Transcriptional regulation of gliomagenesis

描述(申请人提供)：恶性胶质瘤，最常见的原发脑肿瘤亚型，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，其患者的平均生存期约为1年，目前尚无有效的治疗方法。缺乏进展至少在一定程度上可以归因于细胞的高度增殖和侵袭性。因此，即使在积极的多模式治疗后，侵袭的GBM细胞也可以逃脱治疗并导致肿瘤复发。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，我们建议评估一种新的假设，即在人GBM中异常表达的FOXM1可能通过b-catenin介导的机制导致GBM细胞的增殖和侵袭，从而促进肿瘤的发生。为了验证这一假设，我们建议评估FOXM1与b-catenin在b-catenin靶基因表达中的协同作用；FOXM1-b-catenin相互作用在细胞增殖和胶质瘤细胞侵袭中的作用；以及FOXM1-b-catenin相互作用在维持GBM细胞致瘤性方面的重要作用。此外，我们建议确定Wnt信号通路在GBM中FOXM1过表达中的作用。如果这项拨款申请的特定目标完成，我们不仅将了解一般情况下和胶质瘤中异常调节的b-连环蛋白激活的新机制，以及通过异常调节的b-连环蛋白和FOXM1表达/功能发生胶质瘤的新机制，而且我们还将了解FOXM1是否可以作为潜在的治疗靶点。这些信息可能会对翻译产生很大的影响。从长远来看，我们的研究可能会导致分子靶标的验证，这些靶标可以用于设计有效的策略，在临床上控制这种致命的疾病。 公共卫生相关性：多形性胶质母细胞瘤(GBM)是最常见的胶质瘤，其患者的平均生存期约为1年，到目前为止还没有有效的治疗方法。如果这项拨款申请的特定目标完成，我们不仅将了解FOXM1和b-catenin相互作用控制的GBM细胞异常生长和侵袭的新机制，而且我们还将了解FOXM1或其靶点b-catenin是否可以作为潜在的治疗靶点。此信息将具有潜在的翻译影响。从长远来看，我们的研究可能导致分子靶标的确定，这些分子靶标可以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. PUBLIC HEALTH RELEVANCE: 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. If the Specific Aims of this grant application are completed, not only will we understand a new mechanism of GBM tumorigenesis through abnormal cell growth and invasion of GBM cells controlled by the interaction of FoxM1 and b-catenin, but we will also learn whether FoxM1 or its target b-catenin can function as potential therapeutic targets. This information will have potential translational impact. In the long term, our study may lead to the identification of molecular targets that can be used in designing effective strategies to control this deadly disease.