NLRP3炎症小体介导Th亚群失衡在急性髓性白血病中的作用及机制研究

项目名称： NLRP3炎症小体介导Th亚群失衡在急性髓性白血病中的作用及机制研究

项目编号： No.81470319

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： 马道新

作者单位： 山东大学

项目金额： 70万元

中文摘要： 急性髓性白血病(AML)化疗虽已取得较大进展，但多数患者仍出现难治、复发，药物敏感性降低和机体免疫功能异常是其重要原因。炎症小体为新近发现的参与机体免疫的多蛋白复合物，在肿瘤发生发展和耐药中发挥重要作用，其机制可能与介导Th亚群失衡有关。我们前期发现，AML患者中存在NLRP3炎症小体和Th17等亚群异常升高，并与预后不良相关。本课题拟研究AML患者中NLRP3炎症小体对Th17等亚群的分化调控作用；阐明AML患者骨髓中NLRP3炎症小体及其调控的Th17等亚群，对AML细胞增殖、凋亡、周期和药物敏感性等方面作用；进一步通过研究下游相关信号通路，揭示NLRP3/Th17等亚群在AML发生发展和耐药中具体作用机制。同时上调或下调小鼠AML细胞NLRP3表达后，接种C57BL/6(H-2b)小鼠，给予化疗药物或IL-17等干预，体内研究NLRP3调控Th17等亚群在AML发生发展和耐药中作用。

中文关键词： 急性髓性白血病；NLRP3炎症小体；T辅助细胞；发病机制；信号通路

英文摘要： Though chemotherapy has made progress for acute myeloid leukemia, many patients are non-responsed or relapsed. Chemo-resistance and immunological deregulation are the main reasons. Inflammasomes are recently-identified multi-protein complexes involved in human immunology. Inflammasomes play critical roles in cancer development and chemo-resistance, which has been shown related to the imbalance of Th subsets. Our previous study has indicated the increase of NLRP3 inflammasome molecules and Th subsets which correlated with the disease progress in AML patients. We will study the effects of NLRP3 inflammasome on Th subsets and clarify the regulation of NLRP3 on Th subsets differentiation in AML patients. We will clarify the effects of NLRP3 and Th17 on proliferation, apoptosis, cell cycle and chemo-sensitivity of AML leukemia cells. After studying the related signaling pathways, we will illuminate the detailed mechanisms of NLRP3/Th17 in AML development and chemo-resistance. Furthermore, after being up-regulated or down-regulated of NLRP3, murine AML cell line C1498.GFP will be injected into C57BL/6(H-2b) mice. Then the mice will be given chemotherapy drugs or IL-17 intervention, and we will study the effects of NLRP3/Th17 on AML development and chemo-resistance in vivo.

英文关键词： acute myeloid leukemia;NLRP3 inflammasome;T helper cells;pathogenesis;signaling pathway