靶向UBA1调控内质网应激信号并诱导胶质母细胞瘤凋亡的作用与机制

胶质母细胞瘤是最常见的成人原发恶性脑肿瘤和致死率最高的恶性肿瘤之一。胶质母细胞瘤仍缺乏靶向药物，亟待探寻潜在的治疗靶点和药物。内质网应激和未折叠蛋白反应（UPR）一定水平的活化是胶质母细胞瘤生存所必需的。但UPR反应具有双重功能，过度活化将启动细胞凋亡程序。然而调控UPR的基因繁多，具有组织和肿瘤特异性。因此，我们前期建立特异性UPR筛选模型，利用siRNA文库鉴定出泛素样激活酶1（UBA1）基因沉默可显著激活UPR介导的促凋亡蛋白CHOP转录。而且，发现胶质母细胞瘤对UBA1靶向药物的敏感性差异很大。本项目将进一步在细胞和动物水平研究UBA1基因沉默及其抑制剂对胶质母细胞瘤增殖和凋亡等功能的影响；分析对内质网应激和UPR反应的调控机制；多组学阐明UBA1靶向药物在胶质母细胞瘤中敏感性差异的机制。项目完成，可为胶质母细胞瘤的治疗提供新思路，为鉴定适合靶向UBA1治疗的患者提供实验基础。

Glioblastoma multiforme (GBM) is one of the most common primary malignant brain tumors and the most lethal malignant tumors in adults. So far, there is no effective targeted drugs for GBM, thus it is urgent to explore potential therapeutic targets and drugs. The moderate activation of endoplasmic reticulum stress and unfolded protein response (UPR) is essential for glioblastoma survival. However, UPR has dual functions, the overactivation will initiate apoptotic process. However, UPR is regulated by a wide variety of genes with tissue and tumor specificity. Therefore, we established a screening model based on specific UPR. We found that ubiquitin-activating enzyme 1 (UBA1) gene silencing can significantly activate UPR-mediated apoptotic process by siRNA Library. Moreover, the sensitivity of UBA1 specific inhibitors in different glioblastoma cells was found to vary greatly. In this study, we will further study the effects of UBA1 gene silencing and its inhibitors on glioblastoma proliferation and apoptosis at cellular and animal levels; analyze the regulatory mechanism of endoplasmic reticulum stress and UPR response; elucidate the mechanism of differential sensitivity of UBA1-targeted drugs in glioblastoma by multi-omics analysis. The completion of the project can provide new ideas for the treatment of glioblastoma and provide experimental basis for identifying patients suitable for targeted UBA1 therapy.