Transcriptional regulation of gliomagenesis

描述（由申请人提供）：恶性胶质瘤是最常见的原发性脑肿瘤亚型，具有侵袭性和神经破坏性。多形性胶质母细胞瘤（GBM）是最常见的胶质瘤形式，其患者的平均生存期约为1年，目前尚无有效的治疗方法。缺乏进展可至少部分归因于高度细胞增殖和侵袭性。因此，即使在积极的多模式治疗后，侵入的GBM细胞也可以逃避治疗并引起肿瘤复发。然而，对GBM不受控制的细胞增殖和侵袭的细胞和分子机制知之甚少。 基于我们最近的实验结果，我们建议评估新的假设，FoxM 1，这是异常表达在人类GBM，导致细胞增殖和GBM细胞的侵袭，可能通过β-连环蛋白介导的机制，从而有助于致瘤性。为了验证这一假设，我们建议评估FoxM 1的功能，在合作与β-catenin在β-catenin靶基因的表达; FoxM 1-β-catenin相互作用的神经胶质瘤细胞的细胞增殖和侵袭的功能;和FoxM 1-β-catenin相互作用在维持GBM细胞的致瘤性的重要作用。此外，我们建议确定Wnt信号通路在GBM中FoxM 1过表达中的作用。 如果本拨款申请的具体目标得以完成，我们不仅将了解一般情况和胶质瘤中b-连环蛋白激活失调的新机制，以及通过b-连环蛋白和FoxM 1表达/功能失调进行胶质瘤发生的新机制，而且我们还将了解FoxM 1是否可以作为潜在的治疗靶点。这一信息将具有潜在的高翻译影响。从长远来看，我们的研究可能会导致分子靶点的验证，这些靶点可用于设计有效的策略来控制这种致命的疾病。

DESCRIPTION (provided by applicant): Malignant glioma, the most common primary brain tumor subtype, is aggressive and neurologically destructive. The mean survival duration of patients with glioblastoma multiforme (GBM), the most common form of glioma, is approximately 1 year and there is no effective therapy to date. The lack of progress can be attributed, at least in part, to the highly cellular proliferation and invasive. Thus, even after aggressive multimodal therapy, the invading GBM cells can escape the therapy and cause a tumor relapse. However, little is known about the cellular and molecular mechanisms underlying uncontrolled cellular proliferation and invasion of GBM. Based on our recent experimental results, we propose to evaluate the novel hypothesis that FoxM1, which is abnormally expressed in human GBM, causes the cellular proliferation and invasion of GBM cells, possibly through a b-catenin-mediated mechanism, and, thus contribute to tumorigenicity. To test this hypothesis, we propose to evaluate the function of FoxM1 in the cooperation with b-catenin in the expression of b-catenin target genes; the function of FoxM1-b-catenin interaction in cell proliferation and invasion of glioma cells; and the essential role of FoxM1-b-catenin interaction in maintaining the tumorigenicity of GBM cells. Moreover, we propose to determine the role of Wnt signaling pathway in the FoxM1 overexpression in GBM. If the Specific Aims of this grant application are completed, not only will we understand new mechanisms for the dysregulated b-catenin activation in general and in glioma, and for gliomagenesis through dysregulated b-catenin and FoxM1 expression/function, but also will we learn whether FoxM1 can serve as a potential therapeutic target. This information will have potentially high translational impact. In the long term, our study may lead to the validation of molecular targets that can be used in designing effective strategies to control this deadly disease in clinics.