A Role for RIP1 in Gliomagenesis

描述（由申请方提供）：鉴定引发和维持胶质母细胞瘤（GBM）恶性表型的分子改变和信号传导异常是设计治疗的关键步骤。NF-？B和PI 3 K-Akt通路在GBM中失调，并且可能在GBM的发病机制和对治疗的抗性中起关键作用。NF-？B活化是炎症的标志。在这个建议中，我们的目标是表征的死亡结构域包含激酶受体相互作用蛋白（RIP，RIP 1），在GBM的生物学的作用。RIP 1激活NF-？胶质瘤细胞中的B和PI 3 K-Akt通路。此外，RIP 1负调节两个关键的肿瘤抑制信号网络，PTEN和p53通路。RIP 1水平在高达30%的GBM中升高，但在II-III级胶质瘤中不升高。此外，RIP 1表达在GBM中赋予更差的预后，在神经胶质瘤的动物模型中，过表达RIP 1诱导神经胶质瘤细胞的增殖，并且沉默RIP 1抑制神经胶质瘤细胞的增殖。该建议的中心假设是RIP 1通过调节肿瘤细胞中的关键信号通路在GBM的发病机制和对治疗的抗性中起关键作用。该提案的广泛目标是通过实验证明RIP 1促进GBM的恶性表型。在具体目标1中，我们将探讨RIP 1与胶质瘤细胞增殖的机制关系，并确定RIP 1影响胶质瘤细胞增殖和化疗耐药性的特异性效应机制。在具体目标2中，我们将确定RIP 1介导的肿瘤抑制信号转导抑制的机制和生物学意义。在具体目标3中，我们将使用正交各向异性动物模型对神经胶质瘤细胞中RIP 1表达的影响进行基准测试。这项研究可能为炎症在GBM中的作用提供有用的见解，并有助于设计更有效的治疗方法，靶向GBM中的炎症信号通路。 公共卫生相关性：RIP 1是一种参与炎症的蛋白质，在GBM中高度表达，预后不良。我们研究RIP 1促进恶性胶质瘤生长的机制。进一步了解RIP 1在胶质瘤中的作用可能有助于设计更合理的靶向治疗方案。

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.