Arrhythmias in HCM Due to Mutation in cMyBP-C

cMyBP-C 突变导致 HCM 心律失常

• 批准号: 8134106
• 负责人: Richard L Moss
• 金额: $ 62.68万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134106
• 关键词: Ablation; Actins; Action Potentials; Address; Adolescent; Age; Age-Months; Agonist; Amino Acids; Animal Model; Animals; Apical; Arrhythmia; Binding; Biological Assay; C-terminal; Cardiac; Cardiac Myosins; Catheters; Cells; Characteristics; Clinical; Collaborations; Defect; Dependence; Development; Diet; Disease; Doxycycline; Echocardiography; Electrocardiogram; Ensure; Exercise stress test; Exhibits; Functional disorder; Genes; Genetic Polymorphism; Genetic Transcription; Heart; Heart Arrest; Heart Hypertrophy; Heterogeneity; Human; Hypertrophic Cardiomyopathy; Hypertrophy; In Vitro; Incidence; Individual; Intervention; Investigation; Ion Channel; Ions; Kinetics; Knock-in Mouse; Knockout Mice; Lactation; Left; Left Ventricular Hypertrophy; Life; Link; Measures; Microfilaments; Missense Mutation; Mus; Muscle Cells; Mutant Strains Mice; Mutation; Myocardial; Myocardium; Myosin ATPase; Patients; Phenotype; Positioning Attribute; Post-Translational Protein Processing; Predisposition; Pregnancy; Property; Proteins; Pump; Regulation; Relaxation; Repression; Rest; Risk; Risk Factors; Role; RyR2; Series; Severities; Skin; Staging; Stress Tests; Stroke Volume; Structure; Sudden Death; System; Testing; Tetanus Helper Peptide; Tetracyclines; Thick; Thick Filament; Threonine; Time; Transgenes; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Ventricular; Withdrawal; base; constriction; disease phenotype; feeding; genome-wide; human tissue; in vivo; insight; mature animal; mouse model; mutant; myosin-binding protein C; neonate; pressure; prevent; research study; transgene expression

DESCRIPTION: Mutations in several myofibrillar proteins have been implicated as causes of heritable hypertrophic cardiomyopathies (HCM), and among these, mutations in cardiac myosin binding protein-C (encoded by MYBPC3) are among the most common and have been associated with increased risk for sudden cardiac arrest (SCA) at an early age. However, the cause of SCA is not understood, nor is the observation that some patients expressing mutant cMyBP-C exhibit the hypertrophy and functional sequelae that are characteristic of HCM while others do not. To address these issues, this subproject explores the mechanisms of Ca2+ -triggered arrhythmias in animal models of HCM and also identifies factors such as hypertrophy and co-expression of ion channelopathies that contribute to the profound heterogeneity in the clinical manifestations of disease. The specific hypotheses are: (1) the severity of contractile dysfunction, hypertrophy and SCA stratifies with the degree of cMyBP-C dysfunction, being greatest for C-terminal truncations in which the mutant protein is not incorporated into the myofilaments, (2) the risk of SCA in patients with /WY6PC3rHCM is influenced by the concomitant expression of pro-arrhythmic ion channel polymorphisms, and (3) HCM mutations in MYBPC3, alone or in combination with mutations/polymorphisms in ion channels, cause increased risk of SCA beyond that due to hypertrophy alone. We will test these hypotheses in a series of experiments in which the functional consequences of HCM mutations are studied in living animals and in post-mortem tissue from human HCM hearts. In vivo functional assays will include pressure-volume loops and electrocardiography under resting conditions and during exercise stress testing; in vitro functional assays will include assessment of arrhythmic activity in Langendorff-perfused hearts and both Ca2+ handling and action potentials in isolated cells. The time course and reversibility of effects on contractile and electrophysiological function due to variable expression of HCM mutant cMyBP-C will be studied in transgenic animals in which expression of mutant cMyBP-C is controlled by a tetracycline-inducible system. Results from these studies will provide new insights into the mechanisms underlying disease phenotypes in HCM due to mutations in MYBPC3.

描述： 多种肌原纤维蛋白的突变被认为是导致遗传性肥厚性心肌病 (HCM) 的原因，其中，心肌肌球蛋白结合蛋白 C（由 MYBPC3 编码）的突变是最常见的突变，并且与早期心脏骤停 (SCA) 的风险增加有关。然而，SCA 的原因尚不清楚，某些观察结果也不清楚。 表达突变型 cMyBP-C 的患者表现出肥厚和功能性后遗症，这是 HCM 的特征，而其他患者则不然。为了解决这些问题，该子项目探讨了 HCM 动物模型中 Ca2+ 触发心律失常的机制，并确定了导致疾病临床表现的深刻异质性的离子通道病的肥大和共表达等因素。具体假设是：（1）收缩功能障碍、肥大和 SCA 的严重程度与 cMyBP-C 功能障碍的程度，其中突变蛋白未掺入肌丝的 C 端截断最为严重，(2) /WY6PC3rHCM 患者中 SCA 的风险受到促心律失常离子通道多态性的伴随表达的影响，以及 (3) MYBPC3 中的 HCM 突变， 单独或与离子通道突变/多态性相结合，会导致 SCA 的风险增加，而不仅仅是单纯肥大造成的风险。我们将在一系列实验中检验这些假设，在活体动物和人类 HCM 死后组织中研究 HCM 突变的功能后果 心。体内功能测定将包括静息条件下和运动压力测试期间的压力-容量环和心电图；体外功能测定将包括评估 Langendorff 灌注心脏的心律失常活性以及分离细胞中的 Ca2+ 处理和动作电位。将在转基因动物中研究由于 HCM 突变体 cMyBP-C 的可变表达而对收缩和电生理功能影响的时间过程和可逆性，其中突变体 cMyBP-C 的表达受四环素诱导系统控制。这些研究的结果将为了解 MYBPC3 突变导致 HCM 疾病表型的机制提供新的见解。