Graduate Training in Neuroscience
University of Washington
James M. Olson
MD/PhD, Sarah Hughes Chair for Pediatric Oncology; Full Member, Fred Hutchinson Cancer Research Center; Professor, Pediatrics; Adjunct, Department of Pathology and Pharmacology
Pediatric Brain Tumors:We are generating new mouse models of medulloblastoma (pediatric brain tumor) and testing candidate drugs that interfere with the aberrant signaling pathways. We demonstrated efficacy of two drug classes, retinoids and cyclopamine derivatives. Both induce apoptosis in medulloblastoma cells. We elucidated the mechanism by which retinoids induce apoptosis, providing a basis for understanding why some cells are sensitive to this agent and others are resistant. We are developing a national Phase III clinical trial to assess the efficacy of retinoids in children with medulloblastoma.
Brain Development:The neuroD family of transcription factors regulates expression of genes that are necessary for nerve cell development. We demonstrated that neuroD proteins were sufficient to convert rapidly dividing embryonal carcinoma cells into nonreplicating, mature neurons. We then assessed the role of neuroD2 by generating neuroD2-null mice. These mice experienced premature death preceded by ataxia, seizures, motor deficits, and weight loss. Cells that normally express neuroD2 underwent excessive apoptosis in the absence of neuroD2, establishing that this transcription factor is important for neuronal survival in addition to its established role in neuronal differentiation. Ongoing studies will determine how neuroD2 is regulated in developing brain and identify transcriptional targets of neuroD2.
Huntington's Disease: Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin protein. The mutant protein forms intracellular aggregates that incorporate many other proteins, including transcription factors. We hypothesize that the mutant huntingtin protein causes neuronal dysfunction, in part, by altering transcription of genes that are necessary for neurotransmission. We organized a consortium of 60 investigators that conducted microarray studies in neurodegenerative disease models. The results were reported in a special series in Human Molecular Genetics (issue 11(17). Based on this work, we have identified two classes of drugs that show promise in pre-clinical trials.