Interactions between inflammatory and oncogenic signaling pathways in GBM

GBM 炎症和致癌信号通路之间的相互作用

• 批准号: 8735239
• 负责人: AMYN HABIB
• 金额: --
• 依托单位: VA NORTH TEXAS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735239
• 关键词: Adult; Apoptotic; Area; Binding; Biological; Cell Death; Cell Death Induction; Cell Survival; Cells; Cellular Stress; Cessation of life; Characteristics; Complex; Development; Diagnostic; Dissociation; EGF gene; EGFR Gene Amplification; Epidermal Growth Factor Receptor; Experimental Models; Gene Mutation; Glioblastoma; Goals; Inflammation; Inflammatory; Investigation; Laboratories; Life; Ligand Binding; Ligands; Link; MAP3K7 gene; Malignant - descriptor; Malignant neoplasm of brain; Mediating; Mediator of activation protein; NF-kappa B; Necrosis; Oncogenic; Pathogenesis; Pathway interactions; Phosphotransferases; Play; Post-Translational Protein Processing; Primary Brain Neoplasms; Proteins; Proteomics; RIPK1 gene; RIPK3 gene; Receptor Protein-Tyrosine Kinases; Recruitment Activity; Regulation; Reporting; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Protein; Stimulus; Stress; System; Ubiquitination; Veterans; Work; activating transcription factor; caspase-8; effective therapy; epidermal growth factor receptor VIII; human RIPK1 protein; improved; in vivo; interest; mouse model; mutant; novel; outcome forecast; overexpression; public health relevance; response; tumor; tumor growth; ubiquitin ligase

DESCRIPTION (provided by applicant): Project Summary Glioblastoma (GBM) is the most common primary malignant brain tumor in veterans. The prognosis for GBM is dismal and there is an urgent need for novel treatments. The receptor interacting protein (RIP1, RIPK1) has emerged as a central regulator of cell death in cell stress, inflammation, and development. Depending on the cellular context, RIP1 is known to either activate the transcription factor NF-¿B and promote cell survival, or induce apoptotic or necrotic cell death in response to a number of stressful stimuli. Recent studies have shown that activation of NF-¿B plays an important role in the pathogenesis of GBM. In this proposal, we propose to examine the role of RIP1 as a cell life death/switch in glioblastoma (GBM). A characteristic histopathological feature of GBMs is the presence of necrosis within the tumors. We have previously shown that RIP1 is expressed in GBM and confers a worse prognosis. In this proposal we examine the hypothesis that the RIP1 switch in GBM is regulated by EGFR signaling. The experimental goals of this project are to examine whether RIP1 is essential for tumor formation in an experimental model of GBM, and to investigate whether RIP1 regulates the induction of necrotic cell death in GBM. We aim to elucidate the mechanisms used by a mutant EGFRvIII to activate the oncogenic potential of RIP1 and the mechanism used the EGFR wild type (EGFRwt) to switch RIP1 to a cell death mode using an experimental intracranial mouse model of GBM. Additionally, we investigate RIP1 as a target for treatment in GBM using two alternative hypothesis. Hypothesis A: RIP1 silencing will result in inhibition of tumor growth in GBM. Hypothesis B: Activation of the cell death function of RIP1 using the EGFR network will eliminate GBM cells in vivo. Thus, RIP1 studies in GBM have the potential to significantly impact understanding of GBM and improve its treatment.

描述(由申请人提供)： 胶质母细胞瘤(GBM)是退伍军人最常见的原发恶性脑肿瘤。GBM的预后很差，迫切需要新的治疗方法。受体相互作用蛋白(RIP1，RIPK1)在细胞应激、炎症和发育过程中是细胞死亡的中心调节因子。根据细胞环境的不同，已知RIP1可以激活转录因子NF-B并促进细胞存活，或者诱导细胞凋亡或 应激性刺激引起的坏死性细胞死亡。最近的研究表明，核因子-B的激活在GBM的发病机制中起着重要作用。在这项提案中，我们建议研究RIP1在胶质母细胞瘤(GBM)中作为细胞生命死亡/开关的作用。基底节细胞瘤的一个典型的组织病理学特征是肿瘤内存在坏死。我们先前已经证明，RIP1在GBM中表达，且预后较差。在这个建议中，我们检验了GBM中的RIP1开关受EGFR信号调节的假设。该项目的实验目标是在GBM的实验模型中检测RIP1是否对肿瘤的形成是必要的，并研究RIP1是否调节GBM中坏死细胞的诱导死亡。我们旨在阐明突变型EGFRvIII激活RIP1致癌潜能的机制，以及利用EGFR野生型(EGFRwt)通过实验性脑内胶质瘤小鼠模型将RIP1切换到细胞死亡模式的机制。此外，我们使用两种不同的假说来研究RIP1作为治疗基底膜的靶点。假设A：RIP1沉默将导致抑制GBM中的肿瘤生长。假设B：使用EGFR网络激活RIP1的细胞死亡功能将在体内消除GBM细胞。因此，对GBM的RIP1研究有可能显著影响对GBM的理解并改进其治疗。