Arrhythmias in HCM Due to Mutation in cMyBP-C

cMyBP-C 突变导致 HCM 心律失常

基本信息

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
项目类别：
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

项目摘要

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：几种肌原纤维蛋白中的突变已被认为是遗传性肥厚性心肌病（HCM）的原因，其中最常见的是心脏肌球蛋白结合蛋白-C（由MyBPC3编码）的突变是最常见的，并且与早期突然心脏骤停的风险增加了。但是，SCA的原因尚不理解，也没有观察到某些人表达突变CMYBP-C的患者表现出肥大和功能性后遗症，这些后遗症是HCM的特征，而其他人则没有。为了解决这些问题，该子标准探讨了HCM动物模型中Ca2+触发的心律不齐的机制，还鉴定了诸如肥大和离子通道病的共表达等因素，这些因素有助于疾病临床表现中的深刻异质性。具体假设是：（1）收缩功能障碍，肥大和SCA的严重程度随着 CMYBP-C功能障碍的程度，对于不掺入突变蛋白的C末端截断最大，（2） /WY6PC3RHCM患者的SCA风险受到SCA的风险，受到亲核离子离子通道多符号表达的同时表达的影响。单独或与离子通道中的突变/多态性结合使用，仅由于肥大而导致SCA的风险增加。我们将在一系列实验中检验这些假设，在这些实验中，在人类HCM中研究了活动物和验尸组织中HCM突变的功能后果。心。体内功能分析将包括压力量环和心电图在休息条件下以及运动应力测试期间；体外功能分析将包括评估Langendorff灌注心脏中心律不齐的活性以及分离的细胞中的Ca2+处理和动作电位。由于HCM突变体CMYBP-C的可变表达，将在转基因动物中研究对收缩性和电生理功能的影响的时间过程和可逆性，在这种动物中，突变体CMYBP-C的表达受到四环素诱导系统的控制。这些研究的结果将提供有关MYBPC3突变引起的HCM疾病表型基础机制的新见解。