基于基因敲除小鼠研究中性粒细胞自发死亡的分子机制

项目名称： 基于基因敲除小鼠研究中性粒细胞自发死亡的分子机制

项目编号： No.31271484

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 许元富

作者单位： 中国医学科学院

项目金额： 80万元

中文摘要： 中性粒细胞是机体中数量最多、寿命最短的一类免疫相关细胞，在非特异性细胞免疫中起着十分重要的作用。自发死亡是中性粒细胞死亡的主要形式，是维持中性粒细胞体内平衡和促进炎症消退的主要方式，但是到目前为止，自发死亡的分子调控机制还不十分清楚。为此，基于以前的工作基础，我们将在多种基因敲除小鼠体内外深入研究ROS和PtdIns(3,4,5)P3/Akt信号在中性粒细胞死亡中的作用机制，重点关注三个问题：即是ROS是通过怎样的作用机制来抑制G-肌动蛋白聚合成F-肌动蛋白，阻断PI3Kγ的活化路径的？在动物体内，ROS是否还能介导中性粒细胞的死亡,其中又是怎样的作用机制？中性粒细胞自发死亡过程中PI3Kγ-PIP3-Akt信号通路的下游分子是哪些？本研究的完成将阐明中性粒细胞自发死亡的分子调控机制和信号途径，发现遗传性疾病CGD的新的分子致病机理，同时也为临床今后治疗多种感染和炎性疾病提供新的治疗靶点。

中文关键词： 天然免疫；中性粒细胞；细胞死亡；基因敲除；AKT

英文摘要： Neutrophils are the most abundant cell type among circulating white blood cells and normally have a very short life-span (7-20 hours in blood and 1-4 days in tissue),they are also the key innate immune cells, which constitute the first line of host defense against pathogens. Neutrophils readily undergo spontaneous programmed cell death and this death program plays a crucial role in neutrophil homeostasis and the resolution of inflammation. However, the molecular mechanism underlying neutrophil spontaneous cell death is ill defined. Thus, based on the Preliminary Studies, and to further understand the involvement of Ptdlns(3,4,5)P3/Akt signaling in neutrophil spontaneous death, we continued to characterize the molecular mechanisms by which Ptdlns(3,4,5)P3/Akt activity is down regulated during neutrophil spontaneous death. Moreover, the downstream mechanisms responsible for Ptdlns(3,4,5)P3/Akt deactivation- mediated neutrophil death and the contribution of Ptdlns(3,4,5)P3/Akt pathway to neutrophil death in live animals （including knockout mice）were investigated. The specific aims of this study are as follows: (1) To elucidate the molecular mechanisms by which PI3Kγ activity is down-regulated by ROS during neutrophil spontaneous death. (2) To examine the role of NADPH oxidase-mediated ROS production in neutrophil d

英文关键词： Innate immune；neutrophil；cell death；gene knockout；AKT