TRANSCELLULAR LEUKOTRIENE BIOSYNTHESIS AND INFLAMMATION

描述（根据申请人的摘要和具体目标改编）： 脂氧合酶催化单-（S） 羟基-二十碳四烯酸（HETE）。 5-脂氧合酶（5-LO）形成 化学上复杂和有效的脂质介体家族， 参与肺动脉高压病理生理过程的白三烯 炎症性疾病 目前的白三烯生产模式， 活化的细胞需要5-脂氧合酶从可溶性， 细胞溶质区室到膜相关状态，在膜相关状态下， 辅助蛋白、5-脂氧合酶激活蛋白（5-lipoxygenase activating protein，FLAP）。 分子 控制5-LO的活化和再分布的过程很差 明白 Src同源（SH）结构域是分子内保守的氨基酸序列， 酸序列介导蛋白质：蛋白质相互作用， 酪氨酸激酶信号转导通路的基本特征。 的 应用假设脂氧合酶参与细胞信号 通过介导蛋白质的分子内结构域的转导途径： 蛋白质相互作用 总体假设是脂肪氧合酶 在细胞活化中具有重要的和以前未被认识的作用， 这与花生四烯酸酶促转化无关 转化为脂质介质。 具体目标是：1）表征蛋白质： 脂氧合酶和信号蛋白之间的蛋白质相互作用 与SH 3结构域; 2）表征蛋白质：蛋白质之间的相互作用 脂氧合酶和细胞骨架蛋白; 3）表征作用 酪氨酸激酶和丝裂原活化蛋白激酶对脂氧合酶 酶;和4）将5-脂氧合酶表征为GDP/GTP核苷酸交换 蛋白质，或作为核苷酸交换的调节剂。

DESCRIPTION (Adapted from applicant's abstract and specific aims): Lipoxygenase enzymes catalyze the formation of mono-(S) hydroxy-eicosatetraenoic acids (HETE). 5-lipoxygenase (5-LO) forms a chemically complex and potent family of lipid mediators designated leukotrienes which participate in the pathophysiology of pulmonary inflammatory disorders. The current model of leukotriene production in activated cells requires redistribution of 5-lipoxygenase from a soluble, cytosolic compartment to a membrane associated state where it engages an accessory protein, 5-lipoxygenase activating protein (FLAP). Molecular process which govern the activation and redistribution of 5-LO are poorly understood. Src homology (SH) domains are conserved intra-molecular amino acid sequences which mediate protein: protein interactions that are essential features of tyrosine kinase signal transduction pathways. The application hypothesize that lipoxygenases participate in cellular signal transduction pathways via intramolecular domains that mediate protein: protein interactions. The global hypothesis is that lipoxygenase enzymes have an important and previously unrecognized role in cellular activation that is independent of their enzymatic transformation of arachidonic acid into lipid mediators. The specific aims are to: 1) characterize protein: protein interactions between lipoxygenase enzymes and signaling proteins with SH3 domains; 2) characterize protein: protein interactions between lipoxygenase enzymes and cytoskeletal proteins; 3) characterize the effect of tyrosine kinases and mitogen-activated protein kinases on lipoxygenase enzymes; and 4) characterize 5-lipoxygenase as a GDP/GTP nucleotide exchange protein, or as a modulator of nucleotide exchange.