Regulation of the actin filament pointed end dynamics in health and disease

健康和疾病中肌动蛋白丝尖端动态的调节

• 批准号: 10387989
• 负责人: Carol C Gregorio
• 金额: $ 8.53万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387989
• 关键词: Actins; Affect; Architecture; Binding; Binding Proteins; Binding Sites; Cardiac; Cardiomyopathies; Data; Development; Diagnostic; Disease; Goals; Grant; Health; Length; Link; Maintenance; Minus End of the Actin Filament; Molecular; Muscle; Muscle Contraction; Myopathy; Nemaline Myopathies; Pathogenesis; Public Health; Regulation; Research; Role; Sarcomeres; Side; Skeletal Muscle; Structure; Testing; Thin Filament; Tropomyosin; experimental study; improved; new therapeutic target; polymerization; prevent

Alterations in the thin filaments involved in cardiac/skeletal muscle contraction often produce cardiomyopathies/nemaline myopathies with fatal consequences. Our long-term goal is to identify the components and molecular mechanisms regulating actin architecture in muscle during normal development and disease. In the proposal supported by the ongoing grant, our short-term goal is to determine the mechanisms of how thin filament lengths are regulated by the actin filament pointed end binding proteins, leiomodin (Lmod) and tropomoduin (Tmod). Polymerization at the pointed end determines thin filament length and is regulated directly by the binding of Tmod and Lmod. This binding is enhanced by the integral thin filament component, tropomyosin. We hypothesize that maintenance of thin filament length requires the antagonistic action of Tmod and Lmod; that is, the role of Tmod is to prevent elongation at the pointed end while Lmod allows elongation. We also predict that Tmod and Lmod binding and action at the pointed end is determined by different arrangements of their tropomyosin- and actin-binding sites. In our submitted renewal proposal, we will evaluate how Lmod and Tmod affect the formation and then the structure of the thin filament. We will test our recently proposed molecular mechanism for the Lmod/Tmod-dependent regulation of the pointed end of the thin filaments. We will also study the structural and functional consequences of Lmod binding to sides of the already formed thin filaments. Finally, we will establish mechanisms of regulation of Lmod functions. Our data will provide a comprehensive identification of critical components of the regulatory mechanisms underlying thin filament assembly and maintenance in health and disease.The proposed experiments will connect Lmod-related thin filament alterations with familial myopathies. A better understanding of thin filament function and of its regulation is critical to better understand muscle disease pathogenesis, to improve diagnostics and to potentially identify novel drug targets.

参与心肌/骨骼肌收缩的细丝的变化通常会产生 具有致命后果的心肌病/线状肌病。我们的长期目标是确定 在正常发育过程中调节肌肉肌动蛋白结构的成分和分子机制 疾病。在持续拨款支持的提案中，我们的短期目标是确定以下机制： 肌动蛋白丝尖端结合蛋白、leiomodin (Lmod) 和 原调节蛋白（Tmod）。尖端的聚合决定细丝长度并直接调节 通过 Tmod 和 Lmod 的结合。这种结合通过整体细丝组件得到增强， 原肌球蛋白。我们假设维持细丝长度需要 Tmod 的拮抗作用 和Lmod；也就是说，Tmod的作用是防止尖端伸长，而Lmod则允许伸长。 我们还预测 Tmod 和 Lmod 在尖端的结合和作用是由不同的决定的 它们的原肌球蛋白和肌动蛋白结合位点的排列。在我们提交的续订提案中，我们将评估 Lmod 和 Tmod 如何影响细丝的形成和结构。我们将测试最近的 提出了薄尖端 Lmod/Tmod 依赖性调节的分子机制 细丝。我们还将研究 Lmod 与已经存在的两侧结合的结构和功能后果。 形成细丝。最后，我们将建立Lmod功能的调节机制。我们的数据将提供 全面识别细丝基础调节机制的关键组成部分 健康和疾病中的组装和维护。拟议的实验将连接 Lmod 相关的薄层 家族性肌病引起的肌丝改变。更好地了解细丝功能及其调节 对于更好地了解肌肉疾病的发病机制、改进诊断并潜在地识别肌肉疾病至关重要 新的药物靶点。