Calsequestrin in Ventricular Arrhythmia and Sudden Death

Calsequestrin 治疗室性心律失常和猝死

• 批准号: 7407567
• 负责人: Bjorn C Knollmann
• 金额: $ 43.71万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7407567
• 关键词: Affinity; Animals; Antidepressive Agents; Arrhythmia; Binding; Binding Proteins; Calsequestrin; Cardiac; Catecholamines; Cells; Cessation of life; Crossbreeding; Data; Disruption; Electrophysiology (science); Exercise; Functional disorder; Goals; Heart; Heterozygote; Homeostasis; Human; Human Genetics; In Vitro; Incidence; Individual; Infusion procedures; Inherited; Knockout Mice; Lead; Link; Long QT Syndrome; Molecular; Mouse Protein; Mus; Muscle Cells; Mutation; Outcomes Research; Patients; Pharmaceutical Preparations; Phenocopy; Predisposition; Proteins; Range; Research Personnel; Role; Sarcoplasmic Reticulum; Sudden Death; Syndrome; Testing; Tricyclic Antidepressive Agents; Ventricular; Ventricular Arrhythmia; Ventricular Tachycardia; animal breeding; base; in vivo; mouse junctate protein; programs; protein expression; research study; response; sudden cardiac death; triadin

DESCRIPTION (provided by applicant): Cardiac calsequestrin (CASQ2), and its binding partners junctin and triadin-1 (TRDN), are key regulators of sarcoplasmic reticulum (SR) Ca2+ storage and release. In humans, CASQ2 mutations cause a syndrome of catecholaminergic polymorphic ventricular tachycardia and sudden cardiac death. To determine the mechanisms whereby CASQ2 mutations cause electrophysiologic instability but preserve contractile function, we have generated Casq2 null (Casq2-/-) mice. Our preliminary studies demonstrate that despite a lack of Casq2 protein, these mice maintain near normal SR Ca2+ storage, possibly as a result of an expansion of SR volume and drastic reductions in the Casq2 binding proteins triadin-1 and junctin. Casq2-/- mice phenocopy the human CASQ2- linked arrhythmias by developing polymorphic ventricular tachycardia with catecholamine infusion or exercise. Casq2-/- myocytes display premature spontaneous SR Ca2+ releases resulting in after- contractions and triggered beats. Significantly, commonly-used antidepressant drugs, which disrupt Ca2+ binding to CASQ2 in vitro, have also been linked to an increased incidence in sudden cardiac death, raising the possibility of a Casq2-linked form of drug-induced arrhythmias, analogous to the drug-associated long QT syndrome. Based on these human genetic, epidemiological, and mouse data, we hypothesize that disruption of Casq2 causes dysfunctional SR Ca2+ release and contributes to arrhythmia susceptibility and sudden death. To test our central hypothesis, we will examine single cell, whole heart and in vivo electrophysiology, contractile function, Ca2+ homeostasis, protein expression and SR ultrastructure in Casq2-/- , Casq2+/-, triadin-1 null (Trdn-/-) and selectively cross-bred animals. Our goals are to test the individual contribution of Casq2 and triadin-1 to arrhythmia susceptibility and further elucidate the molecular and cellular mechanism(s) that lead to ventricular arrhythmias in response to inherited and possibly drug-induced Casq2 dysfunction. The outcome of this research will not only advance our understanding of the pathophysiology of inherited arrhythmia syndromes, but also help unravel the mechanism(s) responsible for sudden deaths linked to antidepressant medications taken by millions of patients.

描述（由申请人提供）：心脏CALSequestin（CASQ2）及其结合伙伴Junctin和Triadin-1（TRDN）是肌浆网（SR）CA2+存储和释放的关键调节剂。在人类中，CASQ2突变会导致儿茶酚胺能多态性心脏心动过速和心脏猝死综合征。为了确定CASQ2突变引起电生理不稳定性但保留收缩功能的机制，我们已经产生了CASQ2 NULL（CASQ2 - / - ）小鼠。我们的初步研究表明，尽管缺乏CASQ2蛋白，但这些小鼠仍将SR Ca2+储存量接近正常，这可能是由于SR体积的扩展和CASQ2结合蛋白Triadin-1和Junctin的急剧减少而导致的。 CASQ2 - / - 小鼠的表现，人类CASQ2与心律不齐的心律不齐相关性心律不齐，并通过注入儿茶酚胺或运动。 CASQ2 - / - 心肌细胞显示过早的自发SR Ca2+释放，导致收缩和触发节拍。值得注意的是，在体外破坏了Ca2+与CASQ2结合的常用抗抑郁药也与心脏猝死的发病率增加有关，从而增加了与药物相关的长期QT综合征类似的CASQ2连接形式的药物诱导的心律失常。基于这些人类遗传，流行病学和小鼠数据，我们假设CASQ2的破坏会导致功能失调的SR CA2+释放，并导致心律不齐的敏感性和猝死。为了检验我们的中心假设，我们将检查单细胞，全心和体内电生理学，收缩功能，Ca2+稳态，蛋白质表达和蛋白质表达和SR Ultroctructure在CASQ2 - / - ，CASQ2 +/-，Triadin-1 Null（TRDN--/ - ）以及选择性的杂交动物中。我们的目标是测试CASQ2和Triadin-1对心律不齐易感性的个体贡献，并进一步阐明导致心律不齐的分子和细胞机制，以响应遗传性的CASQ2功能障碍，从而导致心室心律不齐。这项研究的结果不仅会提高我们对遗传性心律不齐综合征的病理生理学的理解，而且还有助于揭示导致与数百万患者抗抑郁药有关的猝死的机制。