PHYSICIAN SCIENTIST AWARD

单核细胞刺激导致白细胞介素-1（IL-1）的产生， 用许多不同的化合物来完成。 然而，很少有人能深入了解 IL-1产生的负调节是可用的。 因此本 研究提案是一个两阶段的项目，旨在阐明控制 生产这种单核细胞。 在第一阶段，我们将开始鉴定单核细胞中1）IL-1的时程 蛋白质和基因表达，2）不同刺激对 差异IL-1基因表达，3）IL-1的药理学抑制 蛋白质或基因表达，4）花生四烯酸代谢产物在 IL-1蛋白或基因表达，5）淋巴细胞和淋巴细胞产物 在调节IL-1蛋白或基因表达中的位置。 实验将 在用LPS或其他刺激的外周血单核细胞上进行 IL-1诱导剂。 抑制实验将评估常用的 免疫调节药物（地塞米松和环孢菌素A）、环氧合酶 （吲哚美辛）和脂氧合酶（U60）对花生四烯酸的抑制 新陈代谢. IL-1蛋白表达的分析将需要使用 用于单核细胞分离、小鼠胸腺细胞 用于IL-1功能定量的生物测定和总IL-1的北方分析 使用针对IL-1 mRNA的合成寡核苷酸扩增细胞RNA。 在第二阶段，将应用免疫控制机制， 应用于肺泡巨噬细胞和结节病，我们假设， IL-1调节异常可能导致永久性残疾。 我们将 在正常肺泡巨噬细胞和结节病中鉴定1）时间过程 IL-1蛋白和基因表达的影响，2）不同刺激对 差异IL-1基因表达，3）IL-1的药理学抑制 蛋白质和基因表达，4）正常淋巴细胞的作用， 类结节病中IL-1蛋白和基因的调节作用 表情 这些研究将通过使用标准 小鼠胸腺细胞测定和IL-1 RNA的北方分析。 随着对相关抑制剂的详细研究， 治疗选择将成为免疫介导的 肺部疾病，如结节病。 调节IL-1的产生可能是 在改变预后和功能障碍方面非常重要， 疾病

Monocyte stimulation resulting in interleukin-1 (IL-1) production can be accomplished with many different compounds. Yet little insight into the negative regulation of IL-1 production is available. Therefore, this research proposal is a two-phase project aimed at elucidating control of production of this monokine. In phase one, we will begin to identify in monocytes 1) time course of IL-1 protein and gene expression, 2) the effects of different stimuli on differential IL-1 gene expression, 3) pharmacological inhibition of IL-1 protein or gene expression, 4) the role of arachidonic acid metabolites in IL-1 protein or gene expression, 5) lymphocytes and lymphocyte products' place in regulation of IL-1 protein or gene expression. Experiments will be performed on peripheral blood monocytes stimulated with LPS or other IL-1 inducers. Inhibition experiments will evaluate commonly used immunomodulatory drugs (dexamethasone and cyclosporin A), cyclooxygenase (indomethacin) and lipoxygenase (U60) inhibition of arachidonic metabolism. Analysis of IL-1 protein expression will require use of standard tissue culture techniques for monocyte isolation, mouse thymocyte bioassays for IL-1 functional quantification and Northern analysis of total cellular RNA using a synthetic oligonucleotide directed against IL-1 mRNA. In phase two, application of immunological control mechanisms will be applied to alveolar macrophage and sarcoidosis, where we hypothesize that abnormal IL-1 regulation may lead to permanent disability. We will identify in normal alveolar macrophages and in sarcoidosis 1) time course of IL-1 protein and gene expression, 2) the effects of different stimuli on differential IL-1 gene expression, 3) pharmacological inhibition of IL-1 protein and gene expression, 4) the role of normal lymphocytes, their products and those in sarcoidosis in regulating IL-1 protein and gene expression. These studies will be accomplished through use of standard mouse thymocyte assays and Northern analysis of IL-1 RNA. With pharmacologically relevant inhibitors studied in detail, new therapeutic options will then become available for immunologically mediated lung disease, such as sarcoidosis. Regulation of IL-1 production may be very important in altering prognosis and functional impairment in these diseases.