Defining New Pathways for Complex Human Heart Failure and Arrhythmia

定义复杂人类心力衰竭和心律失常的新途径

• 批准号: 10617851
• 负责人: Elisa Ann Bradley
• 金额: $ 16.09万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-20 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617851
• 关键词: ANK2 gene; ANK3 gene; Actins; Adult; Affect; Ankyrins; Area; Arrhythmia; Biology; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Caring; Cells; Child; Clinical; Communities; Complex; Congenital Cardiovascular Abnormality; Cytoskeleton; Data; Defect; Diagnostic; Dilated Cardiomyopathy; Disease; Elements; Etiology; Evaluation; Exhibits; Functional disorder; Genes; Goals; Heart; Heart Block; Heart Diseases; Heart failure; Heritability; Human; In Vitro; Intercalated disc; Investigation; Ion Channel; Left ventricular structure; Link; Membrane; Membrane Proteins; Mentors; Modeling; Molecular; Morphology; Mus; Muscle Cells; Mutation; Myocardial Contraction; Myocardial dysfunction; Myocardium; Neurons; Pathologic; Pathway interactions; Patients; Persons; Phenotype; Physicians; Physiological; Play; Population; Post-Translational Protein Processing; Protein Isoforms; Proteins; Regulation; Risk Assessment; Role; Scientist; Signal Transduction; Sodium Channel; Spectrin; Stimulus; Structure; Testing; Thinness; Tissues; Variant; Ventricular Arrhythmia; Work; betaIV spectrin; career; congenital heart disorder; disease natural history; disease phenotype; gene product; heart function; human disease; improved; in vivo; insight; loss of function; loss of function mutation; novel; recruit; response; sudden cardiac death; training opportunity; voltage

Project Summary Normal cardiac function requires synchronization of structural and electrical molecules within the heart. Defects affecting cardiac excitability linked to sudden cardiac death affect ½ million people, and those affecting contractile function, such as in the case of cardiomyopathy, impact another 5.7 million patients in the U.S. each year. However, often overlooked are cardiovascular (CV) phenotypes that result in both electrical and contractile dysfunction. This relationship between contractile and electrical elements is critically important to understand in the patient with congenital heart disease (CHD). There are now more adults (ACHD) living with CHD than children, and in this population the most common late manifestation of CHD is a severely complex phenotype hallmarked by both heart failure and arrhythmia. The ACHD community recognizes the importance of each of these entities, and has set forth high-priority areas of study surrounding heart failure and arrhythmia, with the goal of using models aimed at the ‘cellular keystones underlying CHD’. This proposal embraces that focus, shifting from the study of each of these late CV sequela independently, and taking a broader look at the complex CHD phenotypes that result in both electrical and contractile dysfunction. We have identified a molecule which we believe has both CV electrical and contractile consequences, thereby serving as a good foundational model to study complex phenotypes resulting in combination arrhythmia and heart failure. Ankyrins are a membrane- associated protein directly linked with targeting ion channels in myocytes, neurons and other excitable cells. In heart, ankyrins-B and –G, which function to support myocyte actin/spectrin in the cytoskeleton and function in cellular organization, transport, gating and post-translational modification, are associated with critical membrane ion channels. Canonical AnkG is required for normal NaV1.5 channel targeting in the heart. However, we have identified a novel ‘giant’ cardiac ankyrin-G isoform that we implicate is critical for normal cardiac structure, contractility and electrical conduction. Mice lacking ‘Giant AnkG’ display a dilated and thinned left ventricle with reduced systolic function, consistent with a dilated cardiomyopathy phenotype. These same mice also exhibit electrical dysfunction including ventricular arrhythmia and high-degree heart block. Our new preliminary data support our central hypothesis: A single ankyrin gene produces two separate molecules- each with unique roles in cardiac structural and electrical function. We hypothesize that novel cardiac Giant AnkG functions via a unique sodium-channel independent mechanism leading to regulation myocyte structure, membrane organization and abnormal intra- and inter-cellular signaling. Ultimately, loss of function of this large gene product leads to altered myocardial contraction and defective electrical function.

项目概要 正常的心脏功能需要心脏内结构分子和电分子的同步。 与心源性猝死相关的影响心脏兴奋性的缺陷影响了 150 万人，而那些影响 收缩功能（例如心肌病）影响着美国另外 570 万名患者 年。然而，经常被忽视的是心血管（CV）表型，它会导致电和收缩 功能障碍。理解收缩元件和电元件之间的关系至关重要 先天性心脏病 (CHD) 患者。现在患有 CHD 的成年人 (ACHD) 数量比 儿童，在这个人群中，冠心病最常见的晚期表现是严重复杂的表型 以心力衰竭和心律失常为特征。 ACHD 社区认识到每个方面的重要性 这些实体，并提出了围绕心力衰竭和心律失常的高度优先研究领域， 使用针对“先天性心脏病背后的细胞基石”的模型的目标。该提案涵盖了这一重点， 从对每一个晚期CV后遗症的独立研究转向更广泛地审视复杂的情况 导致电和收缩功能障碍的先心病表型。我们已经鉴定出一种分子 我们相信具有 CV 电学和收缩效应，因此可以作为一个良好的基础模型 研究导致心律失常和心力衰竭的复杂表型。锚蛋白是一种膜—— 相关蛋白与肌细胞、神经元和其他可兴奋细胞中的靶向离子通道直接相连。在 心脏、锚蛋白-B 和 -G，其功能是支持细胞骨架中的肌细胞肌动蛋白/血影蛋白，并在 细胞组织、运输、门控和翻译后修饰与关键膜相关 离子通道。 Canonical AnkG 是心脏中正常 NaV1.5 通道靶向所必需的。然而，我们有 发现了一种新的“巨型”心脏锚蛋白-G亚型，我们认为它对于正常心脏结构至关重要， 收缩性和导电性。缺乏“巨型AnkG”的小鼠表现出左心室扩张和变薄 收缩功能降低，与扩张型心肌病表型一致。这些相同的小鼠也表现出 电功能障碍包括室性心律失常和高度心脏传导阻滞。我们的新初步数据 支持我们的中心假设：单个锚蛋白基因产生两个独立的分子——每个分子都有独特的作用 心脏结构和电功能。我们假设新型心脏巨型 AnkG 通过独特的功能发挥作用 钠通道独立机制导致调节心肌细胞结构、膜组织和 细胞内和细胞间信号传导异常。最终，这个大基因产物的功能丧失会导致基因的改变 心肌收缩和电功能缺陷。