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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055686-05
Application #
8089483
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
2008-07-02
Project End
2013-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
5
Fiscal Year
2011
Total Cost
$323,668
Indirect Cost
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
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Vila, Maria C; Rayavarapu, Sree; Hogarth, Marshall W et al. (2017) Mitochondria mediate cell membrane repair and contribute to Duchenne muscular dystrophy. Cell Death Differ 24:330-342
Sreetama, S C; Takano, T; Nedergaard, M et al. (2016) Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis. Cell Death Differ 23:596-607
Leikina, Evgenia; Defour, Aurelia; Melikov, Kamran et al. (2015) Annexin A1 Deficiency does not Affect Myofiber Repair but Delays Regeneration of Injured Muscles. Sci Rep 5:18246
Jaiswal, Jyoti K; Lauritzen, Stine P; Scheffer, Luana et al. (2014) S100A11 is required for efficient plasma membrane repair and survival of invasive cancer cells. Nat Commun 5:3795
Scheffer, Luana L; Sreetama, Sen Chandra; Sharma, Nimisha et al. (2014) Mechanism of Ca²?-triggered ESCRT assembly and regulation of cell membrane repair. Nat Commun 5:5646
Defour, Aurelia; Sreetama, S C; Jaiswal, Jyoti K (2014) Imaging cell membrane injury and subcellular processes involved in repair. J Vis Exp :
Defour, A; Van der Meulen, J H; Bhat, R et al. (2014) Dysferlin regulates cell membrane repair by facilitating injury-triggered acid sphingomyelinase secretion. Cell Death Dis 5:e1306
Heier, Christopher R; Damsker, Jesse M; Yu, Qing et al. (2013) VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects. EMBO Mol Med 5:1569-85
Jaiswal, Jyoti K; Simon, Sanford M (2013) Belling the cat--tagging live cells with quantum dots. Clin Chem 59:995-6

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