Current Research: My laboratory is interested in the molecular mechanisms of human diseases of skeletal and cardiac muscle. By understanding molecular mechanisms of relatively rare genetic disorders, we hope to shed light on common mechanisms that cause more common idiopathic or acquired forms of skeletal muscle and cardiac disease. Currently, we are focused on the mechanisms of muscular dystrophy associated with mutations in the transmembrane dystrophin-glycoprotein complex. There has been an explosion of genetic evidence indicating that the central protein in this complex, dystroglycan, is the key player in a number of muscular dystrophies. However, this is not due to primary mutations in dystroglycan itself, but mutations in enzymes that modify the function of dystroglycan as an extracellular matrix receptor. Patients with muscular dystrophy often develop and succumb to cardiomyopathy. The cellular mechanisms of dystroglycan modification and the resulting pathways leading to muscular dystrophy and cardiomyopathy are currently unclear. We are exploring these pathways using spontaneous mutant, traditional and conditional targeted mouse models as well as human patient samples. In addition, protein complexes containing some of the components
of the dystrophin-glycoprotein complex in muscle are expressed throughout
the body. Human patients and mouse models with defects in dystroglycan
function have altered neuronal migration, synaptic function, peripheral
nerve structure and function, eye development and function, and
neuromuscular junction formation. We are trying to identify some
of the functional ligands of dystroglycan, compensating receptors,
and molecules associated with the dystroglycan complex in non-muscle
tissues that are necessary for these various non-muscle phenotypes
seen in human patients, and whether or not these same molecules
have any functional role in skeletal and cardiac muscle disease. Michele DE, Gomez
CA., Hong KE, Westfall MV, Metzger JM. Cardiac dysfunction in hypertrophic
cardiomyopathy mutant tropomyosin mice is transgene-dependent, hypertrophy-independent,
and improved by beta-blockade. Circ. Res. 91: 255-262, 2002.
Moore SA, Saito F, Chen J, Michele DE, Henry MD, Messing A, Cohn
RD, Ross-Barta SE, Westra S, Williamson RA, Hoshi T, Campbell KP.
Deletion of brain dystroglycan recapitulates aspects of congenital
muscular dystrophy. Nature. 418: 422-425, 2002. Michele DE, Barresi R, Kanagawa M, Saito F, Cohn RD, Satz JS, Dollar
J, Nishino I, Kelley RI, Somer H, Straub V, Mathews KD, Moore SA,
and Campbell KP. Post-translational disruption of dystroglycan-ligand
interactions in congenital muscular dystrophies. Nature. 418: 417-422,
2002. Cohn RD, Henry MD, Michele DE, Barresi R, Saito F, Moore SA, Flanagan
J, Skwarchuk MW, Robbins ME, Williamson R, Campbell KP. Disruption
of DAG1 in differentiated skeletal muscle reveals a role for dystroglycan
in muscle regeneration. Cell. 110: 639-648, 2002. Michele DE and Campbell KP. Dystrophin-glycoprotein complex: Post-translational
processing and dystroglycan function. J. Biol. Chem. 278: 15457-15460
, 2003. Durbeej M, Sawatzki SM, Barresi R, Schmainda KM, Allamand V, Michele
DE, and Campbell KP. Gene transfer establishes primacy of striated
versus smooth muscle sarcoglycan complex in limb girdle muscular
dystrophy. Proc. Natl. Acad. Sci. USA. 100(15):8910-8915, 2003. |
