阻断小鼠TLX-LSD1复合体形成的多肽抑制恶性胶质瘤干细胞增殖的研究

恶性胶质瘤（GBM）是一种高致死率的脑癌。因侵袭性和异质化极高，GBM治疗后易复发，患者平均生存期低于两年。GBM干细胞（GSCs）的存在与GBM的复发相关。因此，抑制GSCs的增殖，可能有助于GBM的治疗。孤儿素受体TLX是调控人GSCs及其小鼠模型脑癌干细胞（BTSCs）增殖的关键基因。我们发现在BTSCs中，TLX结合组蛋白去甲基化酶LSD1，协同对抑癌基因PTEN 和p21启动子区域的H3K4me1和H3K4me2去甲基化，导致PTEN和p21表达降低而维持BTSCs增殖。通过实验，我们发现一条与TLX结合的LSD1多肽能阻断TLX和LSD1的协同作用，抑制BTSCs的增殖。在此课题中，我们将研究该多肽对人GSCs增殖的影响和作用机制；探索通过多联修饰的脂质体应用该多肽的安全性和功效。这项研究将为开发针对GSCs治疗神经干细胞增殖不活跃的老年GBM患者的新型治疗方案奠定基础。

Glioblastoma (GBM) is a highly lethal tumor. Because it is highly aggressive and heterogeneous, it often recurs after treatment. The average survival time of patients is less than two years. The existence of glioblastoma stem cells (GSCs) is related to the recurrence of GBM. Therefore, inhibition of GSC proliferation may improve the treatment of GBM. Tlx, a orphan nuclear receptor, is a critical gene for the proliferation of GSCs and its mouse model, brain tumor stem cells (BTSCs). We found that in BTSCs, Tlx interacts with histone demethylase LSD1 and inhibits the expression of tumor repress genes PTEN and p21, through demethylating H3K4me1 and H3K4me2 at their promoter, to maintain the proliferation of BTSCs. By experiments, we found that a TLX-binding peptide of LSD1 can interfere the synergistic function of TLX and LSD1 and inhibit the proliferation of BTSCs. In this project, we plan to study the function of this peptide on GSC proliferation and its functional mechanism; explore the safety and efficacy of the peptide application through multiple modified liposome. This study may shed light on developing novel therapeutics targeting to GSCs for aged GBM patients who have low proliferation of neural stem cells.