Integrin Alleviation of Muscular Dystrophy

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DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophy (DMD) is a devastating lethal muscle wasting disease that affects nearly 50,000 patients in the US alone and for which there is no effective treatment or cure. Both DMD patients and mdx mice (the mouse model for DMD), have dystrophin gene mutations and lack the dystrophin protein. Although damaged muscle is capable of repair, muscle regeneration in DMD patients is unable to keep pace with muscle damage. Satellite cells are a population of adult muscle stem cells that mediate muscle regeneration and therapeutic strategies have been aimed at increasing the capacity of these cells to repair damaged muscle. The 1721 integrin is a major laminin receptor expressed in satellite cells, myoblasts and vascular smooth muscle. Our laboratory has recently shown that loss of the 17 integrin in mdx mice leads to severe muscular dystrophy which is caused in part by a reduced capacity for muscle repair. These data suggest the 1721 integrin is a major genetic modifier in dystrophic muscle. In addition DMD patients and mdx mice exhibit reduced vascular function. Given the close association of muscle microvasculature and satellite cells, reduced vascular function may negatively impact satellite cell activation, survival and muscle regeneration. The 1721 integrin is highly expressed in vascular smooth muscle cells and myoblasts; however it is unknown if enhancing 17 integrin expression in these cells will further prevent muscle disease in mouse models for DMD. This proposal will test the hypothesis that targeting 17 integrin expression in myoblasts or vascular smooth muscle can serve as an effective integrin-based therapy for muscular dystrophy. We will test this hypothesis in three Specific Aims. First, using mice and isolated primary myoblasts that lack the 17 integrin we will determine the role of the 1721 integrin in muscle repair. Second, we will determine if enhancing the expression of 17 integrin in myoblasts can improve myoblast survival, engraftment and repair of damaged and dystrophic muscle. Finally we will determine if enhanced 17 integrin expression in vascular smooth muscle can improve vascular function and reduce muscle pathology in dystrophic mice. Determining if enhanced 17 integrin expression improves vascular function and muscle regeneration may provide new targeted integrin-based approaches in the treatment of Duchenne and other muscular dystrophies. PUBLIC HEALTH RELEVANCE. Duchenne Muscular Dystrophy is a devastating muscle disease that affects nearly 50,000 children in the United States. Increased skeletal muscle expression of 17 integrin has been shown to be enormously beneficial to mouse models for this disease. This study will use transgenic mice to investigate the role of the 1721 integrin in muscle repair and determine if increasing integrin expression in muscle repair cells or vascular smooth muscle may further improve integrin-based therapies for muscular dystrophy.