Medulloblastomas, embryonal neoplasms arising in the cerebellum, are the most common malignant pediatric brain tumor. We propose several lines of investigation into the roles of c-Myc and N-Myc in medulloblastoma pathobiology. The primary investigator, Dr. Charles Eberhart, is a neuropathologist with a scientific background in Drosophila genetics, who plans a career as an independent clinician scientist researching brain tumors. To accomplish his goals he requires additional training in techniques commonly used to study tumors in the laboratory, including cell culture and mouse transgenic models. Pursuing the specific aims we propose will teach Dr. Eberhart these skills, and enable him to make the transition to an independent career in cancer research. Myc transcription factors are emerging as important modulators of medulloblastoma, biology.
In Specific Aim 1 we investigate links between Myc levels in medulloblastoma specimens and clinical outcome. The effects of Myc are varied, and while several Myc targets have been isolated in fibroblasts and hematologic malignancies, it is likely that the profile of genes regulated by Myc will differ between tumor types. We therefore propose in Specific Aim 2 to identify c-Myc: targets in medulloblastoma cell lines by modulating c-Myc levels and evaluating the changes in gene expression profiles using microarrays.
In Specific Aim 3 we confirm the clinical importance of these targets by analyzing their expression in medulloblastoma tumor samples with varying c-Myc levels. Finally, in Specific Aim 4 we propose developing a novel medulloblastoma transgenic model by overexpressing c-Myc in the cerebellum of transgenic mice.
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