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.

在条纹的肌肉中，肌动蛋白细丝体系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且经常致命的骨骼和心脏有关肌肉疾病。我们的长期目标是确定组成部分和分子机制在正常发育和疾病期间调节条纹肌肉中的肌动蛋白结构。在这个项目，我们将评估肌动蛋白结合蛋白如何（例如，静脉模素或 LMOD和Tropomoduin或Tmod）会影响薄丝的形成，然后影响薄丝的结构。我们将测试我们最近提出的LMOD/TMOD依赖性分子机制调节细丝的尖端。我们还将研究结构和功能 LMOD结合到已经形成的细丝的两侧的后果。最后，我们会的建立LMOD功能调节的机制。我们提出三个目标以识别 LMOD函数的全频谱的基本分子机制：（1）破译角色通过尖端调节来维持适当的细丝长度的LMOD；（2）至确定LMOD的肌动蛋白结合位点在细丝激活中的作用；（3）检验假设该LMOD函数由Ca2+调节。我们的数据将提供全面的标识薄丝组件的监管机制的关键组成部分和健康和疾病维护。