Regulation of cardiac pacemaker cell cyotarchitecture

心脏起搏细胞细胞结构的调节

• 批准号: 10376808
• 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/10376808
• 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; Mechanics; Mediating; Mediator of activation protein; Membrane; Mesenchymal; Modeling; Molecular; Molecular Analysis; Molecular Profiling; Morphogenesis; Myocardial; Myocardium; N-Cadherin; Operative Surgical Procedures; Optics; Pathway interactions; Pattern; Periodicity; Pharmacology; Phenotype; Process; Proteins; Regulation; Role; Sinoatrial Node; System; Testing; Therapeutic; TimeLine; Translating; Transplantation; base; 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; scaffold; 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： 心脏的节奏跳动由辛里尔（SA）节点起搏器细胞引发的电脉冲控制 （件）。 SA节点功能障碍表现在各种人类心脏病中，目前是领先的 原因是机械起搏装置的手术植入。不管病因学或表现的年龄， 触发sa节点功能障碍的细胞缺陷知之甚少，强调了迫切需要定义 支持和维持PC的电活动的细胞，分子和微环境相互作用。的 该提案的重大兴趣，PC具有在节奏下发起电力冲动的独特能力 理论上应抑制其活性的离子条件。特定的是越来越明显的 细胞结构特征，包括缺乏高导体插入式磁盘和小细胞尺寸，Confor 可保护PC免受离子抑制的电源特性。 PC细胞结构的失调， 因此，代表了电气功能障碍和心律不齐的重要脆弱性。目前，几乎 关于PC细胞结构的调节和维护，尚无任何了解。长期目标 该建议是通过定义发展事件来解决当前知识的这一基本差距 最初对PC功能所需的表型特征进行模式。我们的整体工作假设是独特的 形成的SA节点内存在的微环境条件抑制了粘附的结形成，该结构在 转弯，促进支持PC兴奋性（即小尺寸和不良的电耦合）的细胞属性。这 假设将以三个特定目的进行检验，以定义SA节点微环境控制 细胞结构（AIM 1），确定粘附连接形成的损失是否调节PC尺寸/电活动 （AIM 2），并确定PC表型的上游分子调节剂（AIM 3）。通过定义事件 模式PC细胞结构结构本提案将创建一个新的全面和机械模型 发展。此外，通过定义模式和维持PC表型的条件，这些研究将 发现可能在少年和/或成人的SA节点功能障碍的情况下被破坏的途径，以及 建立基本的细胞生物学范例，需要将其作为基于细胞的治疗剂 心律不齐的校正继续前进。