FLOW SHEAR INDUCED NF-KB MEDIATED REGULATION

流动剪切诱导的 NF-KB 介导的调节

• 批准号: 6637295
• 负责人: SUMATHY MOHAN
• 金额: $ 14.45万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6637295
• 关键词: DNA binding protein; antioxidants; aorta; atherosclerosis; biological signal transduction; enzyme activity; enzyme inhibitors; free radical oxygen; gel mobility shift assay; gene expression; genetic promoter element; genetic regulation; human tissue; leukocyte adhesion molecules; molecular pathology; monocyte; northern blottings; nuclear factor kappa beta; oxidative stress; protein kinase; protein structure function; transcription factor; vascular cell adhesion molecule; vascular endothelium; western blottings

Atherosclerotic lesions typically occur in areas of low shear flow regions. The mechanisms involved in developing these lesions are poorly understood. Our long-term goal is to develop strategies for novel interventional procedures and agents to control enhanced endothelial-monocyte (En-Mn) adhesion that favors the development of the disease. Recently, we reported that prolonged low shear, as opposed to high shear stress, causes a persistent activation of the key transcriptional regulator NF- kappaB in human aortic endothelial cells (HAEC). The objective of this proposal is to identify the mediators that cause the differential activation of NF-kappaB in prolonged low and high shear stress in HAEC. The central hypothesis is that shear stress-induced reactive oxygen species (ROS) mediate activation of NF-kappaB through differential regulation of upstream signaling mechanisms. These mechanisms determine the differences in the inflammatory events mediating the development of atherogenesis in lesion prone low shear areas and resistant high shear regions. The hypothesis will be examined by three specific aims: 1) To determine the upstream signaling mechanisms that regulate the activation of NF-kappaB; 2) To ascertain the role of ROS that would possibly trigger activation of the upstream signaling kinases; and 3) To investigate the role of Ap-1 and octamer binding protein in the differential regulation of the NF- kappaB mediated vascular cell adhesion molecule (VCAM-1) gene expression in low and high shear exposed HAEC. The rationale of this study is that once the key players that regulate the persistent activation of NF-kappaB in low shear stress are identified, it will be possible to modulate the expression of NF- kappaB mediated VCAM-1 expression involved in En-Mn adhesion. The outcome would be significant because ascertaining the mechanisms involved in the NF-kappaB signaling pathway would identify key mediators that favor the enhanced En-Mn adhesion that leads to the development of the disease. This knowledge would help in developing novel therapeutic strategies for selective targeting of those mediators. Understanding of NF- kappaB signaling mechanisms in VCAM-1 regulation can also be applied to other inflammatory conditions.

动脉粥样硬化病变通常发生在低剪切流区域。 人们对这些病变发生的机制知之甚少。 我们的长期目标是制定新的介入手术和药物策略，以控制增强的内皮单核细胞（En-Mn）粘附，从而有利于疾病的发展。 最近，我们报道，与高剪切应力相反，长时间的低剪切会导致人主动脉内皮细胞 (HAEC) 中关键转录调节因子 NF-kappaB 的持续激活。 本提案的目的是确定在 HAEC 中长期低剪切应力和高剪切应力下导致 NF-kappaB 差异激活的介质。 核心假设是剪切应力诱导的活性氧 (ROS) 通过上游信号机制的差异调节介导 NF-κB 的激活。 这些机制决定了在易于病变的低剪切区域和抵抗性高剪切区域中介导动脉粥样硬化形成的炎症事件的差异。 该假设将通过三个具体目标进行检验：1）确定调节 NF-κB 激活的上游信号机制； 2) 确定ROS可能触发上游信号激酶激活的作用； 3)研究Ap-1和八聚体结合蛋白在低剪切和高剪切暴露的HAEC中NF-κB介导的血管细胞粘附分子(VCAM-1)基因表达的差异调节中的作用。 这项研究的基本原理是，一旦确定了在低剪切应力下调节 NF-kappaB 持续激活的关键因素，就有可能调节参与 En-Mn 粘附的 NF-kappaB 介导的 VCAM-1 表达。结果将是意义重大的，因为确定 NF-kappaB 信号通路中涉及的机制将确定有利于增强 En-Mn 粘附从而导致疾病发展的关键介质。 这些知识将有助于开发选择性靶向这些介质的新治疗策略。 对 VCAM-1 调节中 NF-kappaB 信号传导机制的了解也可应用于其他炎症性疾病。