Functional consequences of FHC mutations in cardiac MyBPC

心脏 MyBPC 中 FHC 突变的功能后果

基本信息

批准号：
8456650
负责人：
Julian Stelzer
金额：
$ 39.47万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8456650
关键词：
ATP phosphohydrolase Acceleration Accounting Actins Actomyosin Acute Address Adolescent Adult Affect Agonist Alleles Animals Behavior Cardiac Cardiac Muscle Contraction Cardiac Myosins Cardiomyopathies Catheterization Child Complementary DNA Contractile Proteins Data Defect Dependency Development Dilated Cardiomyopathy Disease Dose Familial Hypertrophic Cardiomyopathy Family suidae Fiber Foundations Functional disorder Gene Transfer Generations Goals Heart Heart Arrest Heart Diseases Heart failure Human Hypertrophic Cardiomyopathy Infusion procedures Inherited Kinetics Label Laboratories Link Magnetic Resonance Imaging Measures Mechanics Mediating Microfilaments Missense Mutation Molecular Morphology Mus Muscle function Mutation Myocardium Myopathy Myosin ATPase Organ Population Proteins Recombinants Regulation Relaxation Resolution Role Sarcomeres Severity of illness Skin Stress Structure Subfamily lentivirinae Sudden Death Techniques Testing Thick Filament Thin Filament Ventricular Workload design disease-causing mutation effective therapy electric impedance hemodynamics improved in vivo insight mutant myosin-binding protein C novel novel therapeutics pressure protein protein interaction public health relevance reconstitution research study treatment strategy young adult

项目摘要

DESCRIPTION (provided by applicant): The long-range goal of this proposal is to define the mechanisms by which mutations in cardiac myosin binding protein C (MyBPC) cause hypertrophic (HCM) and dilated cardiomyopathy (DCM), a disease that affects 0.2% of the population worldwide, and is the leading cause of sudden death in young adults. Mutations in MyBPC are among the most common causes of inherited cardiomyopathy accounting for more than 40% of all known cases, and are associated with heart failure and sudden cardiac arrest. Because MyBPC is a critical modulator of actomyosin interactions, the initial functional deficit caused by mutations in MyBPC is expected to manifest as a defect in the regulation of cardiac muscle contraction at the myofilament level. However, the precise molecular mechanisms by which mutations in MyBPC alter contractile function and cause disease are not understood, and it has yet to be established if MyBPC expressing mutations can incorporate into the sarcomere to directly alter contractile function. A lack of fundamental insights into how MyBPC mutations cause HCM and DCM severely limits our ability to devise effective therapies to overcome the disease and its functional consequences. The proposed experiments will elucidate the functional effects of mutations in MyBPC known to cause a range of disease severity in children and adults, and will test the hypothesis that missense mutations in MyBPC incorporate into the sarcomere to directly alter contractile function in three principal aims designed to: 1) Establish the functional effects of MyBPC mutations on the Ca2+-dependencies of steady-state force and dynamic cross-bridge function in cardiac fibers reconstituted with MyBPC expressing HCM and DCM causing mutations, 2) Define the effects of MyBPC mutations on ATPase activity, thin filament regulation of force generation, and cross-bridge kinetics, using steady-state and transient kinetic analysis of fluorescently labeled proteins, and 3) Determine the in vivo functional consequences of missense mutations in MyBPC by assessing ventricular structure and function using pressure-volume catheterization and high resolution cardiac magnetic resonance imaging in animals subjected to acute gene transfer of mutant MyBPC. It is expected that results from these integrative studies will provide novel insights of the underlying mechanisms by which mutations in MyBPC cause cardiac dysfunction and will aid in the development of novel therapeutic strategies for treatment MyBPC related HCM and DCM.

描述（由申请人提供）：该提案的远程目标是定义心脏肌球蛋白结合蛋白C（MYBPC）中突变导致肥厚症（HCM）和扩张的心肌病（DCM）的机制，这种疾病会影响全球人口的0.2％，并导致年轻人死亡。 MYBPC中的突变是遗传性心肌病的最常见原因之一，占所有已知病例的40％以上，并且与心力衰竭和心脏骤停有关。由于MYBPC是肌动蛋白相互作用的关键调节剂，因此预计由MYBPC突变引起的最初功能缺陷将表现为在肌膜水平上心脏肌肉收缩的调节中的缺陷。但是，MYBPC中突变改变收缩功能并引起疾病的确切分子机制尚不清楚，并且如果MYBPC表达突变可以纳入肌膜以直接改变收缩功能，则尚待确定。缺乏对MYBPC突变如何导致HCM和DCM的基本见解严重限制了我们设计有效疗法以克服疾病及其功能后果的能力。提出的实验将阐明MYBPC中突变的功能效应，已知会导致儿童和成人的一系列疾病严重程度，并将检验以下假设：MyBPC中的错义突变纳入SARMERE，直接在三个主要目标中直接改变收缩功能，旨在：1）建立了MyBPC突变的功能，并在CA2+稳定效应方面的功能稳定效应，并具有稳定的稳定效应 - 稳定性 - 稳定效应的效应是稳定的 - 依赖性的效应，并构成了稳定效应。 fibers reconstituted with MyBPC expressing HCM and DCM causing mutations, 2) Define the effects of MyBPC mutations on ATPase activity, thin filament regulation of force generation, and cross-bridge kinetics, using steady-state and transient kinetic analysis of fluorescently labeled proteins, and 3) Determine the in vivo functional consequences of missense mutations in MyBPC by assessing ventricular structure and使用压力体积导管插入术和高分辨率心脏磁共振成像的功能，受到突变体MYBPC急性基因转移的功能。预计这些综合研究的结果将提供有关MYBPC突变引起心脏功能障碍的基本机制的新见解，并将有助于开发用于治疗MYBPC相关的HCM和DCM的新型治疗策略。