Olson Lab Research Interests
 Olson Lab |
Neural differentiation, brain tumor genesis and neurodegenerative diseases
Our laboratory studies pediatric brain tumors, brain development and Huntington's disease. Translation of laboratory findings to clinical therapeutics is accelerated through an extensive network of academic and industry collaborations.
Pediatric Brain Tumors
Medulloblastoma is the most common malignant brain tumor of childhood. Our laboratory studies signal transduction pathways that are necessary for medulloblastoma survival. In collaboration with the Pomeroy, Golub and Beachy laboratories, we showed that the sonic hedgehog (shh) pathway is active in most medulloblastomas and that pharmacologic inhibition of this pathway leads to rapid cell death (Nature 415:436, 2002; Science 297:1559, 2002). We generated a genetically precise transgenic mouse model of medulloblastoma that has a 50% tumor incidence at 6 months compared to the previous gold standard that had a 15% incidence at 1 year. Genomic analysis of tumors in this mouse model revealed increased notch pathway activity, which was confirmed in human medulloblastoma samples. Pharmacologic or genetic inhibition of notch signaling caused apoptosis in medulloblastoma cells (Cancer Research 64:7794, 2004). Further translational studies in patient-derived primary cells and mouse models demonstrated that retinoids induce medulloblastoma apoptosis through activation of the p38 MAP kinase pathway and that histone deacetylase inhibitors induce extensive apoptosis at concentrations that are well tolerated in patients (Nature Medicine 9:1033, 2003; submitted manuscript). The latter two studies led to development of national phase III and phase I clinical trials.
Brain Development
The neuroD family of transcription factors regulates expression of genes that are necessary for nerve cell development. In collaboration with David Turner, we demonstrated that neuroD proteins were sufficient to convert rapidly dividing embryonal carcinoma cells into nonreplicating, mature neurons (Development 127:693, 2000). We generated neuroD2 null and heterozygous mice that experienced premature death preceded by ataxia, seizures, motor deficits, and weight loss (Dev. Biol. 234:74, 2001; Dev. Biol. 265:234, 2004). Analysis of these mice revealed a previously unrecognized role of neuroD2 in maintaining neuronal survival. Recent studies show that the basolateral amygdala, which processes fear and other emotions, is absent in neuroD2 null mice and that neuroD2 heterozygotes show impaired anxiety and fear responses in behavioral testing. Current efforts are focused on understanding the molecular mechanisms by which neuroD2 regulates cell cycle arrest and neuronal differentiation.
Huntington's Disease
Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin protein (Nature Med 7:419, 2001). 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 from 19 Universities that conducted gene expression profiling studies in models of HD and other neurodegenerative diseases. The results can be seen in a special series of articles in Human Molecular Genetics (issues 11(17) and 11(19), 2002). Based on hypotheses generated by these studies, we are currently testing the efficacy of pharmacologic agents in mouse HD models.
Nanotechnology, Molecular Imaging, and Clinical Pharmacology
Our laboratory is involved in interdisciplinary studies involving nanotechnology and molecular imaging for neurologic disease diagnosis, treatment, and response evaluation. Dr. Olson is the author of "Clinical Pharmacology Made Ridiculously Simple," a textbook geared toward medical students making the transition from classroom pharmacology to clinical pharmacology. The principles of pharmacology and the relationships that we have developed in research divisions of pharmaceutical companies accelerate translation of our basic research into clinical practice.
