LIPOPROTEIN/GENETIC MODIFICATION AND ADHESION MOLECULES

脂蛋白/基因修饰和粘附分子

• 批准号: 2609169
• 负责人: Bobby Khan
• 金额: $ 8.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2001-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2609169
• 关键词: atherosclerosis; cell adhesion molecules; cytokine; enzyme linked immunosorbent assay; flow cytometry; gene expression; genetic regulation; human fetus tissue; low density lipoprotein; molecular pathology; northern blottings; oxidation reduction reaction; oxidative stress; selectins; tissue /cell culture; transcription factor; tumor necrosis factor alpha; vascular endothelium

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.

氧化应激与血管细胞黏附分子-1的表达 血管内皮细胞(VCAM-1)表达是血管内皮细胞损伤的早期特征。 动脉粥样硬化和其他炎症性疾病的发病机制。我们 最近证实了氧化还原(氧化还原)之间的联系 敏感调控机制与血管内皮生长因子的表达 内皮细胞基因，如VCAM-1，参与早期 动脉粥样硬化特有的炎症过程。要探索 动脉粥样硬化形成的分子决定因素，这一提议将表征 低密度修饰的分子调控机制 脂蛋白对血管内皮细胞黏附分子-1基因表达的调节 并鉴定内皮细胞氧化还原的特异性 敏感的转录调节因子(S)，介导这一效应。 使用集成的免疫学、生化、细胞和分子 培养人血管内皮细胞的生物学方法 氧化和糖化修饰的低密度脂蛋白的调节作用，如 作为VCAM-1细胞因子激活的初级调节因子和调节剂， ICAM-1和E-选择素将被定义。这一组合方法将是 用于定义修饰低密度脂蛋白中的特定氧化剂化合物 调节VCAM-1的表达。使用这些定义的氧化剂，在体外 “基因敲除”方法被提出，使用合成的寡核苷酸，以 确定特定的、内源性表达的转录因子的作用 内源性血管细胞黏附分子-1基因调控中的调控因子(S) 表情。