Characterizing the functions and relevance of 4EBP1 in glioblastoma

胶质母细胞瘤(GBM)是一种侵袭性的脑肿瘤，需要新的、更有效的治疗措施。由于肿瘤血管系统的缺陷，基底膜正在经历低营养状态。因此，GBM需要开发分子策略来适应这些应激条件。了解这些策略应该会揭示这种疾病的潜在治疗目标。我们发现4EBP1，一个mRNA翻译调节因子，在营养剥夺下是一个潜在的细胞保护因子。值得注意的是，我们观察到，与健康患者相比，GBM患者显示出高水平的4EBP1。因此，我们建议对4EBP1在GBM中的生物学功能和临床意义进行研究。为此，我们将在分子水平上剖析4EBP1如何支持GBM细胞对低营养条件的抵抗，包括对代谢的影响。此外，4EBP1在支持GBM进展中的功能将在体内使用小鼠模型进行评估。最后，我们将使用大量可用的GBM样本来表征4EBP1与GBM患者预后的相关性。总体而言，我们建议的项目的目标是探索4EBP1在GBM中的生物学作用及其与患者预后的相关性，以确定4EBP1是否可能成为这种疾病的治疗靶点。

Glioblastoma (GBM) is an aggressive brain tumor, for which novel and more efficient therapeutic interventions are warranted. GBM are experiencing low nutrients conditions due to defects in the tumor vasculature. In consequence, GBM needs to develop molecular strategies to adapt to these stressful conditions. Understanding these strategies should reveal potential therapeutic targets for this disease. We identify 4EBP1, an mRNA translation regulator, as a potential cellular protective factor under nutrient deprivation. Strikingly, we observed that GBM patients exhibit high levels of 4EBP1 compared to healthy patients. Therefore, we propose to study the biological function and clinical relevance of 4EBP1 in GBM. To this aim, we will dissect at the molecular level how 4EBP1 may support GBM cells resistance to low nutrients conditions, including the impact on metabolism. In addition, the function of 4EBP1 in supporting GBM progression will be assessed in vivo using mouse models. Finally, we will characterize the relevance of 4EBP1 for prognosis of GBM patients using a large collection of GBM samples available to us. Overall, the goal of our proposed project is to explore the biological role of 4EBP1 in GBM and its relevance for patients prognosis, with the potential of determining whether 4EBP1 may be a therapeutic target in this disease.