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

描述（由申请人提供）：肌肉萎缩症通常是由蛋白质突变引起的，导致肌层不稳定。然而，几个实验室的研究表明，由异常蛋白表达缺陷引起的三好肌病（MM）和肢带肌营养不良（LGMD） 2B与受伤的肌膜愈合不良有关。受伤肌肉愈合不良被认为是由于钙触发的囊泡胞吐不良。我们最近发现，非异色素MM患者在愈合细胞伤口方面也很差。几种不同囊泡的胞吐受到缺乏异铁素的影响，而在非异铁素MM细胞中，这些囊泡的胞吐似乎都不缺乏。因此，目前尚不清楚这些囊泡中的哪一个（如果有的话）是导致dysferlin缺陷细胞愈合不良的原因。该方案利用蛋白质组学和细胞生物学分析来鉴定- 1)导致异铁素依赖性和独立型MM细胞愈合不良的囊泡，以及2)调节这些囊泡胞外分泌的分子。公共卫生相关性。提出的工作旨在确定细胞和分子缺陷负责一种肌肉萎缩症与受伤的肌肉细胞无法愈合。这项工作将有助于损伤细胞愈合不良引起的肌营养不良的预测、诊断和治疗。

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.