化疗耐药形成是目前限制肺腺癌临床TKI靶向治疗的重要瓶颈，往往涉及表观遗传学及重要信号通路的调控异常，以及众多耐药关键基因的遗传改变。我们前期在人肺腺癌EGFR-TKI耐药细胞建立的基础上研究发现，Notch通路上重要受体Notch-1的异常激活可能参与了肺癌腺EGFR-TKI靶向治疗耐药表型的形成，高通量芯片筛选结合生物信息学分析结果提示，其下游LncRNA SNHG15与miR-451之间存在可能的结合调控关系。本课题拟在前期已取得的研究成果上，运用基因调控、荧光素酶活性实验、RNA免疫沉淀、位点突变、RNA pull down等分子生物学实验技术，从体内外结合临床标本探寻LncRNA SNHG15与miR-451之间的相互作用调控其下游靶基因MDR-1表达，最终参与调控Notch-1介导的肺腺癌EGFR-TKI化疗耐药形成的分子机制，为肺腺癌个体化治疗和逆转耐药提供新的靶点。

Chemoresistance is the most significant obstacle of the clinical efficacy by TKI target treatment in lung adenocarcinoma nowadays. The mechanism involved in epigenetics change and aberrant key signaling regulation, as well as genetic transform in multiple drug resistance ralted protein. On the previous basis of establishment of EGFR-TKI-resistant lung adenocarcinoma cell lines, our group has investigated that aberrant activation of Notch-1, one of the improtant receptor in Notch signaling pathway, may be involved in the phenotype of TKI-resistant in lung adenocarcinoma. Combined with high quality Microarray screening results and bioinformatics analyses, We focused that LncRNA SNHG15 and miR-451 are both downstream target of Notch-1, a possible combination and regulation may be exist, however the exact mechanisim was needed further study. Based on previous research acheivement, with genetic regulation, luciferase activity assay, RNA immunoprecipitation, site-specific mutation, RNA pull down assay and other technology of molecular biology, the aim of this study is to reveal the molecular mechanism of interactions between LncRNA SNHG15 and miR-451 participated in Notch-1 induced EGFR-TKI resistance in human lung adenocarcinoma, MDR-1 was directly retulated by miR-451 which might be play a significant role in the process. It will provide a novel target for reversing chemoresistance and clinical individualized treatment of lung adenocarcinoma.