Myopalladin’s role in cardiac muscle function and disease

项目摘要 项目标题：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，大多数心脏畸形仍然是一个谜，因为科学家和临床医生继续研究如何遗传 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。 主要类型的心肌病。Myopalladin被认为参与调节肌节的组织 然而，对Myopalladin与细胞内其他关键分子的相互作用了解不足 肌节阻碍了心肌病和其他衰弱肌肉的新疗法的开发 疾病。Myopalladin的突变会导致不同的心肌病表型，但人们对此知之甚少； 因此，我们的目标是揭示肌节细丝组装的分子机制。 发生。 Myopalladin和Palladin属于紧密相关的免疫球蛋白(Ig)结构域家族 在组织肌动蛋白细胞骨架中具有基本的、但尚未确定的角色的蛋白质。中以前的工作 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的速度和 肌动蛋白细丝的稳定性。我们最近的研究结果表明，Myopalladin也能结合和捆绑丝状物 然而，肌动蛋白能抑制肌动蛋白的聚合，并强烈抑制解聚。事实是，一个 Myopalladin中的许多突变位于类似的肌动蛋白结合区，这表明 肌动蛋白调节的紊乱可能发生在心肌病中。此应用程序目标是提供新的 对Myopalladin在心脏结构、功能和疾病中的作用仍在很大程度上难以捉摸的洞察。我们会 通过整合结构的多学科研究来研究myopalladin的功能特性 以及肌动蛋白组装和肌节结构特征的分离蛋白的功能分析 培养的和活的细胞。我们将验证我们的假设，即myopalladin通过以下方式促进细丝肌动蛋白的延长 检查对这一调节至关重要的相互作用，这些相互作用也可能被心肌病相关的 最近发现了突变。这样的研究将是我们对家族性疾病的理解的重大进步。 并可能推动开发新的检测和治疗心脏疾病的策略。

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.