骨髓微环境中的中性粒细胞产生的ROS对急性粒系造血的调控作用

项目名称： 骨髓微环境中的中性粒细胞产生的ROS对急性粒系造血的调控作用

项目编号： No.31471116

项目类型： 面上项目

立项/批准年度： 2015

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： 86万元

中文摘要： 大量的中性粒细胞在感染和炎症条件下会从外周血和骨髓中被募集到受累的组织部位，而这会在骨髓中启动一种急性粒系造血来补偿中性粒细胞，以维持体内的细胞自稳，然而其中调控急性粒系造血的分子机制至今还不是十分清楚。活性氧簇（ROS）能在造血调控方面起着重要作用，而且最近的体内外研究结果表明ROS能促进造血干祖细胞的增殖。我们在研究中发现在急性炎症条件下骨髓中的ROS水平升高了，而提升的ROS水平是主要依赖于中性粒细胞中的NADPH氧化酶（NOX2），这就提示我们中性粒细胞中产生的ROS可能在启动急性粒系造血方面起着重要作用。为此，我们拟开展以下研究：1. 骨髓微环境中的ROS是否是急性炎症诱导的急性粒系造血所需要的主要起始因子；2.骨髓中调控急性粒系造血的ROS的来源、作用方式和作用机制。该研究的完成将为今后临床上加速骨髓移植后的粒系造血和免疫重建提供一种创新性的治疗策略。

中文关键词： 骨髓微环境；粒系造血；中性粒细胞；呼吸氧簇；造血干/祖细胞

英文摘要： A large amount of neutrophils are recruited to the affected tissues during acute infection and inflammation. It is known that bone marrow (BM) granulopoiesis is enhanced to compensate the loss of peripheral blood neutrophils. However the cellular mechanism controlling inflammation-induced emergency granulopoiesis is still ill-defined. Reactive oxygen species (ROS) can play a regulatory role in hematopoiesis. Recent studies and our own data demonstrate that ROS are able to increase the proliferation of cultured hematopoietic stem cells (HSC) and progenitor cells (HPC). Our preliminary results show that ROS level in the BM is elevated during acute inflammation and this elevation of ROS level depends on phagocyte NADPH oxidase (a.k.a. NOX2 complex), which is predominantly expressed in neutrophils. These intriguing results led us to hypothesize that NADPH oxidase-mediated ROS production by BM neutrophils plays a critical role in initiating emergency granulopoiesis during acute inflammation. To further understand the role ROS in emergency granulopoiesis, we will continue to investigate whether neutrophil-dependent ROS production is required for acute inflammation-induced emergency granulopoiesis. In addition, we will provide evidence that ROS produced by neutrophils regulate emergency granulopoiesis via a paracrine mechanism and Identification of the target of ROS in emergency granulopoiesis will be a major task for this research. Results from this study will provide novel therapeutic strategy to promote immune reconstitution and manipulate granulopoiesis after BM transplantation.

英文关键词： bone marrow niche;granulopoiesis;neutrophil;ROS;hematopoietic stem/progenitor cell