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我们的研究项目“甲基转移酶KMT1A抑制剂的筛选及其靶向抑制膀胱癌干细胞的机制研究”获得国家自然科学基金青年科学基金项目资助

时间 : 2017-01-01


摘要:膀胱癌的发病率在我国泌尿系统肿瘤中高居第一位,目前尚无特异有效的治疗方法。膀胱癌干细胞作为靶向治疗的最佳选择,具有自我更新、无限增殖和多向分化潜能,是膀胱肿瘤发生、发展、复发和转移的根源,但膀胱癌干细胞自我更新的分子机理仍不清楚。因此,阐明其干性维持的分子作用机制和筛选获得其靶向抑制剂具有重要意义。我们前期研究发现组蛋白甲基转移酶KMT1A在膀胱癌干细胞中的高表达具有特异性,当其功能缺失后,膀胱癌干细胞的干性维持被严重破坏。在此基础上,本项目以膀胱癌干细胞中高表达的KMT1A作为抑制靶点,采用肿瘤免疫学和表观遗传学等方法筛选特异性强、毒副作用小的KMT1A抑制剂;评估其靶向抑制膀胱癌干细胞和膀胱肿瘤的效果,确定膀胱癌干细胞的最佳KMT1A抑制剂;揭示其抑制膀胱癌干细胞的作用机制。本项目的完成将阐明靶向KMT1A对膀胱癌干细胞的抑制效果,为发展靶向干预膀胱癌干细胞的新治疗手段提供理论依据。

Abstract: The incidence of bladder cancer ranks first in urogenital neoplasms in China, but there are no specific and effective therapies. As the ideal target of the targeted therapy, bladder cancer stem cells (BCSCs) possess the characteristics of self-renewal, infinite proliferation and pluripotency, and are the source of bladder cancer tumorigenesis, progression, recurrence and metastasis. However, the self-renewal mechanisms of BCSCs remain unclear. Therefore, it is of great importance to clarify the mechanisms of stemness and screen of targeted inhibitors of BCSCs. Our previous studies uncovered that histone methyltransferase KMT1A was highly and specifically expressed in BCSCs. Moreover, depletion of KMT1A significantly abrogated self-renewal of BCSCs. In the proposed project, we plan to screen of a KMT1A inhibitor harboring the high-specificity and low side effects targeting to KMT1A in BCSCs with the tumor immunological and epigenetic methods. Furthermore, the optimal KMT1A inhibitor of BCSCs will be picked out with the evaluation of the inhibitory effects to BCSCs and bladder tumor, in vitro and in vivo. Finally, the inhibitory mechanisms of KMT1A inhibitor to BCSCs will be elucidated with the analysis of transcriptome and epigenomics of BCSCs. Collectively, the results of this project will illuminate the suppressive effects of KMT1A inhibitor targeting KMT1A in BCSCs and provide a theoretical and practical foundation to develop novel therapies targeted BCSCs.


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