LOW MW G PROTEIN (RAP) IN NEUTROPHIL ACTIVATION

中性粒细胞参与机体免疫的许多方面， 防御系统，并且是炎性细胞的组成部分。 反应 了解中性粒细胞功能是如何被激活的， 对于这些疾病的有效治疗干预， 地区 信号转导过程是由结合启动的 已知化学引诱物受体配体的结合涉及GTP结合 蛋白质（G蛋白）。 我们已经确定了一个新的低分子量G 在人类中性粒细胞中的蛋白质，称为rapl。 初步数据表明 rapl可能与中性粒细胞NADPH的蛋白质成分相互作用， 氧化酶系统，并能对氧化酶的活性产生影响， 一个重组的系统。 我们还证明了rap 1是一个 cAMP依赖性蛋白激酶的底物，这种磷酸化 通过模拟配体化学引诱物的条件/试剂增强 受体的rap 1可能能够直接与N-甲酰肽相互作用 受体，或者作为受体的附加转换器 信号传导，或作为经由Gn减弱嗜中性粒细胞活化的手段。 的 RAPL磷酸化的调节作用还有待确定， 与内源性介质抑制 中性粒细胞功能。 我们建议开发特异性的rapl探针， 纯化的rapl蛋白制剂，以研究其物理和功能 RAP在人中性粒细胞中的大分子相互作用 相互作用 Lo与中性粒细胞N-甲酰肽受体，NADPH氧化酶系统， 和其他潜在的效应物（GAP）将被检查。 的影响 RAP在调节这些相互作用中的共价修饰将是 机械地确定和定义。 拟议的研究将使 我们更好地了解调节中性粒细胞活化，以及 以阐明RAP和相关G蛋白的正常细胞作用。

The neutrophil participates in many aspects of the body's immune defense system and is an integral cellular component of the inflammatory response. An understanding of how neutrophil functions are activated and regulated is paramount for effective therapeutic intervention in these areas. The signal transduction process that is initiated by the binding of chemoattractant receptor ligands is known to involve GTP binding proteins (G proteins). We have identified a novel low molecular weight G protein In human neutrophils, termed rapl. Preliminary data indicates that rapl may interact with protein components of the neutrophil NADPH oxidase system and can produce effects on the activity of the oxidase in a reconstituted system. We have additionally shown rap1 to be a substrate for cAMP-dependent protein kinase and this phosphorylation is enhanced by conditions/agents which mimic liganded chemoattractant receptor. rap1 may be able to interact directly with the N-formyl peptide receptor, either to serve as an additional transducer of receptor signalling, or as a means to attenuate neutrophil activation via Gn. The regulatory roles of rapl phosphorylation have yet to be defined but are clearly relevant to the ability of endogenous mediators to inhibit neutrophil function. We propose to develop specific rapl probes and purified rapl protein preparations to study physical and functional macromolecular interactions of rap in the human neutrophil. Interactions of Lo with neutrophil N-formyl peptide receptor, NADPH oxidase system, and other potential effectors (GAP's) will be examined. The influence of covalent modifications of rap in regulating these interactions will be determined and defined mechanistically. The proposed studies will enable us to better understand the regulation of neutrophil activation, as well as to elucidate the normal cellular roles of rap and related G proteins.