Job Description

Our objective is to fully define the function of dystrophin in striated muscle to understand how its absence or abnormality leads to the pathologies observed in Duchenne and Becker muscular dystrophies.  Our unique approach integrates biochemical and biophysical analyses of the very large dystrophin protein with in vivo assessments of its function in transgenic mouse models of muscular dystrophy.  We have shown that dystrophin is a monomer that binds laterally along an actin filament through the concerted actions of two distinct and spatially separated actin binding sites and is necessary for strong mechanical coupling between the sarcolemma and costameric actin filaments.  We have also demonstrated that the dystrophin homologue utrophin can substitute for dystrophin in coupling costameric actin filaments to the sarcolemma when transgenically overexpressed in dystrophin-deficient skeletal muscle and binds actin filaments with similar affinity as dystrophin, but through distinct modes of contact.  Finally, we showed that dystrophin directly binds to microtubules and is required to organize the subsarcolemmal microtubule lattice of skeletal muscle.  Several of these advances were made possible by methods that we pioneered to express and purify biochemical amounts of full-length recombinant dystrophin and utrophin. Continuing to build on the project’s history of innovation, we have developed new cell and animal models that enable us to investigate the critical roles of roles of cytoplasmic non-muscle actin isoforms in skeletal muscle.  We are also investigating small molecule approaches to stabilize aberrant dystrophins expressed in some muscular dystrophy patients. Finally, we are also pursuing state-of-the-art in vivo rescue experiments and proteomic screens to further define the physiological role of microtubule lattice organization by dystrophin.

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