脑胶质瘤是最常见原发中枢神经系统肿瘤，恶性程度高，极易复发，患者死亡率高，现有治疗方式仍未有突破性进展。深入研究胶质瘤基因调控网络变化，筛选关键信号通路，对靶向药物开发、患者生存期延长等具有重要意义。申请人前期用长链非编码RNA芯片筛选出胶质瘤中显著上调的假基因UBDP1，并在样本和细胞系中验证了其与UBD表达相关，两者均具有促进胶质瘤恶性增殖的能力；信息分析发现UBDP1和UBD有共同miRNA结合区域，如miRNA-4747可同时调控两者表达。基于此我们提出“假基因UBDP1通过竞争性结合miRNA促进癌基因UBD表达，进而促使胶质瘤恶性进展”的科学假设。本项目拟通过基因敲除、转录组测序、胶质瘤干细胞、PDX模型等技术，探索UBDP1-miRNA-UBD网络共同调控胶质瘤恶性表型机制及下游信号通路，明确靶向假基因调控网络治疗胶质瘤临床转化潜能，为提高胶质瘤患者预后提供分子理论依据。

Gliomas are the most common primary brain tumors and characterized by rapid proliferation and invasive growth. Despite current aggressive treatment, almost all of gliomas can recur which makes patients face a poor clinical outcome. Therefore, it is of very high priority to explore the vital genetic changes and core pathways involved in glioma progression, which will pave new ways to developing targeted therapies. Previously, we have found a pseudogene UBDP1 dramatically upregulated in glioma based on lncRNA microarray and its expression positively related to the parent gene UBD in glioma tissues and cells. Moreover, both of UBDP1 and UBD could significantly promote glioma cell proliferation. Bioinformatic analysis was then performed and showed that there existed common miRNA (such as miRNA-4747) binding sites within UBD and UBDP1 sequences. Exogenous miRNA-4747 could obviously suppress the expression of UBD and UBDP1 in glioma cells. Accordingly, we speculate that the pseudogene UBDP1 can compete with UBD for miRNA binding which will result in increased expression of oncogenic UBD in glioma. Here, this project intends to elucidate the UBDP1-miRNA-UBD regulatory network involved in glioma progression and explore core pathways underlying the downstream of UBDP1 with multiple methods and materials including CRISPR-Cas9, next-generation sequencing, glioma stem cell, and patient-derived xenograft. We hope to take deep insights into the oncogenic mechanisms driven by pseudogenes in glioma and identify novel targets for drug development, both of which will help promote the prognosis of glioma patients in the future.