以去泛素化酶UCH37为靶点治疗脑胶质瘤恶性增殖的分子机理研究

恶性胶质瘤是最常见的难治性神经系统恶性肿瘤，有易复发和高死亡率的特性，使现有治疗方式和理念一直缺乏突破性进展，阐明脑胶质瘤发生分子机理，开拓新干预靶点是该领域非常迫切的前沿课题。前期课题组提炼胶质瘤芯片数据和信息分析发现去泛素化酶UCH37和USP14表达与恶性程度密切相关，调控胶质瘤发生发展，同时UCH37和USP14特异性抑制剂金诺芬正开展临床II抗肿瘤试验性治疗。项目拟用慢病毒稳转胶质瘤细胞株、RNA干扰靶蛋白表达siRNA及回复技术、蛋白芯片、免疫共沉淀和与microRNA相关调控等方法研究UCH37参与胶质瘤增殖侵袭、放化疗敏感中上下游调控分子、蛋白信号通路和恶性生物学行为的分子机制；在此基础上，构建裸鼠荷瘤动物模型在体内研究去泛素化酶抑制剂潜在的治疗价值，评价UCH37作为治疗靶点及判断胶质瘤生存期及复发独立因子的可行性，为个体化治疗选择提供分子依据，有重要临床价值。

Malignant glioma is the most common primary brain tumor and is very refractory to treatment with high rate of recurrence and mortality. Lacking of significant progresses in therapeutics, it is of very high priority to elucidate mechanisms underlying gliomagenesis and explore novel therapeutic approaches and/or targets. Insights from our earlier tissue microarray profiling and bioinformatics analysis suggest that the expression of a group of genes including deubiquitinating enzymes UCH37 and USP14, and E3 ubiquitin ligase CHIP positively correlated with the degree of glioma malignancy and may play crucial roles in gliomagenesis and/or disease progression. Importantly, the small molecule inhibitor of UCH37 and USP14 is now under Phase II clinical trial to treat chronic myeloid leukemia. Thus, in the present study, we first wish to utilize both established cell lines and primary glioma cells and carry out functional and mechanistic dissection of UCH37 in gliomagenesis, proliferation, invasion, drug sensitivity and disease relapse. Moreover, working with both in vitro primary cell culture and in vivo exnograft model, we are keen to evaluate the efficacy and the potential usage of UCH37 inhibitor in treating glioma. Positive outcomes shall not only strongly indicate a crucial role for UCH37 in gliomagenesis, but also provide a novel drug target and viable individualized treatment for patients with the related lesions.