NUCLEAR FACTOR KAPPA BETA AND THE INITIATION OF THE ATHEROSCLEROTIC LESION

血管内皮在血液和血管之间形成动态界面 元素和外周组织。 内皮细胞可以经历 对正常生理功能至关重要的功能变化 过程和非适应性改变， 动脉粥样硬化 多个基因相关的启动 动脉粥样硬化病变具有功能性核因子-κ B） 元素这种转录因子的激活可以协调 许多内皮细胞产物的表达，这些产物在 动脉粥样硬化病变的发生和发展。 增加 NF-κ B抑制剂的表达降低NF-κ B 激活并减少κ B依赖基因的表达。 这种调节机制确保了kappaB的诱导是 短暂的，激活的内皮细胞返回到静止状态， 状态 这种动态平衡可能会被相关联的代理人抵消 与动脉粥样硬化的发生有关。 一系列相互关联的研究是 根据三个具体目标提出，以检验假设， NF-kappaB/IkappaB自身调节系统在肿瘤的发生发展中起重要作用 动脉粥样硬化病变的形成。 多发性致动脉粥样硬化 可以激活NF-κ B的试剂使用不同的信号转导 这些通路都集中在一个共同的目标上，IkappaB-α。 这种组成性磷酸化的 抑制剂导致抑制剂降解， 转录激活因子易位到细胞核中。 在 第一个具体目标，组成型和诱导型激酶 控制转录因子系统的激活将是 鉴定和纯化分子克隆的新激酶。 在 第二个特定目标，转录因子的激活状态 系统将与启动和进展相关 动物模型和人的动脉粥样硬化病变 标本 在第三个具体目标中， 调节系统动脉粥样硬化病变的形成在体内将是 在动脉粥样硬化易感小鼠模型中进行测试。粥样硬化 将在p50靶向突变的动物中进行检查 在转基因动物中， 内皮细胞中IkappaB-α表达特异性失调 细胞 这些研究的结果应确定 NF-kappaB/IkappaB自身调节系统在启动和 动脉粥样硬化的进展。

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.