Interactions between inflammatory and oncogenic signaling pathways in GBM

描述（由申请人提供）： 胶质母细胞瘤（GBM）是退伍军人中最常见的原发性恶性脑肿瘤。GBM的预后很差，迫切需要新的治疗方法。受体相互作用蛋白（RIP 1，RIPK 1）已成为细胞应激，炎症和发育中细胞死亡的中心调节因子。根据细胞环境，已知RIP 1激活转录因子NF-κ B B并促进细胞存活，或诱导细胞凋亡， 坏死性细胞死亡是对许多应激刺激的反应。近年来的研究表明，NF-β B的活化在GBM的发病机制中起重要作用.在这个提议中，我们建议检查RIP 1作为胶质母细胞瘤（GBM）中的细胞生命死亡/开关的作用。GBM的典型组织病理学特征是肿瘤内存在坏死。我们以前已经表明，RIP 1在GBM中表达，并赋予更差的预后。在这个提议中，我们研究了GBM中RIP 1开关受EGFR信号调节的假设。该项目的实验目标是研究RIP 1是否是GBM实验模型中肿瘤形成所必需的，并研究RIP 1是否调节GBM中坏死细胞死亡的诱导。我们的目的是阐明突变型EGFRvIII激活RIP 1的致癌潜力的机制，以及EGFR野生型（EGFRwt）使用GBM的实验性颅内小鼠模型将RIP 1切换到细胞死亡模式的机制。此外，我们研究RIP 1作为治疗GBM的目标，使用两个备择假设。假设A：RIP 1沉默将导致GBM中肿瘤生长的抑制。假设B：使用EGFR网络激活RIP 1的细胞死亡功能将在体内消除GBM细胞。因此，GBM中的RIP 1研究有可能显著影响对GBM的理解并改善其治疗。

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.