Furthermore, by defining the conditions that pattern and maintain PC phenotype, these studies will uncover pathways that may become disrupted in juvenile and/or adult cases of SA node dysfunction, as well as establish basic cell biological paradigms that will need to be accounted for as cellular-based therapeutics for the correction of cardiac arrhythmias continue to advance.