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（由适用提供）：体育活动不可能通过生化信号通路的急性变化和蛋白质表达的长期改变来适应骨骼肌的负载变化。一个重要的机械传感器是肌酸酯（SG）复合物，该复合物在Duchenne和Limb Girdle肌肉肌营养不良（LGMD）中从肌肉膜（Sarcolemma）丢失。缺乏γ-SG损失会导致严重的肌肉变性和信号传导缺陷，以响应机械负荷而不会引起收缩损伤的易感性，这表明LGMD病理部分是由于通过SG复合物造成正常机械传导信号传导而导致的。在最近的一项进步中，申请人发现Supervillin的肌肉特异性同工型Archvillin是一种γ-SG-SG和营养不良蛋白相互作用的蛋白，并且Archvillin与磷酸化的关联。 ERK1/2（p-erk）在肌肉偏心收缩后，仅当存在γ-SG时，才会急剧增加。 AIM 1是确定Archvillin与γ-SG和p-ERK的静止和延伸后的分子碱基。目的2是确定基准素损失对正常和营养不良肌肉中机械信号转导的后果。 AIM 3是在临床试验中使用药物进行其他疾病，以确定初步研究和AIM 1中鉴定的分子途径的上调或下调如何影响GSG - / - 小鼠中肌肉病理学的进展，这是人类LGMD2C的模型。这些目的的完成将阐明构核素在肌肉中的机械化学信号转导中的作用，鉴定SG介导的信号传导中的新蛋白质，并确定对识别途径的调节是否具有治疗潜力。