For decades the clinical and research programs at the Children's Hospital Boston and Massachusetts General Hospital have been major centers for research into the causes and treatments of muscular dystrophies. The investigators of this Program Project have been instrumental in many of the pivotal accomplishments in muscular dystrophy research, starting with the landmark discovery of the gene altered in Duchenne muscular dystrophy, and followed by the identification of numerous genes involved in other dystrophies and congenital myopathies. As a result, the work performed by members of this program has had a direct impact on the care of patients with muscular dystrophy. The current proposal extends the collaborative interaction of the investigators of our previous program project to understand the pathogenesis and develop treatments for muscular dystrophy. Project 1 will use zebrafish to identify new genes and pathways involved in the disease process, and dystrophic zebrafish models to evaluate cell therapy for treating muscular dystrophy by identifying cells most capable of engrafting into damaged or diseased tissues. Project 2 will characterize the functional domains of dysferlin, and their role in membrane repair, using myotube cultures, transgenic mice and a zebrafish model. In addition, a truncated, functional dysferlin will be identified for viral-mediated systemic delivery of the dysferlin gene, and pilot studies of viral-mediated delivery of dysferlin constructs to mice will be conducted. The goal of Project 3 is to understand the molecular basis for myotubular myopathy, and to use this information to develop therapies for affected patients. A zebrafish model will be developed to determine the physiological functions of myotubularin and related family members, and a mouse Mtm1 gene knockout model of myotubular myopathy will be used to develop gene therapeutic methods to treat this disorder. Project 4 aims to study myogenic cell populations residing in human skeletal muscle and how they interact with one another, with the goal of identifying a highly proliferative, myogenic cell fraction that is amenable to therapeutic applications. Subsets of human muscle precursor cells will be identified and tested in both in vitro and in vivo models of skeletal muscle repair, including models of dystrophin, dysferlin and myotubularin deficiency. Core A will, provide the essential administrative support needed for the program to function as a unified whole. Core B will provide clinical data and tissue collection, entry of data into databases within the Harvard Neuromuscular Disease Project (HNDP) Portal, and will perform Affymetrix and/or Illumina expression arrays of all specimens for the projects. Core C will focus on large-scale transcriptome data acquisition, standardization, and analyses within and between each project, and will provide statistical analysis of the expression array data generated in Core B.
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