Myotubularin and the Pathogenesis of Myotubular Myopathy

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DESCRIPTION (provided by applicant): Congenital myopathies are a heterogeneous group of muscle diseases that commonly present as weakness and hypotonia in infancy. Congenital myopathies are individually rare, but overall represent a significant cause of childhood morbidity and mortality. This application is centered on the development of an understanding of muscle formation, muscle maintenance and muscle disease as relates to congenital myopathies. The candidate's goal is to establish a research and clinical career in muscle biology and disease. His immediate goal is develop proficiency in the techniques utilized to study skeletal muscle in zebrafish, and to apply those techniques to the study of a question relevant to the pathogenesis of congenital myopathies. Specifically, he will master genetic and cell biologic manipulations in the developing zebrafish, with a focus on the examination of phosphoinositide signaling and membrane trafficking in skeletal muscle. He will apply these techniques to the study of myotubularin, a gene product hypothesized to be critical for endosomal dynamics and known to be the causative factor in the pathogenesis of myotubular myopathy. He will also study the relationship between myotubularin and the homologous gene MTMR14, which is mutated in another form of centronuclear myopathy. The goal of the research project is to establish the function of myotubularins in muscle development and homeostasis, and to determine the relationship between myotubularin dysfunction and muscle disease. In addition, the candidate will supplement the research project with a variety of non-laboratory experiences. These will include attendance at scientific courses in genetics and in pediatric muscle disease, participation in annual scientific meetings relevant to muscle biology, and advanced instruction in clinical neuromuscular disease. In all, this combination of laboratory and academic training in muscle biology will provide a strong foundation for the candidate's long term goal of establishing expertise in the field of pediatric muscle disease, and of utilizing his research to significantly advance understanding of the pathogenesis and treatment of congenital myopathies. RELEVANCE (See instructions): This application has high relevance to public health. In particular, the research is aimed at advancing the understanding of muscle disease in children. In addition, the training program is designed to provide the candidate with critical knowledge and expertise that will be applied to future studies aimed at understanding and treating childhood muscle disease.