TRANSCELLULAR LEUKOTRIENE BIOSYNTHESIS AND INFLAMMATION

描述(根据申请者的抽象和具体目标改编)： 脂肪氧合酶催化单链-(S)的形成 羟基二十碳四烯酸(HETE)。5-脂氧合酶(5-LO)形成 指定的化学复杂和有效的脂类介体家族 白三烯参与肺组织病理生理的研究进展 炎症性疾病。白三烯生产的现行模式 激活的细胞需要5-脂氧合酶从可溶性的， 胞液隔间到膜结合状态，在这种状态下它与 辅助蛋白，5-脂氧合酶激活蛋白(FLAP)。分子 控制5-LO活化和再分布的过程很差 明白了。SRC同源(SH)结构域是保守的分子内氨基 调节蛋白质的酸序列：蛋白质相互作用 酪氨酸激酶信号转导通路的基本特征。这个 脂氧合酶参与细胞信号传递的应用假说 通过分子内结构域介导蛋白质的转导通路： 蛋白质的相互作用。全球假说是脂氧合酶 在细胞激活中扮演着以前未被认识到的重要角色 这不依赖于它们对花生四烯酸的酶转化 转化为脂质调节剂。其具体目的是：1)表征蛋白质： 脂氧合酶与信号蛋白之间的蛋白质相互作用 具有SH3结构域；2)鉴定蛋白质：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的影响 4)5-脂氧合酶是一种GDP/GTP核苷酸交换 蛋白质，或作为核苷酸交换的调节器。

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.