Understanding the mechanism and role of cell membrane repair in Miyoshi Myopathy

了解细胞膜修复在三好肌病中的机制和作用

• 批准号: 7533906
• 负责人: JYOTI K JAISWAL
• 金额: $ 31.47万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-02 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7533906
• 关键词: ANXA2 gene; Affect; Annexin A1; Attention; Binding; Biochemical; Biological; Calcium; Candidate Disease Gene; Cell membrane; Cell surface; Cells; Cleaved cell; Clinical; DYSF gene; Defect; Diagnosis; Disease; Endocytosis; Endosomes; Exocytosis; Family; Fibroblasts; Figs - dietary; Golgi Apparatus; Healed; Knowledge; Label; Laboratories; Lead; Life; Limb structure; Limb-Girdle Muscular Dystrophies; Localized; Lysosomes; Mediating; Membrane; Molecular; Mus; Muscle; Muscle Cells; Muscular Dystrophies; Mutation; Myoblasts; Myopathy; Patients; Pharmaceutical Preparations; Play; Proteins; Proteome; Proteomics; Public Health; Rest; Role; Sarcolemma; Site; Small Interfering RNA; Symptoms; Testing; Thinking; Time; Toxin; Vesicle; Work; Wound Healing; base; cellular imaging; comparative; healing; improved; prevent; repaired; response; trafficking

DESCRIPTION (provided by applicant): Muscular dystrophy is commonly caused by mutation in proteins that lead to sarcolemmal instability. However, work from several laboratories indicates that Miyoshi myopathy (MM) and limb girdle muscular dystrophy (LGMD) 2B, caused by defects in dysferlin expression is associated with poor healing of wounded sarcolemma. Poor healing of wounded muscles is believed to be due to poor calcium-triggered vesicle exocytosis. We have recently identified that non-dysferlin MM patient's are also poor at healing cellular wounds. Exocytosis of several different vesicles is affected by lack of dysferlin, while exocytosis of none of these vesicles appears to be deficient in non-dysferlin MM cells. Thus, it is not clear which of these (if any) vesicles are responsible for the poor healing of dysferlin deficient cells. This proposal utilizes proteomic and cell biological analysis to identify - 1) the vesicles responsible for poor healing of dysferlin-dependent and independent MM cells and 2) the molecules that regulate exocytosis of these vesicles. PUBLIC HEALTH RELEVANCE. The proposed work aims to identify cellular and molecular defect responsible for a type of muscular dystrophy associated with the inability of wounded muscle cells to heal. This work would aid in prediction, diagnosis and therapy of muscular dystrophies caused by poor healing of wounded cells.

描述（由申请人提供）：肌营养不良症通常是由导致肌膜不稳定的蛋白质突变引起的。然而，多个实验室的工作表明，由 Dysferlin 表达缺陷引起的三好肌病 (MM) 和肢带型肌营养不良症 (LGMD) 2B 与受伤肌膜愈合不良有关。受伤肌肉愈合不良被认为是由于钙触发的囊泡胞吐作用不良所致。我们最近发现，非 Dysferlin MM 患者的细胞伤口愈合能力也很差。几种不同囊泡的胞吐作用受到 Dysferlin 缺乏的影响，而在非 Dysferlin MM 细胞中，这些囊泡的胞吐作用似乎都不存在缺陷。因此，尚不清楚这些囊泡中的哪一个（如果有的话）导致 Dysferlin 缺陷细胞的愈合不良。该提案利用蛋白质组学和细胞生物学分析来识别 - 1）导致 Dysferlin 依赖性和独立 MM 细胞愈合不良的囊泡，以及 2）调节这些囊泡胞吐作用的分子。公共卫生相关性。这项工作旨在确定导致一种肌肉营养不良症的细胞和分子缺陷，这种肌肉营养不良症与受伤的肌肉细胞无法愈合有关。这项工作将有助于预测、诊断和治疗因受伤细胞愈合不良引起的肌营养不良症。