Convergence of the Cox-2 and 5-Lipoxygenase Pathways

摘要 花生四烯酸与环氧合酶或脂氧合酶反应产生前列腺素和 分别为白三烯。这些二十烷基类化合物是动态平衡和病理生理的重要调节器。 过程，包括炎症和癌症。我们之前已经描述了一种独特的催化活性 环氧合酶的诱导亚型COX-2与5-脂氧合酶产物5-羟基-2反应。 花生四烯酸。环氧合酶-2催化5-羟基花生四烯酸氧化生成半缩酮(HK) 二十碳二烯和5-羟基-前列腺素(5-OH-PGs)。这两组二十烷类化合物都是由 美国，后者直到最近才出现。我们假设这些新的二十烷类化合物起着自分泌和旁分泌的作用。 髓系、淋巴系和内皮细胞功能的调节器。我们将分析HKS和5-OH-PGs在 内皮细胞小管生成、T细胞激活和分化、受体结合和激活、激酶 信号和血小板聚集。在特定目标1中，我们将检验HKS介导内皮细胞的假设 细胞的小管发生和迁移通过激酶信号转导。我们还将分析HKS如何调节T细胞 激活和分化。在特定目标2中，我们将检验5-OH-PG与传统PG结合的假设 受体和中介信号。初步研究表明，5-羟基-前列腺素能与EP受体结合， 对血小板聚集有影响。为了验证这一假设，我们将确定5-OH-的结合亲和力 PGS作用于人前列腺素受体，并确定其作为激动剂或拮抗剂的信号转导。在……里面 具体目的3我们将分析5-羟基-前列腺素对人血小板聚集的影响。我们的研究将 大幅扩大由COX-2特异性形成的二十烷类化合物的范围。对生物学的解释 新型二十烷酸类化合物的活性将有助于更好地理解它们的生物合成酶在 炎症以及抑制前列腺素和白三烯的药物的疗效 生物合成。

Abstract The reaction of arachidonic acid with cyclooxygenase or lipoxygenase gives rise to prostaglandins and leukotrienes, respectively. These eicosanoids are important regulators of homeostatic and pathophysiologic processes, including inflammation and cancer. We have previously described a unique catalytic activity of the inducible isoform of cyclooxygenase, COX-2, in a reaction with the 5-lipoxygenase product, 5-hydroxy- arachidonic acid. COX-2 catalyzed oxygenation of 5-hydroxy-arachidonic acid gives rise to hemiketal (HK) eicosanoids as well as 5-hydroxy-prostaglandins (5-OH-PGs). Both groups of eicosanoids were discovered by us, the latter only very recently. We hypothesize that these novel eicosanoids act as autocrine and paracrine regulators of myeloid, lymphoid, and endothelial cell function. We will analyze the role of HKs and 5-OH-PGs in endothelial cell tubulogenesis, T cell activation and differentiation, receptor binding and activation, kinase signaling, and platelet aggregation. In specific aim 1 we will test the hypothesis that HKs mediate endothelial cell tubulogenesis and migration through kinase signaling. We will also analyze how HKs mediate T cell activation and differentiation. In specific aim 2 we will test the hypothesis that 5-OH-PGs bind traditional PG receptors and mediate signaling. Preliminary studies have shown that 5-OH-PGs bind at EP receptors and have an effect on platelet aggregation. To test this hypothesis we will determine the binding affinity of 5-OH- PGs at human prostanoid receptors and determine their signal transduction as agonists or antagonists. In specific aim 3 we will analyze the effect of 5-OH-PGs on the aggregation of human platelets. Our studies will substantially expand the range of eicosanoids formed specifically by COX-2. Elucidation of the biological activities of the novel eicosanoids will help better understand the function of their biosynthetic enzymes in inflammation as well as the therapeutic effects of the drugs used to inhibit prostaglandin and leukotriene biosynthesis.