REGULATION OF HUMAN PHAGOCYTE FUNCTION BY RAC PROTEINS

描述（改编自研究者摘要）：人吞噬细胞 白细胞在宿主防御多种 传染源 当遇到微生物时，它们经历 依赖于细胞骨架的形态和功能改变， 并且通常伴有膜呼吸爆发活动， 开始产生有毒的氧代谢物;这两个过程都是 由GTMEN监管，Rac。调查人员发现了一本小说 一类Rac效应蛋白，其被趋化性刺激激活， 人嗜中性粒细胞，p21活化蛋白激酶（PAKs）。 最近 有证据表明，这些激酶在中性粒细胞 与免疫功能相关的信号传导。 本项目将研究某些Rac依赖性中性粒细胞是否 通过阐明PAK激活过程， 并通过鉴定嗜中性粒细胞中PAK靶蛋白。 他们 将通过突变研究GTP酶激活PAK的机制， 分析Rac 1、Rac 2、Cdc 42和PAK本身。 使用纯化的组分， 完整的中性粒细胞和已建立的细胞系，上游信号的作用 除了激活Rac/Cdc 42外，还将通过以下研究阐明： 调节脂质第二信使和新的PAK结合蛋白。 到 定义PAK如何介导细胞对Rac或CdC 42的反应，他们将继续研究 下游效应子的识别。 最初，他们的研究将 专注于NADPH氧化酶组分作为PAK磷酸化靶点， 扩展到识别新的PAK激活或相互作用的中性粒细胞蛋白。 他们将对这些蛋白质进行生物化学表征并评估其作用 在PAK介导的信号通路中使用细胞方法。 这些 研究应该使我们能够进一步了解Rac/PAK调节的事件 在宿主防御和炎症性疾病中的作用

DESCRIPTION (Adapted from Investigator's abstract): Human phagocytic leukocytes play important roles in host defense against a variety of infectious agents. Upon encountering a microorganism, they undergo morphological and functional alterations dependent upon the cytoskeleton, and usually accompanied by membrane respiratory burst activity that initiates the generation of toxic oxygen metabolites; both processes are regulated by the GTPase, Rac. The investigators have identified a novel class of Rac effector proteins which are activated by chemotactic stimuli in human neutrophils, the p21-activated protein kinases (PAKs). Recent evidence indicates that these kinases play important roles in neutrophil signaling as it relates to immune functions. This project will investigate whether certain Rac-dependent neutrophil responses are mediated through PAK by elucidating the PAK activation process in more detail and by identifying PAK target proteins in neutrophils. They will investigate mechanisms of PAK activation by GTPases through mutational analysis of Rac1, Rac2, Cdc42 and PAK itself. Using purified components, intact neutrophils and established cell lines, the role of upstream signals in addition to activated Rac/Cdc42 will be elucidated through studies of regulatory lipid second messengers and of novel PAK binding proteins. To define how PAK mediated cellular responses to Rac or CdC42, they will pursue the identification of downstream effectors. Initially, their studies will focus on NADPH oxidase components as PAK phosphorylation targets and will be extended to identify novel PAK-activated or interacting neutrophil proteins. They will characterize these proteins biochemically and evaluate their role in PAK-mediated signalling pathways using cellular approaches. These studies should enable us to gain further insight in Rac/PAK regulated events in host defense and inflammatory diseases.