Structure-Function Analysis of Sarcospan

Sarcospan 的结构功能分析

基本信息

批准号：
9102741
负责人：
Rachelle Hope Crosbie
金额：
$ 36.99万
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 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9102741
关键词：
Actins Address Adhesions Affect Animal Model Binding Cell surface Cells Client Communication Complex Cytoskeleton DNA Sequence Alteration Development Direct Lytic Factors Disease Duchenne muscular dystrophy Dystrophin ECM receptor Event Extracellular Matrix Funding Future Gene Expression Genes Glycoproteins Golgi Apparatus Growth Health Human Injury Integral Membrane Protein Integrins Investigation Link Mediating Membrane Molecular Molecular Chaperones Mus Muscle Muscle Cells Muscle Contraction Muscular Atrophy Muscular Dystrophies Mutation Natural regeneration Neuromuscular Junction Outcome Pathogenesis Pathology Pathway interactions Patients Peripheral Phenotype Play Proteins Reporting Research Role SSPN gene Sarcolemma Signal Transduction Skeletal Muscle Structure Testing Therapeutic Transportation Utrophin Work alpha Dystroglycan base efficacy testing genetic manipulation glycosylation glycosyltransferase improved innovation insight mdx mouse muscular dystrophy mouse model new therapeutic target overexpression protein complex reduced muscle strength repaired

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. My research group has developed the use of secondary genes, such as SSPN and Akt, as a strategy to ameliorate dystrophic muscle. Such approaches are advantages in that they have the potential to target all DMD cases, regardless of the specific dystrophin mutation. The current 3R01 proposal builds on discoveries made during the first and second funding period by interrogating specific mechanisms by which SSPN ameliorates disease in dystrophin-deficient mdx mice. We will test the efficacy of SSPN in human-derived DMD muscle cells and determine the minimal domains of SSPN that are therapeutic. Our studies will reveal a chaperone function for SSPN in determining the cell surface expression of adhesion complexes (DGC, UGC, and α7ß1 integrin) that are known to ameliorate mdx disease. We hypothesize that SSPN may function as a 'single-client' chaperone to regulate cell surface localization of adhesion complexes in muscle. The outcomes of the proposal will change our understanding of DMD pathogenesis and provide necessary insight for development of SSPN- based therapy. We will generate animal models that will be valuable for many future projects in the field. Furthermore, we expect that our results will illuminate molecular pathways that could counter a broad range of muscle wasting disorders due to loss of extracellular matrix contact.

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，作为一个整体，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导致肌营养不良蛋白缺失引起的。我的研究小组开创了与肌跨蛋白功能相关的多项关键发现，肌跨蛋白是肌营养不良蛋白-糖蛋白复合物的组成部分，我们已经证明肌跨蛋白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 mdx 小鼠中存在轻度的 sarcospan 过度表达，该小鼠在小鼠中具有突变。肌营养不良蛋白基因，通过稳定功能类似于肌营养不良蛋白-糖蛋白复合物的蛋白质复合物的表达来拯救肌营养不良症。这些方法的优势在于它们有可能针对所有 DMD 病例，无论特定的肌营养不良蛋白突变如何。当前的 3R01 提案建立在第一和第二资助期的发现基础上。探究 SSPN 改善肌营养不良蛋白缺陷 mdx 小鼠疾病的具体机制我们将测试 SSPN 在人源性 DMD 肌肉细胞中的功效，并确定 SSPN 具有治疗作用的最小结构域。确定已知可改善 mdx 疾病的粘附复合物（DGC、UGC 和 α7ß1 整合素）的细胞表面表达，我们发现 SSPN 可能发挥作用。调节肌肉中粘附复合物的细胞表面定位的“单一客户端”伴侣，该提案的结果将改变我们对 DMD 发病机制的理解，并为基于 SSPN 的治疗的开发提供必要的见解。此外，我们预计我们的结果将阐明可以对抗由于细胞外基质接触丧失而导致的广泛肌肉萎缩疾病的分子途径。