Defining Novel Mechanisms underlying Human Arrhythmogenic Cardiomyopathy

定义人类致心律失常性心肌病的新机制

• 批准号: 10005450
• 负责人: Nathaniel Patrick Murphy
• 金额: $ 3.58万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005450
• 关键词: ANK2 gene; Affect; American; Animal Model; Arrhythmia; Atrial Fibrillation; Binding; Biochemical; Candidate Disease Gene; Cardiac; Cardiovascular Diseases; Cessation of life; Clinical; Complex; Data; Deposition; Development; Diagnosis; Disease; Family; Fatty acid glycerol esters; Fibrosis; Functional disorder; Genes; Genetic; Goals; Heart; Heart Diseases; Heart failure; Hereditary Disease; Human; Individual; Life; Link; Medical Genetics; Membrane; Modeling; Molecular; Molecular Genetics; Mus; Mutation; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenocopy; Physicians; Play; Population; Proteins; Regulation; Role; Scientist; Signaling Molecule; Sinus; Stains; Structure; Testing; Training; Trichrome stain method; Variant; Ventricular Arrhythmia; WNT Signaling Pathway; Work; arrhythmogenic cardiomyopathy; base; beta catenin; career; combat; genetic variant; in vivo; loss of function; men; mortality; mouse model; novel; sudden cardiac death; young adult

Project Summary/Abstract Defining Novel Mechanisms underlying Human Arrhythmogenic Cardiomyopathy Arrhythmogenic cardiomyopathy (AC, also termed ARVC) is a complex and potentially fatal disease commonly associated with ventricular arrhythmias in young adults. AC is an inherited disorder primarily associated with loss-of-function gene variants in cardiac desmosomal proteins. However, as the full spectrum of AC disease genes is still unknown, we unfortunately lack critical information essential for the diagnosis and treatment of this devastating disease. We seek to identify a new genetic/molecular mechanism for human AC. Our data that include clinical, pathological, genetic, in vivo, biochemical, and molecular studies support a new and unexpected molecular mechanism underlying human AC. Specifically, we have identified ANK2 (encodes AnkB) as a human AC candidate gene. Notably, unlike most AC disease genes, AnkB is not a desmosomal protein. Patients harboring ANK2 loss-of-function variants display AC resulting in sudden cardiac death. A new mouse model of cardiac-restricted AnkB deletion phenocopies human AC displaying structural remodeling, fibrosis, and early mortality. Finally, our data support an unanticipated mechanism for cardiac AnkB. Specifically, our data support that: 1) AnkB directly binds β-catenin, a molecule tightly linked with cardiac Wnt signaling in AC, and 2) β-catenin regulation is altered in hearts of human ANK2 AC and AnkB cKO hearts. Our objective is to define the molecular mechanisms underlying AnkB dysfunction in human AC. Our preliminary data support a conclusion that AnkB is critical for cardiac structural and electrical function, and plays an unexpected role in β-catenin regulation. Further, our data supports that AnkB dysfunction in humans and mice results in maladaptive remodeling, heart failure, arrhythmia, and ultimately early death associated with altered β-catenin activity.

项目总结/摘要 人类致心律失常性心肌病的新机制 致心律失常性心肌病（Arrhythmogenic cardiomyopathy，AC）是一种复杂的、潜在的致命性疾病， 与年轻人的室性心律失常有关。AC是一种遗传性疾病，主要与 心脏桥粒蛋白的功能丧失基因变体。然而，由于AC疾病的全谱 基因仍然是未知的，不幸的是，我们缺乏诊断和治疗的关键信息。 这种毁灭性的疾病。我们试图确定一个新的人类AC的遗传/分子机制。我们的数据 包括临床、病理学、遗传学、体内、生物化学和分子研究，支持一种新的， 人AC潜在的意想不到的分子机制。具体来说，我们已经确定了ANK 2（编码 AnkB）作为人AC候选基因。值得注意的是，与大多数AC疾病基因不同，AnkB不是桥粒蛋白。 蛋白携带ANK 2功能丧失变体的患者显示AC，导致心源性猝死。一个新 心脏限制性AnkB缺失表型模仿人AC的小鼠模型显示结构重塑， 纤维化和早期死亡率。最后，我们的数据支持心脏AnkB的一个意想不到的机制。 具体来说，我们的数据支持：1）AnkB直接结合β-catenin，一种与心脏Wnt紧密相连的分子 AC中的信号传导，和2）β-连环蛋白调节在人ANK 2 AC和AnkB cKO心脏的心脏中改变。我们 目的是确定人类AC中AnkB功能障碍的分子机制。我们的初步 数据支持这样的结论，即AnkB对心脏结构和电功能至关重要， 在β-catenin调节中发挥意想不到的作用。此外，我们的数据支持人类和小鼠的AnkB功能障碍， 导致适应不良的重塑、心力衰竭、心律失常，并最终导致与改变的 β-连环蛋白活性。