CELL DEATH AND DIFFERENTIATION IN MEDULLOBLASTOMA

髓母细胞瘤(MBS)是典型的原始神经外胚层 小脑肿瘤(PNETs)，它们是最常见的 儿童脑瘤。直到最近，对基本细胞的理解 这些肿瘤的生物学和发病机制在很大程度上仍然是谜。 然而，现在已经确定，许多MB细胞和几乎所有MB 细胞系类似于未成熟的中枢神经系统(CNS)神经元或 他们的祖先。由于住房抵押贷款证券化几乎只发生在幼儿中 当异位未成熟神经元和神经外胚祖细胞 最常见的是小脑，MBS可能是由于 神经外胚祖细胞经历程序性细胞死亡或 完成正常的神经元分化程序。这可能是 其次是获取遗传损伤中的残留物 诱导肿瘤转化的神经外胚层前体细胞。 此外，神经营养素及其受体的不适当表达 神经外胚祖细胞和微血管内皮细胞上的同源受体可能起关键作用 在MBS的诱导和发展中的作用。为了深入了解 这些常见的儿童脑肿瘤的发生和发展， 并找出干扰正常发育的分子缺陷 可能阻止神经外胚祖细胞退出的事件 细胞周期和终末分化为神经元或 在细胞死亡的过程中，我们计划检查细胞之间的关系 真人的死亡、增殖和神经元分化 MBS和PNETs以及在细胞系和转基因小鼠模型中的表达 这些肿瘤。我们还将描述神经营养素受体的特征 在正常发育的小脑以及人的MBS中均有表达。 和人类MR来源的细胞系。然后这些信息将被用于 设计诱导神经元分化或细胞死亡的策略 MB细胞系通过基因工程表达神经营养因子 受体，并对其同源神经营养因子作出反应。 这些研究的独特之处在于，它们延伸到对 用于细胞培养和动物模型分析的人体活检样本 MBS和PNBTS。综上所述，这些研究将提供新颖和 对关键过程的重要见解(即细胞死亡、增殖、 分化)是肿瘤发生和发展的关键因素。 这些研究还将阐明神经营养因子在 MBS和PNBTS的出现和发展。对这些基本内容的洞察 生物过程可以为新技术的发展奠定基础 多发性骨髓瘤的基因疗法。

Medulloblastomas (MBs) are prototypical primitive neuroectodermal tumors (PNETs) of the cerebellum, and they are among the most common pediatric brain tumors. Until recently, understanding of the basic cell biology and pathogenesis of these tumors remained largely enigmatic. However, it is now established that many MB cells and nearly all MB cell lines resemble immature central nervous system (CNS) neurons or their progenitors. Since MBs occur almost exclusively in young children when heterotopic immature neurons and neuroectodermal progenitors are most common in cerebellum, MBs may arise from the failure of neuroectodermal progenitor cells to undergo programmed cell death or to complete a normal program of neuronal differentiation. This may be followed by the acquisition of genetic lesions in residual neuroectodermal progenitors that induce neoplastic transformation. Further, the inappropriate expression of neurotrophins and their cognate receptors in neuroectodermal progenitors and MBs may play a key role in the induction and progression of MBs. To gain insights into the initiation and progression of these common pediatric brain neoplasms, and to identify molecular defects that interrupt normal developmental events that might prevent neuroectodermal progenitor cells from exiting the cell cycle and terminally differentiating into neurons or undergoing cell death, we plan to examine the relationship between cell death, proliferation and neuronal differentiation in authentic human MBs and PNETs as well as in cell lines and transgenic mouse models of these tumors. We also will characterize the neurotrophin receptors expressed in the normal developing cerebellum, as well as in human MBs and human MR-derived cell lines. This information will then be used to design strategies to induce neuronal differentiation or cell death in MB cell lines by engineering these cell lines to express neurotrophin receptors and to respond to their cognate neurotrophins. These studies are unique in that they extend from the assessment of human biopsy samples to the analysis of cell culture and animal models of MBs and PNBTs. Taken together, the studies will provide novel and important insights into key processes (i.e. cell death, proliferation, differentiation) that are central to tumor initiation and progression. These studies also will clarify the role that neurotrophins play in the emergence and progression of MBs and PNBTs. Insights into these basic biological processes could set the stage for the development of novel gene therapies for MBs.