Myopalladin’s Role in Cardiac Muscle Function and Disease

Myopalladin 在心肌功能和疾病中的作用

基本信息

批准号：
10292264
负责人：
MORIAH R BECK
金额：
$ 42.85万
依托单位：
WICHITA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10292264
关键词：
Actins Affect Aging Architecture Binding Biochemical Biochemistry Bioinformatics Biological Assay Biological Process Biology Biomedical Engineering Biophysics C-terminal Cardiac Cardiomyopathies Cells Chemicals Cytoskeleton DISC components Data Development Disease Drosophila genus Education F-Actin Family Fluorescence Future Goals Growth Heart Heart Abnormalities Heart Diseases Human Immunoglobulin Domain Industrial Health Inherited Kinetics Knowledge Learning Length Link Literature Maintenance Mass Spectrum Analysis Measurement Measures Microfilaments Molecular Molecular Biology Morphology Muscle Muscle Proteins Muscle function Mutation Myocardial dysfunction Myocardium Myopathy Pathogenesis Phenotype Play Prevention Process Property Protein Engineering Proteins Publishing Regulation Research Research Infrastructure Role Sarcomeres Scientist Sedimentation process Skeletal Muscle Structure Students Techniques Testing Thin Filament Universities Wichita Work base crosslink depolymerization design experimental study graduate student in vivo inherited cardiomyopathy innovation insight instrumentation interdisciplinary curriculum mechanical properties multidisciplinary mutant myopalladin novel novel therapeutics polymerization programs protein function protein protein interaction protein structure function single molecule undergraduate research experience undergraduate student

项目摘要

Project Summary Project Title: Myopalladin’s role in cardiac muscle function and disease Decades of research have provided fundamental insight into the human heart’s structure and function. Yet, most cardiac malformations remain a mystery as scientists and clinicians continue to examine how inherited mutations and aging affect the normal biological functions of proteins associated with cardiac dysfunction. Recently, mutations in the muscle protein myopalladin have been linked to the pathogenesis of three of the four major types of cardiomyopathy. Myopalladin is thought to be involved in regulating the organization of sarcomere structure, however insufficient knowledge of myopalladin’s interactions with other key molecules in the sarcomere has hampered development of new therapies for cardiomyopathies and other debilitating muscle diseases. Mutations in myopalladin cause diverse cardiomyopathic phenotypes that are poorly understood; therefore, our goal is to uncover the molecular mechanisms and discover how sarcomere thin filament assembly occurs. Myopalladin and palladin belong to a family of closely related immunoglobulin (Ig)-domain-containing proteins that have essential, but uncharacterized roles in organizing the actin cytoskeleton. Previous work in the Beck lab revealed that palladin binds directly to actin and increases both the rate of actin polymerization and the stability of actin filaments. Our more recent results indicate that myopalladin also binds and bundles filamentous actin, however myopalladin reduced actin polymerization and strongly inhibits depolymerization. The fact that a number of mutations in myopalladin are located within the analogous actin-binding region suggests that a disruption in actin regulation may occur in cardiomyopathy. The objective of this application is to provide new insights into the still largely elusive role of myopalladin in cardiac structure, function, and disease. We will investigate the functional properties of myopalladin by employing multidisciplinary studies that integrate structural and functional analysis of isolated proteins with characterization of actin assembly and sarcomere structure in cultured and live cells. We will test our hypothesis that myopalladin promotes thin filament actin elongation by examining interactions critical for this regulation that may also be disrupted by the cardiomyopathy-associated mutations recently identified. Such studies will be a significant advance in our understanding of familial cardiomyopathy and may motivate the development of new strategies to detect and treat cardiac disease.

项目概要项目名称：Myopalladin 在心肌功能和疾病中的作用数十年的研究为人类心脏的结构和功能提供了基本的见解。然而，随着科学家和参议员继续研究如何遗传，大多数心脏畸形仍然是一个谜。突变和衰老会影响与心脏功能障碍相关的蛋白质的正常生物学功能。最近，肌肉蛋白 Myopalladin 的突变与四种疾病中的三种的发病机制有关。 Myopalladin 被认为参与调节肌节的组织。结构，但是对 myopalladin 与其他关键分子的相互作用了解不够肌节阻碍了心肌病和其他肌肉衰弱的新疗法的开发肌帕拉丁突变会导致多种心肌病表型，但人们对此知之甚少；因此，我们的目标是揭示分子机制并发现肌小节细丝如何组装发生。 Myopalladin 和 Palladin 属于密切相关的含有免疫球蛋白 (Ig) 结构域的家族在组织肌动蛋白细胞骨架中具有重要但未表征的作用的蛋白质。 Beck 实验室发现 Palladin 直接与肌动蛋白结合，并增加肌动蛋白聚合速率和我们最近的结果表明肌钯蛋白也结合并成束丝状。然而肌动蛋白减少肌动蛋白聚合并强烈抑制解聚。肌帕拉丁中的许多突变位于类似的肌动蛋白结合区域内，这表明心肌病中可能会发生肌动蛋白调节的破坏，该应用的目的是提供新的。我们将深入了解肌帕拉丁在心脏结构、功能和疾病中的作用。通过整合结构的多学科研究来研究 Myopalladin 的功能特性对分离蛋白质进行功能分析，并表征肌动蛋白组装和肌节结构我们将通过培养和活细胞来检验肌帕拉丁促进细丝肌动蛋白伸长的假设。检查对于这种调节至关重要的相互作用，这些相互作用也可能受到心肌病相关的干扰最近发现的这些突变将是我们对家族的理解的重大进步。心肌病，并可能促进开发检测和治疗心脏病的新策略。