Regulation of cardiac pacemaker cell cyotarchitecture

摘要： 心脏节律性跳动是由窦房结起搏细胞产生的电脉冲控制的 (个)。SA结节功能障碍表现在广泛的人类心脏疾病中，目前是主要的 外科植入机械起搏器的原因。无论病因或发病年龄， 触发SA结节功能障碍的细胞缺陷尚不清楚，突显出迫切需要定义 支持和维持PC电活动的细胞、分子和微环境相互作用。的 对这一提议非常感兴趣，PC具有在以下条件下有节奏地引发电脉冲的独特能力 理论上应该抑制其活性的离子条件。越来越明显的是，具体的 细胞结构特征，包括缺乏高电导插入盘和小细胞尺寸， 保护PC免受离子抑制的电生特性。PC细胞结构失调， 因此，它很容易受到电功能障碍和心律失常的影响。目前，几乎 对PC细胞结构的调节和/或维护一无所知。的长期目标 这一提议是为了解决当前知识中的这一根本差距，方法是定义 最初设计PC功能所需的表型特征。我们的总体工作假设是唯一的 形成SA节点内存在的微环境条件抑制了粘连结的形成，在 反过来，促进支持PC兴奋性的蜂窝属性(即，小尺寸和较差的电气耦合)。这 假设将在定义SA节点微环境是否控制的三个特定目标中进行测试 细胞结构(目标1)，确定黏附连接形成的丢失是否调节PC大小/电活动 (目标2)，并确定PC表型的上游分子调节因子(目标3)。通过定义以下事件 模式PC细胞体系结构该方案将创建一种新的综合的、机械化的PC模型 发展。此外，通过定义形成和保持PC表型的条件，这些研究将 发现青少年和/或成人SA结节功能障碍病例中可能受到干扰的通路，以及 建立基本的细胞生物学范例，需要作为基于细胞的疗法来解释 心律失常的纠正工作继续取得进展。

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.