A Role for RIP1 in Gliomagenesis

描述(由申请人提供)：识别启动和维持胶质母细胞瘤(GBM)恶性表型的分子改变和信号异常是设计治疗方案的关键步骤。在GBM中，NF-B和PI3K-Akt信号通路处于失控状态，可能在GBM的发病机制和耐药机制中发挥关键作用。核因子-β活化是炎症的一个标志。在这项建议中，我们的目的是表征死亡结构域包含的激酶受体相互作用蛋白(RIP，RIP1)在GBM生物学中的作用。RIP1可同时激活胶质瘤细胞中的NF-β和PI3K-Akt信号通路。此外，RIP1还负向调节两个关键的肿瘤抑制信号网络，即PTEN和P53通路。RIP1水平在高达30%的胶质瘤中升高，但在II-III级胶质瘤中不升高。此外，在胶质瘤动物模型中，RIP1的表达使胶质瘤的预后变差，RIP1的过度表达诱导胶质瘤细胞的增殖，而沉默RIP1则抑制胶质瘤细胞的增殖。这一建议的中心假设是，RIP1通过调节肿瘤细胞中的关键信号通路，在GBM的发病机制和耐药中发挥关键作用。这项建议的主要目标是通过实验证明RIP1促进了GBM的恶性表型。在具体目标1中，我们将探索RIP1偶联与胶质瘤细胞增殖的机制关系，并确定RIP1影响胶质瘤细胞增殖和化疗耐药的特异性效应机制。在特定的目标2中，我们将确定RIP1介导的抑制肿瘤抑制信号的机制和生物学意义。在具体目标3中，我们将使用正交性动物模型对RIP1在胶质瘤细胞中的表达效果进行基准测试。这项研究可能对炎症在基底膜中的作用提供有用的见解，并有助于设计更有效的针对基底膜炎症信号通路的治疗方法。 公共卫生相关性：RIP1是一种参与炎症的蛋白质，在GBM中高表达，预后不良。我们研究了RIP1促进恶性胶质瘤生长的机制。提高对RIP1在胶质瘤中的认识可能会导致设计更合理的靶向治疗。

DESCRIPTION (provided by applicant): Identification of molecular alterations and signaling abnormalities that initiate and maintain the malignant phenotype in glioblastoma (GBM) is a key step in designing treatment. The NF-?B and PI3K-Akt pathways are deregulated in GBM and likely to play key roles in the pathogenesis of GBM and in resistance to treatment. NF-?B activation is a hallmark of inflammation. In this proposal, we aim to characterize the role of the death domain containing kinase receptor interacting protein (RIP, RIP1), in the biology of GBM. RIP1 activates both the NF-?B and PI3K-Akt pathways in glioma cells. In addition, RIP1 negatively regulates two key tumor suppressor signaling networks, the PTEN and the p53 pathways. RIP1 levels are increased in up to 30% of GBMs but not in Grade II-III gliomas. Furthermore, RIP1 expression confers a worse prognosis in GBM, overexpressing RIP1 induces proliferation of glioma cells and silencing RIP1 inhibits proliferation of glioma cells in an animal model of glioma. The central hypothesis of this proposal is that RIP1 plays a key role in the pathogenesis of GBM and resistance to treatment by regulating key signaling pathways in tumor cells. The broad goal of this proposal is to demonstrate experimentally that RIP1 promotes the malignant phenotype of GBM. In Specific Aim 1, we will explore the mechanistic relationships coupling RIP1 to the proliferation of glioma cells and identify RIP1 specific effector mechanisms influencing proliferation and resistance to chemotherapy in glioma cells. In Specific Aim 2, we will determine the mechanisms and biological significance of RIP1 mediated inhibition of tumor suppressor signaling. In Specific Aim 3 we will benchmark the effect of RIP1 expression in glioma cells using an orthotropic animal model. This study may provide useful insights into the role of inflammation in GBM and help in the design of more effective treatments targeting inflammatory signaling pathways in GBM. PUBLIC HEALTH RELEVANCE: RIP1, a protein involved in inflammation, is highly expressed in GBM and confers a poor prognosis. We investigate the mechanisms used by RIP1 to promote growth of malignant glioma. Improved understanding of RIP1 in glioma may lead to design of more rational targeted treatment.