Structure-Function Analysis of Sarcospan

Sarcospan 的结构功能分析

基本信息

批准号：
9980290
负责人：
Rachelle Hope Crosbie
金额：
$ 34.32万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980290
关键词：
Actins Address Adhesives Affect Atomic Force Microscopy Basement membrane Biological Biological Models Cell Adhesion Cell Communication Cell Differentiation process Cell physiology Cell surface Cell-Matrix Junction Cells Chronic Communication Complex Coupled Cytoskeleton Data Deposition Disease Duchenne muscular dystrophy Dystrophin Dystrophin-Associated Proteins Exercise Exhibits Expression Profiling Extracellular Matrix Fibrosis Funding Gene Expression Genes Glycoproteins Growth Human Inflammation Injury Integral Membrane Protein Integrins Investigation Ligands Link Mediating Membrane Methods Molecular Mus Muscle Muscle Cells Muscle Contraction Muscle Fibers Muscle Weakness Muscle function Muscular Atrophy Muscular Dystrophies Mutation Myocardium Natural regeneration Pathologic Pathology Pathway interactions Peripheral Physiological Play Property Proteins Protocols documentation Research Role SSPN gene Sarcolemma Signal Transduction Skeletal Muscle Specific qualifier value Structure Testing Tissues Wasting Syndrome atomic data cell behavior crosslink improved in vitro Assay in vitro Model induced pluripotent stem cell innovation interstitial mdx mouse mechanical properties mechanotransduction mouse model overexpression preservation prevent progenitor protein expression protein protein interaction receptor repaired scaffold stem cells

项目摘要

PROJECT ABSTRACT Loss of muscle cell adhesion is emerging as a common theme in muscular dystrophies. 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 compensatory proteins that is functionally analogous to the dystrophin-glycoprotein complex, including a7b1 integrin. The current 4R01 proposal builds on discoveries made during the prior funding periods by interrogating specific mechanisms by which sarcospan ameliorates disease in dystrophin- deficient mdx mice. We will test the hypothesis that sarcospan enhances a7b1 integrin outside-in and inside- out signaling. We will investigate the extracellular matrix of mdx muscle that is overexpressing sarcospan to determine how sarcospan affects the composition, organization, and mechanical properties of the extracellular matrix. Lastly, we will use our decellularization protocol to isolate the extracellular matrix and test its interaction with human iPSC-derived skeletal muscle progenitors to test principles of bidirectional communication in a newly developed in vitro model system. We expect that our results will illuminate molecular pathways that counter a broad range of muscle wasting disorders due to loss of extracellular matrix contact.

项目摘要肌细胞粘附力丧失正在成为肌营养不良症的一个常见主题。在骨骼肌中，肌营养不良蛋白-糖蛋白复合物位于肌膜，由外周和整体组成膜蛋白。作为一个整体，该复合物将细胞外基质与细胞内肌动蛋白连接起来细胞骨架并在肌肉收缩期间为肌膜提供结构稳定性。杜兴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-糖蛋白复合物的损失。我的研究小组有开创了与 sarcospan 功能相关的多项关键发现，sarcospan 是身体的一个组成部分肌营养不良蛋白-糖蛋白复合物。我们已经证明肌跨在介导蛋白质中起着重要作用这个复合体中的相互作用。 Sarcospan 影响肌营养不良蛋白-糖蛋白之间的通讯复合体和细胞外基质。重要的是，我们证明 mdx 中轻度肌跨过度表达具有鼠肌营养不良蛋白基因突变的小鼠通过稳定肌营养不良症来挽救肌营养不良症表达补偿蛋白复合物，其功能类似于肌营养不良蛋白-糖蛋白复合物，包括 a7b1 整合素。当前的 4R01 提案建立在之前的发现的基础上通过询问 sarcospan 改善肌营养不良蛋白疾病的具体机制来资助周期 mdx 缺陷小鼠。我们将检验 sarcospan 从外到内增强 a7b1 整合素的假设 - 发出信号。我们将研究过度表达肌跨的 mdx 肌肉的细胞外基质确定肌跨如何影响细胞外的组成、组织和机械特性矩阵。最后，我们将使用我们的脱细胞方案来分离细胞外基质并测试其与人类 iPSC 衍生的骨骼肌祖细胞相互作用以测试双向原理新开发的体外模型系统中的通信。我们期望我们的结果能够阐明对抗由于细胞外基质损失引起的广泛肌肉消耗性疾病的分子途径接触。