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REGULATION OF THE ACTIN FILAMENT POINTED END DYNAMICS IN HEALTH AND DISEASE

健康和疾病中肌动蛋白丝尖头动力学的调节

基本信息

批准号：
10810153
负责人：
Vitold Galkin
金额：
$ 1.2万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2025-08-31
项目状态：
未结题

项目摘要

In striated muscles, actin thin filament architecture is critical for efficient contractile activity, and alterations in thin filament integrity are linked to severe and often lethal skeletal and cardiac muscle diseases. Our long-term goal is to identify the components and molecular mechanisms regulating actin architecture in striated muscle during normal development and disease. In this project, we will evaluate how actin-binding proteins of the tropomodulin family (e.g. leiomodin, or Lmod, and tropomoduin, or 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. We propose three aims to identify underlying molecular mechanisms of the full spectrum of Lmod functions: (1) to decipher the role of Lmod in the maintenance of proper thin filament lengths via pointed end regulation; (2) to establish the role of Lmod’s actin-binding sites in thin filament activation; (3) to test the hypothesis that Lmod functions are regulated by Ca2+. Our data will provide a comprehensive identification of critical components of the regulatory mechanisms underlying thin filament assembly and maintenance in health and disease.

在横纹肌中，肌动蛋白细丝结构对于有效的收缩活动至关重要，细丝完整性的改变与严重的且通常致命的骨骼和心脏疾病有关。肌肉疾病。我们的长期目标是确定其成分和分子机制在正常发育和疾病期间调节横纹肌中的肌动蛋白结构。在这项目，我们将评估如何肌动蛋白结合蛋白的原调节蛋白家族（如leiomodin，或 Lmod和tropomoduin或Tmod）影响细丝的形成，然后影响细丝的结构。我们将测试我们最近提出的Lmod/Tmod依赖的分子机制，调节细细丝的尖端。我们还将研究其结构和功能 Lmod结合到已经形成的细丝的侧面的结果。最后我们将建立Lmod功能调节机制。我们提出了三个目标，以确定潜在的分子机制的Lmod功能的全谱：（1）破译的作用 Lmod在通过尖端调节维持适当的细丝长度方面的作用;（2）建立Lmod肌动蛋白结合位点在细丝激活中的作用;（3）验证假设 Lmod的功能受Ca ~（2+）的调节。我们的数据将提供一个全面的识别细纤维组装的调控机制的关键组成部分，保持健康和疾病。