REST/NRSF-mediated medulloblastoma tumorigenesis

描述（申请人提供）：髓母细胞瘤（MB）是最恶性的小儿脑肿瘤之一，平均5年生存率仅为50%。MB被认为主要来自小脑的外部颗粒层细胞的未分化的神经干/祖细胞（CPC）。虽然发育重要的信号通路，如Wnt和Hedgehog已知在一些MB中被激活，但大多数人类MB的肿瘤发生机制仍然未知。因此，MB研究的一个挑战是了解大多数MB的调节机制。我们先前对人髓母细胞瘤肿瘤样本、CPC组织培养系统和原位颅内小鼠模型系统的研究表明，转录因子REST在很大比例的人MB中起关键作用。在我们目前的研究结果的基础上，我们建议测试的假设，REST介导的MB肿瘤发生的机制涉及阻止CPC的神经元分化的自我更新模式（维护“干”），也通过抑制MB肿瘤发生相关的其他靶基因的转录。我们进一步提出，在许多MB中看到的REST的异常过表达部分是由于REST基因启动子的突变。因此，所提出的研究将产生与我们研究REST介导的MB肿瘤发生的发生和产生基于机制的动物模型的长期目标相关的关键信息，所述动物模型可用于鉴定新的生理学相关治疗靶点和测试MB的现有和新药。本文提出的实验符合NCI脑肿瘤进展审查小组的建议。此外，由于我们提出的项目涉及神经干/祖细胞和髓母细胞瘤，它可能适合于计划公告PA- 05-086（“干细胞和癌症”）。公共卫生相关性：髓母细胞瘤（MB）是最恶性的小儿脑肿瘤之一。该项目在过去已经导致发现了一种新的人类MB调节剂（REST），现在将继续破译REST在髓母细胞瘤机制和可能的治疗中的作用。

DESCRIPTION (provided by applicant): 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"). PUBLIC HEALTH RELEVANCE: Medulloblastoma (MB) is among the most malignant of pediatric brain tumors. This project in the past has lead to the discovery of a novel regulator of human MB (REST) and will now continue to decipher the role of REST in medulloblastoma mechanism and possible therapy.