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

描述（由申请人提供）：肌营养不良通常由导致肌膜不稳定的蛋白质突变引起。然而，来自几个实验室的工作表明，由dysferlin表达缺陷引起的Miyoshi肌病（MM）和肢带型肌营养不良症（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囊泡胞吐不良。我们最近发现，非dysferlin MM患者的细胞伤口愈合也很差。几种不同囊泡的胞吐作用受到dysferlin缺乏的影响，而这些囊泡的胞吐作用在非dysferlin MM细胞中似乎都没有缺陷。因此，尚不清楚这些囊泡中的哪一个（如果有的话）负责dysferlin缺陷细胞的不良愈合。该提议利用蛋白质组学和细胞生物学分析来鉴定1）负责dysferlin依赖性和非依赖性MM细胞的不良愈合的囊泡和2）调节这些囊泡的胞吐作用的分子。公共卫生相关性。拟议的工作旨在确定细胞和分子缺陷负责一种类型的肌营养不良症与受伤的肌肉细胞无法愈合。这项工作将有助于预测，诊断和治疗由受伤细胞愈合不良引起的肌营养不良症。

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.