TRANSCRIPTIONAL CONTROL OF LEUKOCYTE ADHESION MOLECULES

血白细胞与血管内皮细胞的黏附是一种 在各种病理生理过程中必不可少的一步。在过去 在项目期间，鉴定了两个可诱导的黏附分子和 在本计划项目中详细描述了这些特点。两种内皮细胞- 白细胞黏附分子-I(ELAM-1或E-选择素)与血管细胞 黏附分子(VCAM-1)在体外培养的内皮细胞中的表达 暴露于细胞因子白介素1β或肿瘤坏死因子- 阿尔法。ELAM-1在人血管内皮细胞上选择性表达 炎症部位的微血管。VCAM-1是一种单核选择性 血管内皮细胞表达的白细胞黏附分子 免疫和非免疫性炎症反应与动脉粥样硬化 如树突状细胞。对监管的详细了解 这些细胞因子诱导的分子的表达可能提供重要的 对炎症/免疫过程控制的见解。 具体目标1：确定核因子-kB家族成员在 细胞因子诱导ELAM-1基因表达的激活和抑制。 特定目标2：鉴定具有核因子-kB功能的内皮抑制物 调节细胞因子诱导的ELAM-1基因的表达。 具体目标3：组装几个人类Elam-1微型基因，插入这些 构建小鼠胚系并探索转基因模式 血管内皮细胞活化模型中几种血管床的表达。

The adhesion of blood leukocytes to the vascular endothelium is an essential step in a variety of pathophysiological process. During the past project period, two inducible adhesion molecules were identified and characterized in detail in this Program Project. Both endothelial- leukocyte adhesion molecule-I (ELAM-1 or E-selectin) and vascular cell adhesion molecule (VCAM-1) are expressed by cultured endothelium after exposure to the cytokines interleukin-1beta or tumor necrosis factor- alpha. ELAM-1 is selectively expressed on human vascular endothelium in microvessels at sites of inflammation. VCAM-1 is a mononuclear-selective leukocyte adhesion molecule expressed by endothelial cells at sites of immune and non-immune inflammatory responses and atherosclerosis, as well as by dendritic cells. Detailed understanding of the regulation of expression of these cytokine-induced molecules may provide important insights into the control of inflammatory/immune processes. Specific Aim 1: Determine the role of NF-kB family members in the cytokine-induced activation and repression of ELAM-1 gene expression. Specific Aim 2: Characterize the endothelial inhibitors of NF-kB capable of regulating the cytokine-induced expression of the ELAM-1 gene. Specific Aim 3: To assemble several human ELAM-1 minigenes, insert these constructs into the germ line of mice and explore the pattern of transgene expression in several vascular beds in models of endothelial activation.