Inflammatory response is associated with various muscular dystrophies and exacerbates the disease progression. In particular, dysferlin-deficient muscular dystrophy has been found to exhibit extensive muscle inflammation. Previous studies established a role of dysferlin in plasma membrane repair. We and other groups recently demonstrated that the innate immune system including the complement pathway and the NLRP3 (Nod-like receptor family, pyrin domain containing 3) inflammasome are activated in dysferlin-deficient muscle. However, the molecular mechanisms that initiate and perpetuate the immune activation are not well understood. The long-term goal of this research proposal is to understand the molecular mechanisms of muscle inflammation in dysferlin-deficient muscular dystrophy and explore the therapeutic potential of targeting the inflammatory signaling pathways in the treatment of this disease. Our pilot studies found that vesicles (in particular, the vesicle composed of charged lipids) strongly induce IL-1? secretion from macrophages through activation of the NLRP3 inflammasome. This observation led us to hypothesize that intracellular vesicles leaked out from dysferlin-deficient muscle activates the NLRP3 inflammasome, causing muscle inflammation. Our planned experiments will significantly advance understanding of the interplay between skeletal muscle with membrane repair defect and the immune system by measuring responses of macrophages to skeletal muscle-derived vesicles, manipulating expression of the NLRP3 inflammasome components and ex vivo and in vivo animal model studies. These data will begin to define potential therapeutic targets for regulation of inflammatory responses, thereby treating the diseases associated with defective membrane repair.

Public Health Relevance

Muscle inflammation is associated with a number of diseases including dysferlin-deficient muscular dystrophy. Our project is designed to understand the molecular mechanisms of muscle inflammation and explore the therapeutic potential of targeting the inflammatory responses in the treatment of this disease. These studies will aid in defining therapeutic targets for the treatment of muscular dystrophies associated with compromised plasma membrane integrity through interfering the NLRP3 inflammasome. PUBLIC HEALTH RELEVANCE: Our recent study demonstrated that genetic ablation of the complement system (part of the innate immune system) partially ameliorates the disease progression in dysferlin-deficient mice, suggesting manipulating the inflammatory responses represents an attractive means of therapy for this untreatable disease. We are further exploring the molecular mechanisms of muscle inflammation associated with dysferlinopathy. These studies will aid in designing therapeutic strategies for targeting the inflammatory responses, thereby treating the diseases associated with plasma membrane defects.

National Institute of Health (NIH)
Research Project (R01)
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Skeletal Muscle Biology and Exercise Physiology Study Section (SMEP)
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Boyce, Amanda T
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Loyola University Chicago
Schools of Medicine
United States
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