LIPOPROTEIN/GENETIC MODIFICATION AND ADHESION MOLECULES

氧化应激与血管细胞粘附分子-1的表达 血管内皮细胞上的VCAM-1是血管内皮细胞凋亡的早期特征。 动脉粥样硬化和其他炎性疾病的发病机制。 我们 最近已经证明了氧化还原（氧化还原） 敏感的调节机制和血管内皮细胞的表达 内皮细胞基因，如VCAM-1，参与早期 动脉粥样硬化特征的炎症过程。探讨 动脉粥样硬化形成的分子决定因素，这项建议将表征 修饰低密度的分子调控机制 低密度脂蛋白对血管内皮细胞VCAM-1基因表达的调节 内皮细胞，并确定特定的氧化还原 敏感的转录调节因子介导这种效应。 利用免疫学、生物化学、细胞学和分子学的综合方法， 培养的人血管内皮细胞的生物学方法， 修饰LDL（氧化和糖化）的调节作用， 主要调节剂和作为VCAM-1的细胞因子活化的调节剂， ICAM-1和E-选择素将被定义。 这种综合方法将是 用于定义修饰LDL中的特定氧化剂化合物， 调节VCAM-1的表达。 使用这些确定的氧化剂， “敲除”方法提出，使用合成的寡核苷酸， 定义特定的内源性表达转录因子的作用， 内源性VCAM-1基因调控中的调节因子 表情

Oxidative stress and expression of the vascular cell adhesion molecule-1 (VCAM-1) on vascular endothelial cells are early features in the pathogenesis of atherosclerosis and other inflammatory diseases. We have recently demonstrated a linkage between oxidation-reduction (redox) sensitive regulatory mechanisms and the expression of vascular endothelial cell genes, such as VCAM-1, that are involved in the early inflammatory processes characteristic of atherosclerosis. To explore the molecular determinants of atherogenesis, this proposal will characterize the molecular regulatory mechanisms through which modified low density lipoprotein (LDL) regulates VCAM-1 gene expression in human vascular endothelial cells and to identify the specific oxidation-reduction sensitive transcriptional regulatory factor(s) that mediate this effect. Using an integrated immunological, biochemical, cellular, and molecular biological approach in cultured human vascular endothelial cells, the regulatory effects of modified LDLs, both oxidized and glycated, as primary regulators and as modulators of cytokine activation of VCAM-1, ICAM-1, and E-selectin will be defined. This combined approach will be used to define the specific oxidant compounds within modified LDL that regulate VCAM-1 expression. Using these defined oxidants, an in vitro "knockout" approach is proposed, using synthetic oligonucleotides, to define the role of specific, endogenously expressed transcriptional regulatory factor(s) in the regulation of endogenous VCAM-1 gene expression.