Grant: Operating Grant - PA: Musculoskeletal Health, Arthritis, Skin and Oral Health

A muscle cell is specialized for turning energy into contractile force. In order to do this efficiently, the contractile fibers of the cell (made of proteins called actin and myosin) must be properly assembled and aligned with one another, and muscle cells must be properly attached to each other and to the surrounding support tissues. Defects in either of these processes lead to muscle diseases (myopathies), and if heart muscle is also affected, lead to cardiomyopathies. There are a very large number of proteins involved at these specialized attachment points, and their assembly and interaction with one another is both critically important for normal muscle function, and poorly understood. The research described in this proposal will examine the 'Molecular Sudoku' involved in this assembly process. The Pilgrim lab originally identified a protein in a simple nematode worm that coordinates protein assembly in the muscles of that animal, and showed that a related protein carries out the same process in vertebrate muscle as well, but it is not yet clear exactly how the protein works. Since this protein has been proposed to be associated with human cardiomyopathies, it will be important to understand it's mode of action. The experiments proposed will examine the role of this protein in the earliest stages of muscle development, and will identify and characterize the proteins involved in other mutations known to be necessary for early muscle development. The experiments will benefit from the use of a simple model organism, the zebrafish commonly known from home aquaria, to study muscle development, because the proteins used in fish and human muscles are almost identical, zebrafish develop much faster than mammals and are much less expensive to study