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.

血管细胞粘附分子1的氧化应激和表达 （VCAM-1）在血管内皮细胞上是早期特征 动脉粥样硬化和其他炎症性疾病的发病机理。 我们 最近已经证明了氧化还原（氧化还原）之间的联系 敏感的调节机制和血管的表达 内皮细胞基因，例如VCAM-1，与早期有关 动脉粥样硬化的炎症过程。探索 动脉粥样硬化的分子决定因素，该建议将表征 通过修饰低密度的分子调节机制 脂蛋白（LDL）调节人血管中VCAM-1基因的表达 内皮细胞并确定特定的氧化还原 介导这种作用的敏感转录调节因子。 使用综合免疫学，生化，细胞和分子 培养的人血管内皮细胞中的生物学方法， 修饰的LDL的调节作用，均被氧化和糖化，如 主要调节剂和作为VCAM-1的细胞因子激活的调节剂， 将定义ICAM-1和E-选择素。 这种联合方法将是 用于定义修饰的LDL中的特定氧化剂化合物 调节VCAM-1表达。 使用这些定义的氧化剂，体外 使用合成寡核苷酸提出了“敲除”方法 定义特异性，内源表达的转录的作用 内源VCAM-1基因调节中的调节因子 表达。