地塞米松(Dex)是治疗急性淋巴细胞白血病(ALL)的首选药，但因需长期大剂量应用而引发严重不良反应及耐药。申请者发现传统抗疟药氯喹(CQ)与Dex合用上调Dex的靶点GR从而协同抗ALL，在受体蛋白质水平较好地解释CQ对Dex的增效作用，但CQ-Dex联用上调GR的机制仍不清楚。我们发现ALL中长链非编码(lnc)RNA C1RL-AS1低表达，且其表达与GR编码基因NR3C1正相关，且均靶向miR-155。据此，推测C1RL-AS1作为NR3C1的竞争性内源RNA（ceRNA），CQ-Dex调节该ceRNA协同治疗ALL。本项目拟从细胞生物学、分子生物学、动物疾病模型等方面研究上述ceRNA调控机制，研究其病理生理必要性，并证明CQ-Dex通过调节该ceRNA网络发挥协同治疗ALL作用。本项目的完成，将为高效低毒的协同增效药物的发展提供理论基础，并为临床精准诊疗ALL提供依据。

Dexamethasone(Dex) is the most effective and potent agent in the treatment of acute Lymphoblastic leukemia(ALL). However, Dex induces a large range of side effects after its long-term administration at high doses. We previously found that the combination of traditional antimalaria drug chloroquine(CQ) with Dex synergistically supressed the proliferation of ALL, and illuminated the synergistic effect of CQ-Dex at the receptor protein level. However, the underlying mechanism of the CQ-Dex combination regulating GR is still unknown. We find that the expression of long noncoding RNA C1RL-AS1 is low in ALL cells and its expression have a positive correlation with the GR coding gene, NR3C1, which are both targeting miR-155. Therefore, we conclude that C1RL-AS1 is a competing endogenous RNA (ceRNA) of NR3C1, and CQ-Dex synergistically treat ALL via the regulation of this ceRNA. In this program, we plan to elucidate the ceRNA regulation mechanism and the significance of the ceRNA under both physiology and pathophysiology circumstances, and the regulation of CQ-Dex in vivo. We believe that this program will lay the theoretical foundation of drugs synergistically treat ALL with ALL with high efficacy and low toxicity, and provide new target and treating strategy of ALL in ALL accurate diagnosis and treatment.