Muscular dystrophies are a diverse group of primary inherited disorders characterized by progressive weakness and degeneration of skeletal muscle. The long-term goals of this project are to understand the molecular basis of muscular dystrophies using vertebrate models of two genetically distinct forms, and to develop therapies for patients with these debilitating conditions. Congenital rigid spine muscular dystrophy (RSMD1) manifests at birth or in early infancy and is caused by mutations in the SEPN1 gene, whereas myotonic muscular dystrophy (MMD) commonly presents in adulthood and has recently been associated with mis-splicing of the BIN1 gene. Interestingly, SEPN1 and BIN1 both encode proteins important for the biogenesis and function of T-tubules, the structures in skeletal muscles responsible for excitation-contraction coupling at the triads. To further elucidate the pathophysiology of these molecularly related conditions, and to screen small molecule therapeutics on a large scale, appropriate vertebrate models are required. Zebrafish, due to their small size, transparency, high proliferative capacity, and well-characterized genome, have recently emerged as a powerful genetic tool in developmental biology and are proposed here as reliable models for RSMD1 and MMD.
The specific aims of this project are 1) to create and characterize targeted knockouts of the bin1 and sepn1 genes in zebrafish, and 2) to develop these mutants for use in high throughput drug screens to identify lead compounds with therapeutic potential for RSMD1 and MMD. The successful conclusion of these studies will increase general understanding of the basic biology of these disorders, the affected systems, and the mechanisms that lead to skeletal muscle weakness. Furthermore, the identification of small molecules that slow or prevent derangements of skeletal muscle will set the stage for preclinical testing of new therapies that may be used to treat patients with muscular dystrophy and other related neuromuscular diseases.

Public Health Relevance

Neuromuscular diseases, such as the muscular dystrophies central to this proposal, often lead to severe skeletal muscle weakness, the inability to walk and conduct daily activities, respiratory difficulties, and premature death-often in infancy or early childhood. Zebrafish models of muscular dystrophies is deeply relevant to public health because it will model two major forms of human muscular dystrophy in a highly homologous system, forms for which no good vertebrate models are currently available and whose pathophysiological mechanisms have not yet been fully elucidated. Novel zebrafish models of congenital rigid spine muscular dystrophy (RSMD1) and myotonic muscular dystrophy (MMD) will be used to identify small molecules that may ameliorate the characteristic derangements of dystrophic skeletal muscle. The results of this project will be fundamental towards developing future treatments for children and adults born with these crippling neuromuscular disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F10B-S (20))
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Porter, John D
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Harvard University
Schools of Medicine
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Smith, Laura L; Gupta, Vandana A; Beggs, Alan H (2014) Bridging integrator 1 (Bin1) deficiency in zebrafish results in centronuclear myopathy. Hum Mol Genet 23:3566-78