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

描述(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，几个实验室的研究表明，Miyoshi肌病(MM)和肢体带状肌营养不良症(LGMD)2B，由deferlin表达缺陷引起，与损伤的肌膜愈合不良有关。受伤肌肉的愈合不良被认为是由于钙离子引发的囊泡胞吐不良所致。我们最近发现，非受精性多发性骨髓瘤患者在愈合细胞伤口方面也很差。几个不同小泡的胞吐功能受缺乏异铁蛋白的影响，而在非异铁蛋白MM细胞中，这些小泡的胞吐功能似乎都不存在缺陷。因此，目前还不清楚这些小泡中的哪一个(如果有的话)是导致去铁蛋白缺陷细胞愈合不良的原因。这一建议利用蛋白质组和细胞生物学分析来确定-1)导致依赖于干扰素的和独立的MM细胞愈合不良的小泡，以及2)调节这些小泡的胞吐的分子。与公共卫生相关。这项拟议的工作旨在确定导致一种肌肉营养不良的细胞和分子缺陷，这种肌肉营养不良与受伤的肌肉细胞无法愈合有关。这项工作将有助于预测、诊断和治疗因损伤细胞愈合不良而导致的肌营养不良症。

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.