NUCLEAR FACTOR KAPPA BETA AND THE INITIATION OF THE ATHEROSCLEROTIC LESION

核因子 Kappa Beta 与动脉粥样硬化病变的发生

• 批准号: 6477453
• 负责人: Tucker O Collins
• 金额: $ 4.85万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6477453
• 关键词: atherosclerotic plaque; gene expression; gene induction /repression; genetic regulation; genetically modified animals; human tissue; laboratory mouse; nuclear factor kappa beta; protein kinase; vascular endothelium

Vascular endothelium forms a dynamic interface between blood elements and peripheral tissues. Endothelial cells can undergo changes in function that are critical to normal physiological processes, and nonadaptive alterations that are important in atherogenesis. Multiple genes relevant to the initiation of the atherosclerotic lesion have functional nuclear factor-kappaB) elements. Activation of this transcription factor may coordinate the expression of numerous endothelia products which are important in the initiation and progression of atherosclerotic lesions. Increased expression of the NF-kappaB inhibitors decreases NF-kappaB activation and diminishes expression of kappaB-dependent genes. This regulatory mechanism insures that induction of kappaB is transient and that the activated endothelial cell returns to a quiescent state. This dynamic balance may be offset by the agents associated with the onset of atherogenesis. A series of interrelated studies are proposed under three Specific Aims to test the hypothesis that the NF-kappaB/IkappaB autoregulatory system plays an important role in the formation of atherosclerotic lesions. Multiple proatherogenic agents that can activate NF-kappaB use different signal transduction pathways that all converge on one common target, IkappaB-alpha. Inducible phosphorylation of this constitutively phosphorylated inhibitor leads to degradation of the inhibitor and subsequent translocation of the transcriptional activator into the nucleus. In the First Specific Aim, both the constitutive and the inducible kinases controlling activation of the transcription factor system will be identified and putatively novel kinases molecularly cloned. In the Second Specific Aim, the activation state of the transcription factor system will be correlated with initiation and progression of atherosclerotic lesions in both an animal model and human specimens. In the Third Specific Aim, the relevance of this regulatory system to atherosclerotic lesion formation in vivo will be tested in atherosclerosis-susceptible murine models. Atherosclerosis will be examined in animals with targeted mutations in the p50 component of NF-kappaB, and in transgenic animals in which IkappaB-alpha expression is specifically dysregulated in endothelial cells. The results of these studies should determine the role of the NF-kappaB/IkappaB autoregulatory system in the initiation and progression of atherogenesis.

血管内皮形成血液之间的动态界面 元素和周围组织。 内皮细胞可以经历 对正常生理至关重要的功能变化 过程和非适应性改变很重要 动脉粥样硬化。 与启动有关的多个基因 动脉粥样硬化病变具有功能性核因子 - 卡帕布） 元素。该转录因子的激活可能会协调 表达许多重要的内皮产品 动脉粥样硬化病变的启动和进展。 增加 NF-kappab抑制剂的表达降低了NF-kappab 激活和减少Kappab依赖性基因的表达。 这种调节机制确保诱导kappab是 瞬态，激活的内皮细胞返回静止 状态。 这种动态平衡可能被关联的代理所抵消 随着动脉粥样硬化的开始。 一系列相互关联的研究是 提出的三个特定目的是检验的假设 NF-kappab/ikappab自动调节系统起着重要作用 在动脉粥样硬化病变的形成中。 多个促进质基 可以激活NF-kappab的代理使用不同的信号转导 所有的途径都融合了一个常见目标Ikappab-Alpha。 该组成型磷酸化的诱导磷酸化 抑制剂会导致抑制剂降解及随后的 转录激活因子转移到核中。 在 构成性激酶和诱导激酶的第一个特定目标 控制转录因子系统的激活将是 鉴定并推测的新型激酶分子克隆。 在 第二个特定目的，即转录因子的激活状态 系统将与启动和发展相关 动物模型和人类的动脉粥样硬化病变 标本。 在第三个特定目的中，与此相关性 在体内进行动脉粥样硬化病变形成的调节系统将是 在动脉粥样硬化敏感的鼠模型中进行了测试。动脉粥样硬化 将在P50中具有靶向突变的动物中检查 NF-kappab的组成部分，以及在其中的转基因动物中 ikappab-α表达在内皮中特异性失调 细胞。 这些研究的结果应确定 NF-kappab/ikappab启动中的自动调节系统 动脉粥样硬化的进展。