Heart disease is a leading cause of death in patients with Duchenne muscular dystrophy (DMD). DMD is a uniformly fatal disease characterized by severe skeletal muscle injury and cardiomyopathy, resulting from mutations within the dystrophin gene. The clinical importance of the heart requires that dystrophin's function in the myocardium be a central focus in the development of effective therapies for DMD. Dystrophin connects the internal cytoskeleton to the membrane and functions as a mechanical buffer, protecting the membrane from the forces of contraction. The stability of dystrophin's interaction with the membrane is essential to this mechanical function. Importantly, recent studies have demonstrated that the dystrophin associated protein, dystrobrevin (DB) significantly strengthens the dystrophin-membrane interaction in both cardiac and skeletal muscle. This new finding has significant implications for the design of truncated dystrophin constructs intended for delivery by gene therapy vectors. DB binds to both dystrophin and the membrane bound sarcoglycan complex suggesting a potential mechanism for dystrobrevin's reinforcement of the dystrophin-membrane interaction. DB also plays an important role in maintaining the dystrophin signaling complex, primarily through interactions with the signaling adapter protein syntrophin. DB's important role in modulating the dual mechanical and signaling functions of dystrophin, make a full understanding of DB's interactions essential for the design of mu-dystrophin constructs suitable for genetic therapy. Little is known about the physiological mechanisms by which DB potentiates dystrophin's function in vivo. This limited understanding of factors regulating dystrophin's central functions represents an important gap in biomedical knowledge, inhibiting the ability to design fully functional mu- dystrophin constructs. The long-term goal is to develop a fully functional mu-dystrophin constructs that will form the basis of a viral mediated gene therapy for DMD. The overall objectives of this application are to 1) understand the role of DB in stabilizing the dystrophin signaling complex and reinforcing dystrophin's mechanical interaction with the membrane and 2) translate this knowledge into physiologically relevant improvements in the design of mu-dystrophin constructs. The central hypothesis is that DB is essential to forming the full dystrophin signaling complex and significantly strengthens the dystrophin-membrane interaction and that inclusion of a DB binding domain in mu-dystrophin constructs will result in significant improvements of mu-dystrophin functionality within the heart.
Duchenne muscular dystrophy is a uniformly fatal disease of cardiac and skeletal muscle afflicting thousands of young boys across the United States. At present, there is no cure for this devastating disease, but the work presented here will provide critical information towards the development of an effective therapy for Duchenne muscular dystrophy.
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