Regulation of cardiac pacemaker cell cyotarchitecture

心脏起搏细胞细胞结构的调节

• 批准号: 10629165
• 负责人: Michael C Bressan
• 金额: $ 38.88万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-05 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10629165
• 关键词: Ablation; Activation Analysis; Address; Adherens Junction; Adolescent; Adopted; Adult; Age; Anatomy; Arrhythmia; Biological; Biological Pacemakers; Cadherins; Cardiac; Cell Separation; Cell Size; Cell physiology; Cell-Cell Adhesion; Cells; Cellular Morphology; Cellular Structures; Cellular biology; Characteristics; Chick Embryo; Coupling; Data; Defect; Development; Devices; Diagnosis; Disease; Electric Capacitance; Embryo; Etiology; Event; FLRT3 gene; Functional disorder; Genetic Transcription; Heart; Heart Diseases; Heart Rate; Human; Intercalated disc; Knowledge; Maintenance; Maps; Mechanics; Mediating; Mediator; Membrane; Mesenchymal; Modeling; Molecular; Molecular Analysis; Molecular Profiling; Morphogenesis; Myocardial; Myocardium; N-Cadherin; Operative Surgical Procedures; Optics; Pathway interactions; Pattern; Periodicity; Phenotype; Process; Proteins; Regulation; Repression; Role; Sinoatrial Node; System; Testing; Therapeutic; Translating; Transplantation; clinically relevant; design; gastrulation; high resolution imaging; implantation; in vivo; insight; interest; knock-down; loss of function; next generation; nodal myocyte; novel; overexpression; overexpression analysis; pharmacologic; programs; scaffold; segregation; timeline; transcription factor

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.

抽象的： 心脏的节律性跳动由窦房 (SA) 结起搏细胞发起的电脉冲控制 （件）。窦房结功能障碍在多种人类心脏病中都有体现，是目前最主要的心脏病 机械起搏装置手术植入的原因。无论病因或发病年龄如何， 引发 SA 节点功能障碍的细胞缺陷尚不清楚，这凸显了迫切需要定义 支持和维持 PC 电活动的细胞、分子和微环境相互作用。的 对此提案非常感兴趣，个人计算机具有在以下情况下有节奏地启动电脉冲的独特能力 理论上应该抑制其活性的离子条件。越来越明显的是，具体 细胞结构特征包括缺乏高电导闰盘和小细胞尺寸，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，很容易出现电功能障碍和心律失常。目前，几乎 关于 PC 细胞结构的调节和/或维持尚不清楚。的长期目标 该提案旨在通过定义以下发展事件来解决当前知识中的这一根本差距： 最初对 PC 功能所需的表型特征进行模式化。我们的总体工作假设是独一无二的 形成 SA 节点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，这些目标将定义 SA 节点微环境是否控制 细胞结构（目标 1），确定粘附连接形成的丧失是否调节 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）。通过定义事件 模式 PC 细胞结构 该提案将创建一个新的综合性和机械性的 PC 模型 发展。此外，通过定义形成和维持 PC 表型的条件，这些研究将 揭示在 SA 节点功能障碍的青少年和/或成人病例中可能被破坏的通路，以及 建立基本的细胞生物学范例，需要将其视为基于细胞的疗法 心律失常的矫正工作继续推进。