Structure-Function Analysis of Sarcospan

Sarcospan 的结构功能分析

基本信息

批准号：
7655936
负责人：
Rachelle Hope Crosbie
金额：
$ 33.44万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-24 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7655936
关键词：
Actins Address Adhesions Affect Agrin Binding Biochemical Characteristics Communication Complex Cytoskeleton Data Disease Duchenne muscular dystrophy Dystroglycan Dystrophin Elements Exhibits Extracellular Matrix Funding Genes Glycoproteins Grant Integral Membrane Protein Integrins Internet Knockout Mice Laboratories Laminin Link Masks Mechanics Mediating Membrane Molecular Mus Muscle Muscle Contraction Muscular Dystrophies Mutation Pathology Peripheral Phenotype Physiological Play Positioning Attribute Prevention Property Proteins Research Role Sarcoglycans Sarcolemma Signal Transduction Skeletal Muscle Structure Testing Therapeutic Transferase Transgenic Mice Transgenic Organisms Utrophin aged design extracellular human PHEMX protein human SSPN protein improved interest mdx mouse muscle strength overexpression premature protein complex public health relevance scaffold

项目摘要

DESCRIPTION (provided by applicant): In skeletal muscle, the dystrophin-glycoprotein complex is located at the sarcolemma and is composed of peripheral and integral membrane proteins. As a whole, this complex links the extracellular matrix to the intracellular actin cytoskeleton and provides structural stability to the sarcolemma during muscle contraction. Duchenne muscular dystrophy, the most common form of dystrophy, is caused by mutations in the dystrophin gene that result in loss of dystrophin protein and the entire dystrophin-glycoprotein complex. My research group has pioneered several key discoveries related to the function of sarcospan, an integral component of the dystrophin-glycoprotein complex. We have shown that sarcospan plays an important role in mediating protein interactions within this complex. Sarcospan affects communication between the dystrophin-glycoprotein complex and the extracellular matrix. Importantly, we demonstrate that mild sarcospan over-expression in mdx mice, which possess a mutation in the murine dystrophin gene, rescues muscular dystrophy by stabilizing expression of a complex of proteins that is functionally analogous to the dystrophin-glycoprotein complex. We propose to investigate the molecular mechanism(s) of SSPN-mediated amelioration of mdx phenotype and reveal the compensatory mechanisms that may mask a potentially interesting and enlightening phenotype in the SSPN-null mice. We will also complete our characterization of SSPN's `rescue effect' by examining muscle mechanics. Our hypothesis provides a mechanism for cross-talk between transmembrane/cytoskeletal complexes (i.e. integrins and DGC) that may illuminate how compensatory mechanisms are regulated. Results from each of the Aims will provide new information on the role of sarcospan as an important structural element within the dystrophin-glycoprotein complex and uncover new information on sarcospan's function in signaling and disease. PUBLIC HEALTH RELEVANCE Our proposal addresses questions related to how disruption of the dystrophin-glycoprotein complex causes Duchenne muscular dystrophy. During our previous funding period, we discovered that sarcospan, an integral component of the dystrophin-glycoprotein complex, is able to ameliorate dystrophin-deficient muscular dystrophy in mice. We plan to test the physiological properties of these mice and investigate the mechanisms of sarcospan amelioration.

描述（由申请人提供）：在骨骼肌中，肌营养不良蛋白-糖蛋白复合物位于肌膜处，由外周膜蛋白和内在膜蛋白组成。总体而言，该复合物将细胞外基质与细胞内肌动蛋白细胞骨架连接起来，并在肌肉收缩期间为肌膜提供结构稳定性。杜氏肌营养不良症是最常见的营养不良形式，是由肌营养不良蛋白基因突变引起的，导致肌营养不良蛋白和整个肌营养不良蛋白-糖蛋白复合物的丢失。我的研究小组开创了与肌跨功能相关的几项关键发现，肌跨是肌营养不良蛋白-糖蛋白复合物的一个组成部分。我们已经证明肌跨在介导该复合物内的蛋白质相互作用中发挥着重要作用。 Sarcospan 影响肌营养不良蛋白-糖蛋白复合物与细胞外基质之间的通讯。重要的是，我们证明，在具有鼠抗肌营养不良蛋白基因突变的 mdx 小鼠中，肌跨膜轻度过度表达，可以通过稳定功能类似于抗肌营养不良蛋白-糖蛋白复合物的蛋白质复合物的表达来挽救肌营养不良症。我们建议研究 SSPN 介导的 mdx 表型改善的分子机制，并揭示可能掩盖 SSPN 缺失小鼠中潜在有趣和启发性表型的补偿机制。我们还将通过检查肌肉力学来完成对 SSPN“救援效应”的表征。我们的假设提供了跨膜/细胞骨架复合物（即整联蛋白和 DGC）之间的串扰机制，这可能阐明补偿机制是如何调节的。每个目标的结果都将提供关于肌跨作为肌营养不良蛋白-糖蛋白复合物中重要结构元件的作用的新信息，并揭示关于肌跨在信号传导和疾病中的功能的新信息。公共卫生相关性我们的提案解决了与肌营养不良蛋白-糖蛋白复合物破坏如何导致杜氏肌营养不良相关的问题。在我们之前的资助期间，我们发现肌跨蛋白（肌营养不良蛋白-糖蛋白复合物的组成部分）能够改善小鼠肌营养不良蛋白缺陷型肌营养不良症。我们计划测试这些小鼠的生理特性并研究肌跨改善机制。