Areas of Interest
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.
- Ph.D. University of Michigan, 2000