Role of ankyrin-B in human arrhythmia

锚蛋白-B 在人类心律失常中的作用

• 批准号: 8496850
• 负责人: Peter J. Mohler
• 金额: $ 36.3万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496850
• 关键词: Animal Model; Ankyrins; Antibodies; Arrhythmia; Atrial Fibrillation; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Catecholamines; Cell membrane; Cells; Charge; Complex; Data; Defect; Developed Countries; Development; Disease; Embryo; Family; Functional disorder; Funding; General Population; Genes; Genetic Variation; Goals; Heart; Heart Atrium; Heart Diseases; Human; Ion Channel; Ions; Learning; Maintenance; Membrane; Membrane Protein Traffic; Membrane Proteins; Molecular; Movement; Mus; Muscle Cells; Pathway interactions; Patients; Phenotype; Physiology; Play; Population; Positioning Attribute; Predisposition; Property; Proteins; Publishing; Regulation; Regulatory Pathway; Research; Role; Signaling Protein; Sinus; Testing; Ventricular; Ventricular Arrhythmia; base; in vivo; innovation; innovative technologies; insight; loss of function mutation; membrane biogenesis; mortality; novel; prevent; programs; sudden cardiac death; therapeutic target; tool; translational study

DESCRIPTION (provided by applicant): Defects in cardiac excitability are the basis for human arrhythmia and sudden cardiac death, a leading cause of mortality in developed countries. Ion channels and transporters control the movement of charged ions across cell membranes. In the heart, the coordinate activities of these proteins regulate the transmembrane electrochemical gradient to control depolarization/repolarization, and thus cardiac excitability. Normal function of ion channels and transporters requires defined biophysical properties as well as precise expression, organization, and regulation in defined membrane domains. Findings generated during our first period of funding support a new paradigm for human cardiac disease (arrhythmia) based on dysfunction in proteins that are required for proper expression and local regulation of ion channels and transporters at specific excitable membranes. Specifically, we discovered that ankyrin proteins, previously considered static membrane adapters, play dynamic roles in ion channel, transporter, and signaling protein targeting in ventricular cardiomyocytes. Patients harboring loss-of-function mutations in the ankyrin-B gene (ANK2) display a severe and complex cardiac phenotype. Phenotypes may include sinus node dysfunction, atrial fibrillation (AF), conduction defects, catecholamine-induced polymorphic ventricular arrhythmia, and/or sudden cardiac death. Moreover, we have learned that common ANK2 gene variants in the general population are associated with QTc alterations and ventricular arrhythmia susceptibility, that AnkB levels are strongly altered in large animal models of cardiovascular disease, and that the ANK2 is a candidate gene for AF susceptibility in the general human population. However, despite these translational studies implicating AnkB as a key player in cardiac excitability, the specific molecular roles of AnkB in heart remain surprisingly unknown. In fact, the identities of the in vivo cellular components of the AnkB-targeting pathway (or other cardiac targeting pathways) are still unknown. Finally, lack of an animal model of AnkB deficiency (global AnkB k/o is embryonic lethal) has prevented efforts to define new roles of AnkB in cardiac physiology and disease. For this first competitive renewal, due to important advances during the first funding cycle and the development of a number of innovative new animal models, we are well-positioned to provide the first in vivo information on the fundamental components (both upstream & downstream) of the entire AnkB-targeting pathway at baseline and in disease. We provide exciting new preliminary data that identifies a novel family of membrane trafficking proteins (EHD proteins) that regulate cardiac membrane excitability and associate with AnkB. We further provide new data that AnkB plays a novel role in targeting select Ca2+ channels in sinus node & atria. Finally, our preliminary data in mice demonstrates novel and unexpected roles of AnkB in cardiac membrane biogenesis and maintenance. Together, our published findings and preliminary data support a central hypothesis that the AnkB-based cellular pathway plays dynamic roles in myocyte membrane excitability and cardiac function. The immediate goals of our research program are to understand the specific cellular role(s) of AnkB in the heart (including upstream regulatory pathways [EHD proteins] and novel downstream targets [Cav1.3]) and determine how AnkB dysfunction leads to complex human cardiac disease. For this first competitive renewal, we present a cast of uncharacterized and innovative animal models, novel molecular tools, innovative technologies, and new antibodies to test the specific roles of the AnkB cellular pathway in vivo.

描述（由申请人提供）：心脏兴奋性缺陷是人类心律失常和心源性猝死的基础，是发达国家死亡的主要原因。离子通道和转运蛋白控制带电离子穿过细胞膜的运动。在心脏中，这些蛋白质的协调活动调节跨膜电化学梯度以控制去极化/复极化，从而控制心脏兴奋性。离子通道和转运蛋白的正常功能需要确定的生物物理特性以及在确定的膜域中的精确表达、组织和调节。 我们第一期资助期间的研究结果支持人类心脏病（心律失常）的新范例，该范例基于蛋白质功能障碍，这些蛋白质是特定可兴奋膜上离子通道和转运蛋白的正确表达和局部调节所必需的。具体来说，我们发现锚蛋白（以前被认为是静态膜适配器）在心室心肌细胞的离子通道、转运蛋白和信号蛋白靶向中发挥动态作用。携带锚蛋白 B 基因 (ANK2) 功能丧失突变的患者表现出严重且复杂的心脏表型。表型可能包括窦房结功能障碍、心房颤动 (AF)、传导缺陷、儿茶酚胺诱导的多形性室性心律失常和/或心源性猝死。此外，我们还了解到，一般人群中常见的 ANK2 基因变异与 QTc 改变和室性心律失常易感性相关，AnkB 水平在心血管疾病的大型动物模型中发生强烈变化，并且 ANK2 是 AF 易感性的候选基因。一般人群。然而，尽管这些转化研究表明 AnkB 在心脏兴奋性中发挥着关键作用，但 AnkB 在心脏中的具体分子作用仍然令人惊讶地未知。事实上，AnkB 靶向途径（或其他心脏靶向途径）的体内细胞成分的身份仍然未知。最后，缺乏 AnkB 缺陷动物模型（全球 AnkB k/o 是胚胎致死的）阻碍了定义 AnkB 在心脏生理学和疾病中新作用的努力。 对于第一次竞争性更新，由于第一个融资周期中的重要进展以及许多创新的新动物模型的开发，我们有能力提供有关基本成分（上游和下游）的第一个体内信息基线和疾病中的整个 AnkB 靶向途径。我们提供了令人兴奋的新初步数据，确定了调节心脏膜兴奋性并与 AnkB 相关的膜运输蛋白（EHD 蛋白）的新家族。我们进一步提供的新数据表明 AnkB 在针对窦房结和心房的特定 Ca2+ 通道方面发挥着新的作用。最后，我们在小鼠中的初步数据证明了 AnkB 在心脏膜生物发生和维护中的新颖且意想不到的作用。我们发表的研究结果和初步数据共同支持了一个中心假设，即基于 AnkB 的细胞通路在心肌细胞膜兴奋性和心脏功能中发挥动态作用。我们研究计划的直接目标是了解 AnkB 在心脏中的特定细胞作用（包括上游调节途径 [EHD 蛋白] 和新的下游靶标 [Cav1.3]），并确定 AnkB 功能障碍如何导致复杂的人类心脏病。在这第一次竞争性更新中，我们展示了一系列未表征的创新动物模型、新颖的分子工具、创新技术和新抗体，以测试 AnkB 细胞通路在体内的特定作用。