Costamere Defects in Muscular Dystrophies

肌营养不良症中的肋部缺陷

基本信息

批准号：
8213728
负责人：
JAMES M ERVASTI
金额：
$ 34.63万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8213728
关键词：
Ablation Actins Address Adult Alleles Animal Model Animals Baculoviruses Biological Assay Caliber Cell Survival Cells Creatine Kinase Cytoskeleton Data Defect Development Dilated Cardiomyopathy Disease Drops Duchenne muscular dystrophy Dystrophin Electrons Embryo Fiber Filament Genetic Crosses Growth Cones Histopathology Human Immunofluorescence Immunologic Immunofluorescence Microscopy In Vitro Injury Knock-out Knockout Mice Laboratories Light Maintenance Measurement Mechanics Messenger RNA Microfilaments Microscopic Morphology Motor Neurons Mus Muscle Muscle Cells Muscle Contraction Muscle Development Muscle Fibers Muscle function Muscular Dystrophies Myocardium Myopathy Neuromuscular Junction Neurons Pathogenesis Performance Phenotype Protein Isoforms Proteins Proteomics Protocols documentation Publishing Reagent Recombinants Role Running Sarcolemma Sarcomeres Series Serum Site Skeletal Muscle Spinal Cord Spinal Muscular Atrophy Striated Muscles Synapses System Techniques Testing Thin Filament Tissues Transgenic Mice axon guidance base dosage flexibility grasp human disease in vivo insight mdx mouse muscular structure neuromuscular transmission neuronal growth novel overexpression protective effect public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): Costameres are subsarcolemmal protein assemblies in striated muscle cells that physically couple force-generating sarcomeres with the sarcolemma. Costameres are clearly important for normal muscle function because several constituent proteins are the primary sites of defect in human muscular dystrophies and dilated cardiomyopathies. We previously demonstrated that the costameric cytoskeleton is enriched in non-muscle "cytoplasmic" ?cyto-actin and that muscle-specific ablation of ?cyto-actin causes a novel form of progressive myopathy. The major objective of this renewal is to elucidate the important, but poorly understood functions of both ¿cyto- and ?cyto-actin isoforms in skeletal muscle. We will make use of novel conditional animal models and isoform-specific reagents generated by my group during the original project period to address several fundamental questions about cytoplasmic actins in normal skeletal muscle function and in human diseases of skeletal muscle tissue. In aim 1, we will investigate the specific contribution of ?cyto-actin to the mechanical function of skeletal muscle, which may also shed light into the mechanism of contraction-induced injury of normal and dystrophin-deficient muscle. In aim 2, the distinct and overlapping roles of ¿cyto- and ?cyto- actins in developing and adult skeletal muscle, particularly in costameres, will be investigated through the characterization of mouse lines in which either ¿cyto-actin, or ¿cyto- and ?cyto-actins have been knocked out specifically in skeletal muscle. In aim 3, we will test the hypothesized role for aberrant ¿cyto-actin localization in the pathogenesis of spinal muscular atrophy both in vivo and in vitro. The results of the proposed studies will most definitively address the unique and important contributions of cytoplasmic actin isoforms to the function of normal and diseased skeletal muscle. PUBLIC HEALTH RELEVANCE: The sarcomeric actin isoforms are well known for their important role in contraction of skeletal and cardiac muscle. However, the roles of non-muscle cytoplasmic actin isoforms in the development/maintenance of specialized muscle structures and their contribution to diseases of skeletal muscle are also important, but remain poorly understood. Through rigorous characterization of skeletal muscle in genetically-modified lines of mice where one or both non-muscle cytoplasmic actins are selectively eliminated in combination with complementary experiments on isolated cells and proteins, the proposed studies will most definitively address the unique and important contributions of non-muscle cytoplasmic actin isoforms to the function of normal and diseased skeletal muscle. In particular, this project is highly relevant to understanding the pathological mechanism of Duchenne muscular dystrophy and spinal muscular atrophy.

描述（由适用提供）：COSTAMERES是在策略肌肉细胞中的亚囊膜蛋白组件，它们将肉瘤与肌膜造成物理生成肉瘤。 Costameres对于正常的肌肉功能显然很重要，因为几种组成蛋白是人类肌肉营养不良和扩张心肌病的主要缺陷部位。我们先前证明了服装骨骼富含非肌肉的“细胞质”？cyto-Actin，并且肌肉特异性的肌肉肌动蛋白会引起一种新型的进行性肌病形式。这种更新的主要目的是阐明骨骼肌中重要但不了解的cyto和cyto-肌动蛋白的功能。我们将利用我的小组在原始项目期间产生的新型有条件动物模型和同工型特异性试剂，以解决正常骨骼肌功能和骨骼肌组织的人类疾病中有关细胞质肌动蛋白的几个基本问题。在AIM 1中，我们将研究Cyto-Actin对骨骼肌机械功能的特定贡献，这也可能使骨骼肌的机械功能降低了合同诱导的正常和肌营养不良蛋白缺陷肌肉的机理。在AIM 2中，将通过小鼠线的表征来研究细胞和细胞肌动物在发育和成年骨骼肌中的明显和重叠作用，其中将研究细胞 - 肌动蛋白，或细胞 - 肌动蛋白和？细胞肌动物的表征，在骨骼肌中已专门敲定。在AIM 3中，我们将测试异常的假设作用 - 细胞 - 肌动蛋白定位在体内和体外的脊髓肌肉萎缩发病机理中。拟议研究的结果将最明确地解决细胞质肌动蛋白同工型对正常骨骼肌和解散的骨骼肌功能的独特和重要贡献。公共卫生相关性：肌肉肌动蛋白同工型以其在骨骼和心脏肌肉收缩中的重要作用而闻名。然而，非肌肉细胞质肌动蛋白同工型在特殊肌肉结构的开发/维持中的作用及其对骨骼肌疾病的贡献也很重要，但仍然很糟糕。 Through rigorous characterization of skeletal muscle in genetically-modified lines of mice where One or both non-muscle cytoplasmic actins are selectively eliminated in combination with completery experiments on isolated cells and proteins, the proposed studies will most definitively address the unique and important contributions of non-muscle cytoplasmic actin isoforms to the function of normal and disseased skeletal muscle.特别是，该项目与理解杜钦肌营养不良和脊柱肌肉萎缩的病理机制高度相关。