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A Role for RIP1 in Gliomagenesis

RIP1 在神经胶质瘤发生中的作用

基本信息

批准号：
8308027
负责人：
AMYN HABIB
金额：
$ 30.77万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-29 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8308027
关键词：
Adult Alkylating Agents Animal Model Apoptosis Benchmarking Biological Biology Cells Coupling DNA Damage Death Domain Feedback Glioblastoma Glioma Gliomagenesis Goals Growth Inflammation Inflammatory Laboratories Lead Link Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Mediating Molecular Oncogenic PTEN gene Pathogenesis Pathway interactions Patients Phosphotransferases Play Positioning Attribute Protein p53 Proteins Regulation Resistance Role Signal Pathway Signal Transduction Sirolimus Stimulus TSC1/2 gene Tumor Suppressor Proteins Work anticancer research chemotherapy clinical efficacy design effective therapy human FRAP1 protein human RIPK1 protein improved in vivo Model inhibitor/antagonist insight mTOR inhibition malignant phenotype mouse model neoplastic cell outcome forecast overexpression prognostic indicator response therapy design treatment strategy

项目摘要

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 orthotopic 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.

识别启动和抑制细胞凋亡的分子改变和信号传导异常，维持胶质母细胞瘤（GBM）的恶性表型是设计治疗NF-B和PI 3 K-Akt通路在GBM中被解除调节，并可能在GBM中发挥作用。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，我们的目的是描述死亡的作用，结构域包含激酶受体相互作用蛋白（RIP，RIP 1），在GBM生物学。 RIP 1激活神经胶质瘤细胞中的NF-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级中不升高神经胶质瘤此外，RIP 1表达在GBM中赋予更差的预后，过表达RIP 1诱导胶质瘤细胞增殖，沉默RIP 1抑制胶质瘤细胞增殖。在神经胶质瘤动物模型中神经胶质瘤细胞增殖。这个问题的核心假设是 RIP 1在GBM的发病机制中起着关键作用，通过调节肿瘤细胞中的关键信号通路进行治疗。这个广泛的目标一个建议是通过实验证明RIP 1促进恶性表型的GBM。在具体目标1中，我们将探索RIP 1 神经胶质瘤细胞的增殖，并确定RIP 1特异性效应机制影响胶质瘤细胞的增殖和对化疗的抗性。具体目标 2、探讨RIP 1介导的细胞凋亡的机制及生物学意义。抑制肿瘤抑制信号传导。在具体目标3中，我们将对效果进行基准测试 RIP 1在神经胶质瘤细胞中的表达。这项研究可能为炎症在GBM中的作用提供了有用的见解，并有助于设计更有效的治疗靶向GBM中的炎症信号通路。