Myc Signaling in Medulloblastomas

描述（由申请方提供）：髓母细胞瘤，胚胎性肿瘤 发生于小脑的脑肿瘤是最常见的小儿恶性脑肿瘤。 我们提出了几条研究c-Myc和N-Myc在细胞凋亡中的作用的路线。 髓母细胞瘤病理生物学首席调查员查尔斯·埃伯哈特博士 是一位具有果蝇遗传学科学背景的神经病理学家， 计划成为一名研究脑瘤的独立临床科学家。 为了完成他的目标，他通常需要额外的技术训练。 用于在实验室中研究肿瘤，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授博士。 埃伯哈特的这些技能，使他能够过渡到一个独立的 从事癌症研究。Myc转录因子正在成为重要的 成神经管细胞瘤的调节剂，生物学在具体目标1中，我们研究链接 髓母细胞瘤标本中Myc水平与临床结果之间的关系。的 Myc的作用是不同的，虽然已经分离出几个Myc靶点， 成纤维细胞和血液恶性肿瘤，这是可能的情况下， 由Myc调控的基因在肿瘤类型之间会有所不同。因此，我们建议， 具体目标2：通过以下方法鉴定髓母细胞瘤细胞系中的c-Myc：靶标 调节c-Myc水平并评估基因表达谱的变化 使用微阵列。在具体目标3中，我们确认了以下临床重要性： 通过分析它们在髓母细胞瘤肿瘤样本中的表达， 不同的c-Myc水平。最后，在具体目标4中，我们建议开发一个 一种新的过表达c-Myc基因的髓母细胞瘤转基因模型 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.