The Sarcoglycan Complex in Skeletal Muscle Mechanotransduction

骨骼肌机械转导中的肌聚糖复合物

基本信息

批准号：
9247122
负责人：
Elisabeth R Barton
金额：
$ 39.04万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247122
关键词：
Ablation Acute Affect Binding Biochemical Cancer Etiology Cell Nucleus Cells Cellular Mechanotransduction Clinical Trials Complex Defect Disease Dissection Down-Regulation Drug usage Duchenne muscular dystrophy Dystrophin Event Focal Adhesions Future GTP-Binding Protein alpha Subunits, Gs Genes Health Human Lead Limb-Girdle Muscular Dystrophies MAPK3 gene Mechanics Mediating Membrane Modeling Molecular Mus Muscle Muscle Contraction Muscle Fibers Muscle function Muscle strain Muscular Atrophy Muscular Dystrophies Myopathy Myosin Type II Nature Neuromuscular Diseases Nuclear Pathologic Pathology Pathway interactions Patients Phosphorylation Physical activity Positioning Attribute Predisposition Property Protein Isoforms Protein Splicing Proteins Research Rest Role Sarcoglycans Sarcolemma Signal Pathway Signal Transduction Skeletal Muscle Stimulus Stretching Therapeutic Work base filamin gamma Sarcoglycan improved knock-down mdx mouse mechanical load mechanotransduction muscle degeneration mutant non-muscle myosin normal aging novel novel strategies novel therapeutics protein expression public health relevance response sensor small hairpin RNA therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Physical activity imposes changes in load to skeletal muscle, which adapts through acute changes in biochemical signaling pathways and longer-term alterations in protein expression. One important mechanical sensor is the sarcoglycan (SG) complex, which is lost from the muscle membrane (sarcolemma) in both Duchenne and Limb Girdle muscular dystrophies (LGMD). Absence of γ-SG loss induces severe muscle degeneration and signaling defects in response to mechanical load without causing susceptibility to contractile damage, suggesting that LGMD pathology arises in part through disruption of normal mechanotransduction signaling through the SG complex. In a recent advance, the applicants have discovered that archvillin, a muscle-specific isoform of supervillin, is a γ-SG- and dystrophin-interacting protein and that archvillin association with phosphorylated ERK1/2 (P-ERK) increases dramatically, if and only if γ-SG is present, following eccentric contraction of muscle. Aim 1 is to determine the molecular bases for the associations of archvillin with γ-SG and P-ERK at rest and following stretch. Aim 2 is to determine the consequences of archvillin loss upon mechanical signal transduction in normal and dystrophic muscles. Aim 3 is to use drugs in clinical trials for other diseases to determine how up- or down-regulation of the molecular pathways identified in preliminary studies and in Aim 1 affects the progression of muscle pathology in gsg-/- mice, a model for human LGMD2C. Completion of these aims will elucidate the role of archvillin in mechanochemical signal transduction in muscle, identify new proteins in SG-mediated signaling, and determine whether modulation of the identified pathways has therapeutic potential.

描述（由申请人提供）：身体活动会给骨骼肌带来负荷变化，骨骼肌通过生化信号通路的急剧变化和蛋白质表达的长期改变来适应，一种重要的机械传感器是肌聚糖（SG）复合物，它会丢失。杜氏肌营养不良症和肢带型肌营养不良症 (LGMD) 中 γ-SG 缺失会导致严重的肌肉退化和信号传导缺陷。在最近的进展中，申请人发现了 archvillin（一种肌肉特异性的 supervillin 亚型），这表明 LGMD 病理部分是通过 SG 复合体正常机械转导信号的破坏而产生的。当且仅当 γ-SG 存在时，γ-SG 和抗肌营养不良蛋白相互作用蛋白以及与磷酸化 ERK1/2 (P-ERK) 相关的 archvillin 显着增加。目前，在肌肉偏心收缩后，目标 1 是确定在休息和拉伸后 archvillin 与 γ-SG 和 P-ERK 关联的分子基础。目标 3 是在其他疾病的临床试验中使用药物，以确定初步研究和目标 1 中确定的分子途径的上调或下调如何影响肌肉病理学的进展。 gsg-/- 小鼠，人类 LGMD2C 模型。完成这些目标将阐明 archvillin 在肌肉机械化学信号转导中的作用，识别 SG 介导的信号传导中的新蛋白质，并确定所识别途径的调节是否具有治疗潜力。