Zebrafish models of muscular dystrophies

Harvard Medical School, Boston MA

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Abstract

DESCRIPTION (provided by applicant): 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.