Limb girdle muscular dystrophy type 2B (LGMD 2B) and Miyoshi myopathy (MM) are caused by defects in a gene that encodes a newly identified protein """"""""dysferlin"""""""". The long-term objectives of this proposal are to characterize the biological properties of dysferlin and its role in the pathogenesis of LGMD 2B and MM and to initiate studies of cell therapy in these diseases.
The specific aims are to: (1) Characterize dysferlin gene mutations and abnormalities of dysferlin protein expression in patients with MM and LGMD 2B and use this information to extend our studies of dysferlin as a novel muscle membrane protein. (2) Use conventional methods (immunoprecipitation, yeast two-hybrid analyses) to identify proteins that interact with normal and mutant dysferlin. (3) Use chip-based mRNA expression arrays to analyze dysferlin-deficient human muscle to identify changes of muscle gene expression that are either common to all dystrophies or specific to the dysferlinopathies. (4) Validate results of expression arrays and characterize genes that are unique to each of the dystrophies and begin to test new hypotheses about the molecular pathogenesis of muscle degeneration in the dysferlinopathies. (5) Analyze muscle stem cell (SP cell) populations in MM and LGMD-2B and the feasibility of SP therapy in a mouse model of dysferlin deficiency. These studies will be important because: (1) the dysferlinopathies constitute a significant proportion of all LGMD; (2) the studies in Aims 1-3 will illuminate aspects of the normal biological properties of this novel protein; (3) studies of pathological muscle in Aims 1-4 will contribute directly to understanding the pathogenesis of LGMD, MM and other muscular dystrophies (including facioscapulohumeral and myotonic dystrophy, included as comparative disease controls); and (4) the investigations in Aim 5 will contribute to the development of therapy for these types of muscular dystrophy.
Showing the most recent 10 out of 54 publications
