项目名称: ATRX信号传导通路在肿瘤发生中的作用及其机制研究
项目编号: No.81472559
项目类型: 面上项目
立项/批准年度: 2015
项目学科: 医药、卫生
项目作者: 焦宇辰
作者单位: 中国医学科学院肿瘤医院
项目金额: 80万元
中文摘要: 染色质重塑蛋白ATRX在染色质结构维护,基因转录调控等方面起到重要作用,但其在肿瘤发生中的作用尚不清楚。在前期研究中,申请人首次在胰腺内分泌瘤,脑胶质瘤等多种肿瘤中发现高频的ATRX突变,这些突变与端粒替代延长机制(ALT)均有密切的关联,并可导致肿瘤细胞广泛的基因表达异常。基于申请人以上前期工作,本课题将在基因敲除细胞系水平上,研究ATRX突变是否可以独立诱发ALT机制,诱发过程是否受细胞组织来源和其他基因突变的影响,以及诱发ALT机制对肿瘤发生的作用。同时,我们将研究ATRX突变对下游基因的表达水平的改变,并通过功能实验研究下游基因表达水平改变在肿瘤发生中的作用。我们还将使用shRNA文库筛选方法,寻找与ATRX突变有合成致死关系的基因,为针对ATRX突变型癌细胞的靶向治疗提供可能的线索。
中文关键词: ATRX突变;端粒替代延长机制;肿瘤的发生;合成致死
英文摘要: The chromatin remodeling protein ATRX (α thalassaemia/mental retardation X-linked) has emerged as a key player in chromatin structure maintenance and gene transcription regulation, but its role in tumorigenesis is poorly understood. In our former studies, we identified frequent mutations in ATRX in several types of human tumors including gliomas and pancreatic neuroendocrine tumors. We further found that these mutations have a perfect correlation with the alternative lengthening of telomere (ALT) mechanism. In addition, ATRX mutations lead to extensive gene expression disruptions in tumor cells. In this study, we will set up ATRX knockout cell lines and determine whehter ATRX mutation is sufficient to induce ALT mechanism. We will also study whether the cell type or other genetic variations could change the ATRX-ALT correlation, and its effect on tumorigenesis. Meanwhile, we will study how ATRX mutations disrupt gene expressions and how these disregulation contribute to tumorigenesis. Finally, we will screen for synthetic lethal partners of ATRX mutations with barcoded shRNA screening method. We will validate the candidates to provides clues for targeted therapy againt ATRX mutant tumor cells.
英文关键词: ATRX mutation;Alternative lengthening of telomere;Tumorigenesis;Synthetic lethality