Dr. James Ervasti is a third year tenure-track faculty member who is engaged in developing a strong independent research program in a stimulating, supportive environment at the University of Wisconsin Medical school. Funds and space have been provided by the Graduate and Medical Schools for a fully equipped laboratory supporting Dr. Ervasti's research regarding the structure and function of proteins in the dystrophin-glycoprotein complex. An RCDA would contribute to Dr. Ervasti's development as an independent researcher by relieving him of administrative and teaching responsibilities for the next five years and making at least 80% of his time available for the discovery of novel molecular partners of the dystrophin-glycoprotein complex. It will also provide time for recruitment and training of PhD and postdoctoral students and for developing interdisciplinary collaborations. Dr. Ervasti is expected to be a long-term member of the Department of Physiology, the Cellular and Molecular Biology Training program, the Molecular Pharmacology Graduate Program and the Cardiovascular Research Center. The long term objective of this research is to characterize the functional protein interactions of the dystrophin-glycoprotein complex in skeletal muscle in order to understand how its absence or abnormality leads to the pathologies observed in several muscular dystrophies and possibly some cardiomyopathies. This proposal specifically seeks to: (1) dissociate the dystrophin-glycoprotein complex to determine whether nondystrophin components of the complex modulate high affinity binding between dystrophin and F-actin; (2) examine the ability of various agents that regulate cytoskeletal protein interactions to modulate high affinity binding between dystrophin and F-actin or induce F-actin crosslinking by dystrophin-glycoprotein complex; (3) identify the high affinity F-actin binding site(s) of native dystrophin; and (4) identify novel proteins that interact with the dystrophin-glycoprotein complex to further elucidate the function of the dystrophin-glycoprotein complex and its contribution to the molecular architecture of the muscle plasma membrane. The research will yield important new information about the molecular mechanisms of muscular dystrophy, and perhaps some cardiomyopathies, by defining the function of dystrophin through its interactions with other proteins in normal muscle. In addition, the research will aid in the rational design of fully functional dystrophin mini-genes for use in dystrophin replacement therapies.
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