The muscular dystrophies are characterized by progressive loss of strength over time. Stimulating muscle growth may delay the time before significant disability and death. The overall theme of this center is to study mechanisms to modulate muscle growth and breakdown for treatment of a variety of muscular dystrophies. IGF-1 is a potent stimulator and myostatin a specific inhibitor of muscle growth. Modulation of both pathways has been shown to ameliorate the mdx model of muscular dystrophy. Recently, protease inhibition with Bowman Birk Inhibitor Concentrate (BBIC) has been found to have similar effects. The center is composed of three sites, Johns Hopkins, University of Pennsylvania and intramural NINDS and includes investigators who are leaders in the field of myostatin and IGF-1 as well as clinical experts in muscular dystrophy. These investigators have a productive history together. In Project 1, Dr. Se-Jin Lee will elucidate the mechanisms by which myostatin activity is regulated with the goal of developing therapeutic agents targeting myostatin activity. In Project 2, Dr. Lee Sweeney will study the effects of inhibiting protein breakdown while stimulating muscle growth in mouse and canine models. In Project 3, Dr. Kathryn Wagner will explore the potential synergistic actions of modulating both IGF-1 and myostatin pathways. In Project 4, Dr. Kenneth Fischbeck will direct a clinical trial with the protease inhibitor, BBIC in Duchenne muscular dystrophy. There are two core facilities: Administrative Core A will provide administrative and scientific support for the entire center as well as facilitate training of new investigators in the area of muscular dystrophy. Physiological assesment Core B is a resource of genetically engineered mice. Modulating muscle growth is an immediately applicable approach to a variety of muscular dystrophies with IGF-1, a myostatin inhibitor, and protease inhibitors already in clinical trials. This MDCRC will provide needed basic, translational and clinical data on the safety and effectiveness of this approach.
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