Neural Progenitor Genes and Brain Tumors

描述（由申请人提供）：自从发现神经干细胞以来，这些细胞与脑肿瘤起源之间的联系已被理论化。我们和其他人最近发现的脑肿瘤干细胞及其与神经干细胞的密切表型关系促使我们探索神经干细胞和脑肿瘤之间共同的增殖机制。我们之前已经发现母系胚胎亮氨酸拉链激酶（MELK）是一种丝氨酸-苏氨酸激酶，是发育中的小鼠大脑中自我更新的神经祖细胞（神经干细胞）增殖的标记物和调控物。我们还发现MELK的表达与脑肿瘤的分级和生存相关，并且它是一个“枢纽”基因，其表达可以预测许多其他细胞周期基因的表达。我们假设MELK是脑肿瘤增殖的重要调节因子，介导脑肿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及其假定的分子途径是否可以作为脑肿瘤治疗的靶点。这项建议将解决这些问题。我们将首先进行实验，以确定MELK是否介导脑肿瘤细胞系的增殖，重点是髓母细胞瘤和多形性胶质母细胞瘤（GBM）。选择这些肿瘤是因为它们很常见，并且有强有力的初步证据支持MELK调节其功能的假设。此外，由于髓母细胞瘤中脑肿瘤干细胞的存在一直受到质疑，因此确定MELK在这些肿瘤中的功能是否与GBM不同将是很重要的。我们将通过确定MELK在调节细胞周期中的作用，介导其功能的基因，以及该功能是由其激酶结构域介导还是由RNA加工功能的关键结构域介导，来建立MELK作用的机制。我们还将确定MELK功能是否对脑肿瘤细胞系在脑内环境中的增殖至关重要。为了确定MELK是否在癌症干细胞中表达，我们将首先测试它是否在来自肿瘤的球形多能祖细胞中表达，然后测试这些祖细胞是否能够引发肿瘤。然后，我们将在体外和体内确定MELK在脑肿瘤干细胞中的作用。通过这些研究，我们将确定MELK或其功能通路是否是脑肿瘤新疗法的合适靶点。对干细胞基因的研究将为脑肿瘤带来有希望的新疗法。这项应用主要针对MELK基因，它是正常神经干细胞增殖（分裂）的关键调节因子，并在脑肿瘤中表达。我们将确定MELK在脑肿瘤细胞（胶质瘤和成神经管细胞瘤）中的功能，以及它对致瘤“癌症干细胞”的增殖是否重要。如果MELK对这些功能很重要，那么它就成为潜在治疗的目标。

DESCRIPTION (provided by applicant): 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, 1 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 pathway will 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 regulator 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.