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：
8606772
负责人：
Julian Stelzer
金额：
$ 38.83万
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/8606772
关键词：
ATP phosphohydrolase Acceleration Accounting Actins Actomyosin Acute Address Adolescent and Young Adult 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）：该提案的长期目标是确定心肌肌球蛋白结合蛋白 C (MyBPC) 突变导致肥厚型 (HCM) 和扩张型心肌病 (DCM) 的机制，这种疾病影响 0.2% 的患者全世界人口中的一个，是年轻人猝死的主要原因。 MyBPC 突变是遗传性心肌病最常见的原因之一，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 是肌动球蛋白相互作用的关键调节剂，因此 MyBPC 突变引起的初始功能缺陷预计将表现为肌丝水平心肌收缩调节的缺陷。然而，MyBPC 突变改变收缩功能并导致疾病的精确分子机制尚不清楚，并且尚未确定表达 MyBPC 的突变是否可以整合到肌节中以直接改变收缩功能。对 MyBPC 突变如何导致 HCM 和 DCM 缺乏基本认识，严重限制了我们设计有效疗法来克服该疾病及其功能后果的能力。拟议的实验将阐明已知会导致儿童和成人一系列严重疾病的 MyBPC 突变的功能影响，并将检验 MyBPC 错义突变融入肌节以直接改变收缩功能的假设，旨在实现三个主要目标： : 1) 确定 MyBPC 突变对用表达 HCM 和 DCM 的 MyBPC 重建的心肌纤维中稳态力和动态跨桥功能的 Ca2+ 依赖性的功能影响，引起突变， 2) 使用荧光标记蛋白的稳态和瞬态动力学分析，定义 MyBPC 突变对 ATP 酶活性、细丝力产生调节和跨桥动力学的影响，以及 3) 确定错义突变的体内功能后果在 MyBPC 中，通过使用压力容积导管插入术和高分辨率心脏磁共振成像来评估接受突变 MyBPC 急性基因转移的动物的心室结构和功能。预计这些综合研究的结果将为 MyBPC 突变导致心脏功能障碍的潜在机制提供新的见解，并将有助于开发治疗 MyBPC 相关 HCM 和 DCM 的新治疗策略。