高级别胶质瘤具有手术放化疗难治性，目前多采用分子靶向药物进行综合治疗。但其异质性又使得在不同个体中很难找到相同的突变位点从而选择有效靶向药物。最新研究表明，在高级别胶质瘤（WHO IV）中，75%伴有人端粒酶逆转录酶亚基hTERT启动子突变而不伴有IDH和1p/19q等其他位点突变。这种突变使得端粒酶活性上调从而导致了肿瘤的异常增殖以及耐药性。因此有效抑制端粒酶将成为治疗原复发高级别胶质瘤的关键。核仁素在脑胶质瘤中过表达，其RNA结合域可与hTERT和hTERC结合，使端粒酶复合体在细胞核富集，增强其稳定端粒的能力。实验中，通过靶向干扰核仁素与hTERT和RNA组分hTERC的结合，抑制端粒酶活性。并对端粒酶抑制后造成的端粒损伤，细胞凋亡，衰老等机制进行探讨。最后我们联合核仁素干扰以及端粒酶抑制作用于高级别胶质瘤，通过协同作用从而达到在低剂量药物浓度下提高端粒酶的抑制效果及肿瘤细胞生长抑制

The outcomes of surgical treatment, radiotherapy and chemotherapy to high-grade glioma (HGG) is poor due to its high malignancy and heterogeneity. Hence, molecular targeted therapy is introduced to the treatment of HGG. However, it is difficult to find the same mutation site in different individuals due to the heterogeneity of HGG. Recent studies have shown that human telomerase reverse transcriptase subunit hTERT promoter mutations are found in 75% of high-grade gliomas (WHO IV) without IDH and 1p/19q mutations. This mutation results in up-regulation of hTERT activity leading to abnormal proliferation and drug resistance of tumors. Therefore, searching for effective methods of inhibiting telomerase activity will become a new direction for high-grade glioma treatment. Nucleolin is over-expressed in gliomas, its RNA-binding domain and carboxyl-terminus bind to hTERT and hTERC, which results in hTERT transportation to nucleus. In this experiment, we will inhibit telomerase activity by preventing nucleolin binding hTERT and hTERC. Then we will investigate the mechanisms of telomere injury, apoptosis and senescence induced by telomerase inhibition. Finally, we inhibit telomerase activity of HGG by combination of nucleolin interference and telomerase inhibitor. We aim to find the synergistic effect so as to increase telomerase inhibition and growth inhibition of HGG cells.