吞噬细胞活化氧产生的机制和调控

吞噬细胞如中性粒细胞及巨噬细胞是天然免疫系统的重要组成部分之一，也是宿主对抗细菌和真菌入侵的主要防御手段。这些细胞通过自身具备的趋化和迁移能力追捕细菌，利用细胞的吞噬功能捕获细菌，然后产生剧毒的氧自由基并释放颗粒酶以杀灭细菌。然而，这些杀菌功能在不适当的情况下被激活后, 可作用于宿主，造成在急、慢性炎症性疾病中常见的组织损伤。本项目将探讨趋化因子引起的中性粒细胞活化和产生超氧阴离子（O2ˉ）的调节机理，以便增强天然免疫功能，减少超氧阴离子对机体的损伤。在现有研究的基础上, 我们将重点对p47phox，一个整合NADPH氧化酶多个信号通路和组件的关键蛋白开展基础研究。第一部分探讨p47phox如何整合NADPH氧化酶的各组成蛋白，生成具有氧化酶活性的复合物。第二部分探讨p38MAPK通路中的蛋白激酶和磷酸酶如何对NADPH氧化酶产生正向和负向调控。阐明这些机制将有助于寻找有效的药物。

Phagocytes such as neutrophils and macrophages are important components of the innate immune system. They are also the primary means of host defense against bacteria and fungi. These cells possess chemotactic and migratory capabilities, can capture invading bacteria, and are able to release granule enzymes and toxic oxygen radicals that kill the captured microorganisms. However, when activated inappropriately, these bactericidal functions may act on the host and cause tissue injury commonly seen in inflammatory diseases. This project will investigate the mechanisms underlying neutrophil activation and superoxide production, with a goal of improving innate immunity and reducing tissue injury by oxygen radicals. Based on preliminary data, we will focus on p47phox, an organizer of NADPH oxidase components and signaling pathways. In the first part, we will investigate how p47phox bring major NADPH oxidase components together, forming a functional oxidase complex. The second part will focus on components of the p38MAPK pathway for their roles in positive and negative regulation of the oxidase. Delination of the mechanisms for NADPH oxidase activation will benefit discoveries of new drug targets, which in turn translate into the development of new immune enhancement and anti-inflammatory drugs.