Many types of cells in metazoan species operate under conditions of mechanical stress, and are evolved to cope with plasma membrane damage. A failure in either the prevention or repair of plasma membrane damage can cause disease, or can influence disease progression, as observed in several muscular dystrophies. A more detailed mechanistic understanding of membrane repair is required to find therapeutic interventions for a variety of diseases where membrane damage underlies the pathophysiology. The first step towards the detailed understanding of the repair mechanism is a comprehensive identification of the component molecules. We developed a method that uses the microscopic nematode C. elegans for identifying molecular and cellular components that mediate the repair of damaged sarcolemma (muscle plasma membrane). By taking advantage of the transparency of the C. elegans body that allows detection of fluorescence proteins in vivo, we developed a novel, simple assay that can easily evaluate the degree of sarcolemmal damage. With this assay, we found that C. elegans dystrophin mutants (a model of Duchenne muscular dystrophy) exhibit sarcolemmal leakage and damage, albeit weak. Based on this finding, we performed a genetic screen to isolate mutants that have defects in sarcolemmal repair and, as a result, aggravate sarcolemmal damage of dystrophin mutants. In this exploratory proposal, we seek to establish the screen as a valuable tool for identifying genes responsible for sarcolemmal repair. With several prominent mutants in hands, we specifically propose to clone causal genes for defects in sarcolemmal repair by a combination of genetic mapping and whole genome sequencing. Once we identify the responsible genes, we will characterize the cloned genes using well-established C. elegans genetic techniques. In parallel, we will determine the relationship between these identified genes to understand how they function together to protect and repair the sarcolemma. The successful completion of this project will lead to a better understanding of the molecular mechanism of sarcolemmal repair and, more importantly, will reveal potential druggable targets for blocking the progression of muscular dystrophies that are influenced by membrane repair.
Many forms of muscular dystrophy, including Duchenne muscular dystrophy, cause a disruption of the integrity of the muscle membrane. Hence, understanding how muscle membrane integrity is maintained and repaired has a therapeutic implication. The proposed C. elegans genetic study will identify and characterize genes responsible for muscle membrane repair.
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