REST/NRSF-mediated medulloblastoma tumorigenesis

髓母细胞瘤(MB)是儿童脑肿瘤中最恶性的一种，具有 平均5年生存率仅为50%。甲基溴被认为主要来自于 小鼠外颗粒层细胞的未分化神经干/祖细胞 小脑。虽然在发育上很重要的信号通路，如Wnt和 已知Hedgehog在一些MBS中被激活，肿瘤发生的机制仍然存在 对于大多数人类MBS来说都是未知的。因此，研究甲基溴的一个挑战是理解 监管大多数住房抵押贷款证券化的机制。我们先前对人髓母细胞瘤的研究 肿瘤标本、CPC的组织培养系统和原位颅内小鼠模型 系统表明，转录因子REST在很大程度上是 人类MBS。 根据我们目前的发现，我们建议检验以下假设： REST介导的MB肿瘤发生涉及通过以下途径阻断CPC的神经元分化 以一种自我更新的模式(保持“茎干”)来逮捕他们，并通过压制 与MB肿瘤发生相关的其他靶基因的转录。我们进一步建议， 在许多MB中发现的REST异常过表达部分是由于REST的突变 基因启动子。因此，拟议的研究将产生与我们的长期- 研究REST介导的MB肿瘤发生和产生机制的学期目标 基于机制的动物模型，既可以用来识别新的、生理上相关的 治疗目标和测试现有的和新的甲基溴药物。 这里提出的实验符合NCI大脑的建议 肿瘤进展回顾小组。此外，因为我们提出的项目涉及到神经 干细胞/祖细胞和髓母细胞瘤，它可能适合于计划公告PA- 05-086(“干细胞与癌症”)。

Medulloblastoma (MB) is among the most malignant of pediatric brain tumors, having an average 5-year survival rate of only 50%. MB is believed to arise mostly from the undifferentiated neural stem/progenitor cells (CPCs) of the external granule layer cells of the cerebellum. Although developmentally important signaling pathways such as Wnt and Hedgehog are known to be activated in some MBs, the mechanism of tumorigenesis remains unknown for the majority of human MBs. Thus, one challenge for studies of MB is to understand the mechanisms that regulate most MBs. Our previous studies with human medulloblastoma tumor samples, a tissue culture system of CPCs, and an orthotopic intracranial mouse model system suggested that the transcription factor REST is a critical player in a major percentage of human MBs. On the basis of our current findings, we propose to test the hypothesis that the mechanism of REST-mediated MB tumorigenesis involves blocking the neuronal differentiation of CPCs by arresting them in a self-renewal mode (maintenance of "stemness") and also by repressing the transcription of other target genes relevant in MB tumorigenesis. We further propose that the abnormal overexpression of REST seen in many MBs is due in part to mutations in the REST gene promoter. Thus, the proposed studies will yield critical information relevant to our long- term goals of studying the genesis of REST-mediated MB tumorigenesis and producing mechanism-based animal models that can be used both to identify new, physiologically relevant targets for therapy and to test existing and new drugs for MB. The experiments proposed here are in accordance with the recommendations of the NCI Brain Tumor Progress Review Group. Furthermore, because our proposed project involves neural stem/progenitor cells and medulloblastoma, it may be suitable for Program Announcement PA- 05-086 ("Stem Cells and Cancer").