The last decade has witnessed remarkable progress in defining primary defects that cause inherited muscle disorders. The genetic heterogeneity of these diseases is enormous; mutations in more than 40 different genes are implicated. Many critical questions remain concerning the pathogenesis of muscle cell degeneration in these diseases and strategies for their treatment. This Program Project will use classical methods of gene and protein analysis and state-of-the-art gene expression array technology to study these questions. The investigators in this program have contributed importantly to the muscular dystrophy field. The proposed 4 projects have unique features but overlapping concepts and methodologies. Project 1 will study the dystrophin-associated complex of proteins, emphasizing the sarcoglycans and the newly described filamin-C. Project 2 will investigate the biology of dysferlin, its potential protein partners, and how these are altered by dysferlin gene mutations. Project 3 will examine the function of myotubularin in normal muscle development and the mechanisms by which its mutations cause developmental myopathies. Project 4 will study the biological and therapeutic properties of muscle stem cells. Three Cores will provide administrative oversight and services essential to the smooth progression of this program. Core B will coordinate sample acquisition and muscle RNA preparation for each project. Core C will perform the microarray analysis of gene expression and provide expertise in bioinformatics and data interpretation.
The aim i s to identify patterns of gene expression that are global in all dystrophies or distinct to specific sets of dystrophies and myopathies; this will provide insight into the molecular basis of normal muscle development and its dysfunction in these disease states. The long-term goal is to use this information in conjunction with the insights from studies of stem cell biology to devise new approaches to the treatment of the muscular dystrophies and related myopathies.
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