A Role for RIP1 in Gliomagenesis

RIP1 在神经胶质瘤发生中的作用

• 批准号: 8147853
• 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
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8147853
• 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; public health relevance; response; therapy design; treatment strategy

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.

描述（由申请人提供）：识别胶质母细胞瘤（GBM）中启动和维持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PI3K-AKT途径在GBM中放松管制，并且可能在GBM的发病机理和对治疗的耐药性中起关键作用。 NF-？B激活是炎症的标志。在此提案中，我们旨在表征含有激酶受体相互作用蛋白（RIP，RIP1）的死亡结构域在GBM生物学中的作用。 RIP1激活神经胶质瘤细胞中的NF-？B和PI3K-AKT途径。此外，RIP1负责调节两个关键的肿瘤抑制信号网络，PTEN和p53途径。 RIP1水平在GBM的30％中升高，而II-III级胶质瘤的水平不高。此外，RIP1表达在GBM中的预后较差，过表达RIP1会诱导神经胶质瘤细胞的增殖，而沉默的RIP1抑制了神经胶质瘤动物模型中神经胶质瘤细胞的增殖。该提案的中心假设是RIP1通过调节肿瘤细胞中的关键信号通路来在GBM的发病机理和对治疗的耐药性中起关键作用。该提案的广泛目标是通过实验证明RIP1促进GBM的恶性表型。在特定的目标1中，我们将探索将RIP1耦合到神经胶质瘤细胞增殖的机械关系，并鉴定RIP1特异性效应器机制，影响胶质瘤细胞中的增殖和对化疗的耐药性。在特定目标2中，我们将确定RIP1介导的抑制肿瘤抑制信号的机理和生物学意义。在特定目标3中，我们将使用正性动物模型基准在神经胶质瘤细胞中基准RIP1表达的效果。这项研究可能会为炎症在GBM中的作用提供有用的见解，并有助于设计针对GBM中炎症信号通路的更有效的治疗方法。 公共卫生相关性：RIP1是一种参与炎症的蛋白质，在GBM中高度表达，并且预后不佳。我们研究了RIP1用于促进恶性神经胶质瘤生长的机制。对神经胶质瘤中RIP1的了解的提高可能会导致设计更合理的靶向治疗。