Myc Signaling in Medulloblastomas

描述(申请人提供)：髓母细胞瘤，胚胎性肿瘤 发生在小脑的，是儿科最常见的恶性脑肿瘤。 我们对c-Myc和N-Myc在细胞周期中的作用提出了几种研究思路 髓母细胞瘤病理生物学。首席调查员查尔斯·埃伯哈特博士， 是一位在果蝇遗传学方面有科学背景的神经病理学家， 计划作为研究脑瘤的独立临床科学家的职业生涯。 为了达到他的目标，他通常需要额外的技术训练。 用于在实验室研究肿瘤，包括细胞培养和小鼠 转基因模型。追求我们提出的具体目标将教会Dr。 埃伯哈特的这些技能，并使他能够过渡到独立的 从事癌症研究的职业。MYC转录因子正在成为重要的 髓母细胞瘤的调节剂，生物学。在具体目标1中，我们调查链接 髓母细胞瘤标本中Myc水平与临床预后的关系这个 Myc的作用是多种多样的，虽然已经在 成纤维细胞和血液系统恶性疾病，很可能是 Myc调控的基因在不同的肿瘤类型中会有所不同。因此，我们建议在 特异靶2鉴定髓母细胞瘤细胞系中c-Myc的靶点 调节c-Myc水平和评估基因表达谱的变化 使用微阵列。在特定的目标3中，我们确认了 通过分析这些靶点在髓母细胞瘤组织中的表达 具有不同的c-Myc水平。最后，在具体目标4中，我们建议开发一种 新型髓母细胞瘤c-Myc转基因模型的建立 转基因小鼠的小脑。

DESCRIPTION (provided by applicant): 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.