NIEMANN-PICK C1: A NEW COMPENSATORY GENE FOR MUSCULAR DYSTROPHIES

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PROJECT 4: NIEMANN-PICK C1: A NEW COMPENSATORY GENE FOR MUSCULAR DYSTROPHIES Muscular dystrophies are among the most prevalent and debilitating human genetic diseases. No cures or treatments are currently available. One promising approach is manipulation of compensatory or "booster" genes that slow the progression of muscle degeneration and improve both lifespan and quality of life. We have discovered a new compensatory gene that may underlie at least a part of the mechanism that causes muscle degeneration. Niemann-Pick C1 (NPC1) disease results, in part, from neuronal degeneration, primarily caused by a major defect in intracellular cholesterol trafficking. We have discovered that NPC1 gene and protein expression is reduced in a muscular dystrophy. Furthermore, muscle-specific transgenic expression of NPC1 significantly ameliorates the severity of the dystrophic phenotype in the mdx mouse. Here, we propose experiments to determine the mechanism that leads to reduction of NPC1 expression in dystrophic muscle and the molecular basis by which increased expression of NPC1 ameliorates the severity of muscular dystrophy in the mdx mouse. Preliminary results suggest that changes in caveolin-3 levels play an important role. Finally, we will test whether NPC1 expression slows the development of the dystrophic phenotype in three limb girdle muscular dystrophies (LGMD2B, 2C and 2F). Each of these LGMDs exhibit abnormal caveolin-3 mediated events and are therefore potential candidates for NPC1 treatment. These studies will improve our understanding of the mechanisms of muscle degeneration and may identify novel therapeutic targets for treatment of Duchenne and Limb Girdle Muscular Dystrophies. RELEVANCE (See instructions): These studies will provide new information about the role of cholesterol and caveolins in muscular dystrophy. By delivering NPC1 to dystrophic muscle, the progression of the disease may be slowed, thereby improving both the quality and length of life. The basic research described here is a necessary and important precursor to the use of this and other compensatory genes in human clinical trials.