REST/NRSF-mediated medulloblastoma tumorigenesis

髓母细胞瘤（MB）是小儿脑肿瘤中最恶性的肿瘤之一， 平均5年生存率只有50%。MB被认为主要来自于 未分化的神经干/祖细胞（CPC）的外部颗粒层细胞的 小脑虽然发育重要的信号通路，如Wnt和 已知Hedgehog在某些MB中被激活，但肿瘤发生的机制仍然存在 对于大多数人类MB来说是未知的。因此，对甲基溴研究的一个挑战是了解 调节大多数肌肉萎缩症的机制。我们以前对人髓母细胞瘤的研究 肿瘤样品、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是一个关键的球员在一个主要的百分比， 人MB。 基于我们目前的研究结果，我们提出了一个假设，即 REST介导的MB肿瘤发生涉及阻断CPC的神经元分化， 阻止它们以自我更新的方式（维持“干性”），并通过抑制 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中观察到的REST的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长期- 研究REST介导的MB肿瘤发生和产生的发生的长期目标 基于机制的动物模型，可用于识别新的，生理相关的 治疗靶点，并测试MB的现有药物和新药。 这里提出的实验符合NCI Brain的建议。 肿瘤进展审查组。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，它可能适合计划公告PA- 05-086（“干细胞和癌症”）。

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").