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.

心脏/骨骼肌收缩涉及的细丝的改变通常会产生 心肌病/肾上腺素肌病和致命后果。我们的长期目标是确定 正常发育过程中调节肌肉肌动蛋白结构的组成部分和分子机制和 疾病。在正在进行的赠款支持的提案中，我们的短期目标是确定 肌动蛋白丝尖末端结合蛋白（LMOD）和 Tropomoduin（TMOD）。尖端的聚合决定薄丝长度，并直接调节 通过TMOD和LMOD的结合。积分细丝组件的增强了这种结合， tropomyosin。我们假设维持薄丝长度需要TMOD的拮抗作用 和lmod;也就是说，TMOD的作用是防止在尖端端伸长，而LMOD允许伸长。 我们还预测，尖端的TMOD和LMOD结合和作用由不同的 它们的肌动蛋白和肌动蛋白结合位点的布置。在我们提交的续签建议中，我们将评估 LMOD和TMOD如何影响薄丝的形成，然后影响薄丝的结构。我们将测试我们最近的 提出的用于薄尖端的LMOD/TMOD依赖性调节的分子机制 细丝。我们还将研究LMOD结合到已经结构的结构和功能后果 形成细丝。最后，我们将建立LMOD功能调节的机制。我们的数据将提供 对薄丝细丝的调节机制的关键组成部分的全面识别 健康和疾病的组装和维护。拟议的实验将连接LMOD相关的薄 家族性肌病的细丝改变。更好地了解细丝功能及其调节 对于更好地了解肌肉疾病发病机理，改善诊断和潜在识别至关重要 新型药物靶标。