TARGETED DISRUPTION OF THE 5-LIPOXYGENASE GENE IN MICE

酶5-脂氧合酶催化的第一步，在形成 白三烯 这些化合物表现出广泛的生物活性， 包括趋化动力学和趋化活性的作用， 粒细胞，支气管痉挛作用，微血管诱导 导致血浆渗漏和刺激气道粘膜的渗透性 分泌物 5-脂氧合酶抑制剂和白三烯受体的用途 拮抗剂已经将白三烯及其作用与 炎性疾病如过敏性鼻炎的病理生理学， 哮喘和肠道疾病，但非特异性药物作用和残留 白三烯的合成阻碍了对 健康和疾病中的白三烯。 我们建议进行实验 为了阐明5-脂氧合酶途径在小鼠中的作用， 同源重组完全消除基因技术 功能和由此产生的白三烯形成。 5-脂氧合酶基因 将在正常小鼠中详细研究表达， 染色体位点特征。 5-脂氧合酶靶向构建体 将被植入胚胎干细胞和携带 将产生失活基因。 纯合无效等位基因小鼠将 研究了5-脂氧合酶基因的表型后果 失活和几种髓样细胞类型的特征在于 生物化学和功能参数。 最后，几个 将测试鼠体内炎症和过敏性模型， 5-脂氧化酶产物的参与。 我们希望这些研究能够 对5-脂氧合酶基因的功能有一个完整而清晰的了解 在一个单一的，确定的物种。

The enzyme 5-lipoxygenase catalyzes the first step in the formation of leukotrienes. These compounds exhibit a broad range of biological effects including chemokinetic and chemotactic activity towards granulocytes, bronchospastic action, induction of microvascular permeability leading to plasma leakage and stimulation of airway mucous secretion. The use of 5-lipoxygenase inhibitors and leukotriene receptor antagonists have linked the leukotrienes and their actions to the pathophysiology of inflammatory disorders such as allergic rhinitis, asthma and bowel disease, but non-specific drug effects and residual leukotriene synthesis have prevented a clear picture of the role of leukotrienes in health and disease. We propose to undertake experiments to clarify the role of the 5-lipoxygenase pathway in mice by using the technique of homologous recombination to completely abrogate gene function and resultant leukotriene formation. 5-Lipoxygenase gene expression will be studied in detail in normal mice and the gene and chromosomal locus characterized. A 5-lipoxygenase targeting construct will be inserted into embryonic stem cells and mice carrying the inactivated gene will be generated. Homozygous null allele mice will be investigated fore the phenotypic consequences of 5-lipoxygenase gene inactivation and several myeloid cell types will be characterized with respect to biochemical and functional parameters. Finally, several murine in vivo inflammatory and anaphylactic models will be tested for the involvement of 5-lipoxygenase products. We expect these studies to give a complete and clear insight into 5-lipoxygenase gene function within a single, defined species.