Neural Progenitor Genes and Brain Tumors

自从神经干细胞被发现以来，这些细胞与脑瘤的起源之间的联系已经 已经被理论化了。我们和其他人最近发现的脑肿瘤干细胞及其近表型 与神经干细胞的关系促使我们探索共同的增殖机制 神经干细胞和脑瘤之间的关系。我们之前已经发现母体胚胎亮氨酸 拉链蛋白激酶(zipper kinase，Melk)是一种丝氨酸-苏氨酸激酶，是细胞增殖的标志物和调节因子。 在发育中的小鼠脑中更新神经前体细胞(神经干细胞)。我们还发现梅尔克 它的表达与脑肿瘤的分级和生存有关，是一种“中枢”基因；它的表达 预测许多其他细胞周期基因的表达。我们假设梅尔克是一个重要的 脑瘤增殖的调节因子，介导脑瘤干细胞的自我更新，并作为 脑肿瘤干细胞的标志物。然而，需要进一步的研究来确定Melk及其推定的 分子通路将成为脑肿瘤治疗的靶点。这项提案将解决这些问题。我们 将首先进行实验，以确定梅尔克是否介导了脑瘤细胞系的增殖， 重点是髓母细胞瘤和多形性胶质母细胞瘤(GBM)。之所以选择这些肿瘤是因为它们 是常见的，并且有强有力的初步证据支持这样的假设，即Melk调节他们的 功能。此外，由于髓母细胞瘤中是否存在脑肿瘤干细胞一直受到质疑，它将 重要的是要确定Melk在这些肿瘤中的功能是否与GBM不同。 我们将通过确定Melk在调节细胞中的作用来建立Melk效应的潜在机制 周期，调节其功能的基因，以及这一功能是由其激酶结构域还是由 对于RNA处理中的功能至关重要的区域。我们还将确定Melk函数是否对 脑肿瘤细胞系在活体环境中的脑内增殖。以确定梅尔克是否 由肿瘤干细胞表达，我们将首先测试它是否通过球体形成多能表达 肿瘤来源的祖细胞，以及这些祖细胞是否有能力启动肿瘤。我们会 然后确定Melk在体外和体内对脑瘤干细胞的作用。通过这些研究，我们将 确定Melk或其功能通路是否是脑部新疗法的合适靶点 肿瘤。莱文摘要：干细胞基因的研究将带来治疗脑瘤的有希望的新疗法。 这个应用集中在一个基因，Melk，它是正常细胞增殖(分裂)的关键调节基因 神经干细胞，在脑瘤中表达。我们将确定Melk在脑肿瘤中的功能 细胞(胶质瘤和髓母细胞瘤)以及它是否对引起肿瘤的“癌症”的增殖很重要 如果Melk对这些功能很重要，那么它就成为潜在治疗的目标。

Since the discovery of neural stem cells, a connection between these cells and the origin of brain tumors has been theorized. The recent discovery by us and others of brain tumor stem cells and their close phenotypic relationship to neural stem cells has prompted us to explore proliferative mechanisms that are in common between neural stem cells and brain tumors. We have previously found that maternal embryonic leucine zipper kinase (MELK), a serine-threonine kinase, is a marker for and regulates the proliferation of self- renewing neural progenitors (neural stem cells) in developing mouse brain. We have also found that MELK expression correlates with brain tumor grade and survival and that it is a "hub" gene; one whose expression predicts the expression of numerous other cell cycle genes. We hypothesize that MELK is an important regulator of brain tumor proliferation, mediates the self-renewal of brain tumor stem cells and serves as a marker for brain tumor stem cells. However, further studies are needed to determine if MELK and its putative molecular pathwaywill serve as targets for brain tumor therapy. This proposal will address these issues. We will first perform experiments to determine whether MELK mediates the proliferation of brain tumor cell lines, focusing on medulloblastoma and glioblastoma multiforme (GBM). These tumors were chosen because they are common and there is strong preliminary evidence supporting the hypothesis that MELK regulates their function. Also, since the presence of brain tumor stem cells in medulloblastoma has been questioned, it will be important to determine whether MELK functions in a different capacity in these tumors compared to GBM. We will establish the mechanisms underlying MELK effects by determining MELK's role in regulating the cell cycle, the genes that mediate its function, and whether this function is mediated by its kinase domain or the domain critical for a function in RNA processing. We will also determine whether MELK function is critical for brain tumor cell line proliferation in the in vivo environment of the brain. To determine whether MELK is expressed by cancer stem cells, we will first'test whether it is expressed by sphere-forming multipotent progenitors derived from tumors and then whether these progenitors are capable of tumor initiation. We will then determine the role of MELK in brain tumor stem cells in vitro and in vivo. Through these studies, we will determine whether MELK or its functional pathway is an appropriate target for novel therapies of brain tumors. Lay summary: A study of stem cell genes will lead to promising new treatments for brain tumors. This application focuses on a gene, MELK, that is a critical regulation of the proliferation (division) of normal neural stem cells and is expressed by brain tumors. We will determine the function of MELK in brain tumor cells (glioma and medulloblastoma) and whether it is important for the proliferation of tumor-causing "cancer stem cells". If MELK is important for these functions then it becomes a target for potential treatments.