NUCLEAR FACTOR KAPPA BETA AND THE INITIATION OF THE ATHEROSCLEROTIC LESION

血管内皮细胞形成血液之间的动态界面 元素和外周组织。内皮细胞可以通过 对正常生理功能至关重要的功能变化 流程和非适应性更改，这些更改在 动脉粥样硬化的形成。多个相关基因的启动 动脉粥样硬化病变具有功能性核因子-kappaB) 元素。该转录因子的激活可能会协调 多种在血管内皮细胞中起重要作用的内皮产物的表达 动脉粥样硬化病变的发生和发展。增加了 核因子-kappaB抑制剂的表达降低核因子-kappaB 激活并减少依赖kappaB的基因的表达。 这种调控机制确保了kappaB的诱导是 并且激活的内皮细胞返回到静止状态 州政府。这种动态平衡可以由关联的代理来抵消 随着动脉粥样硬化的开始。一系列相关的研究包括 在三个具体目标下提出，以检验以下假设 核因子-kappaB/IkappaB自动调节系统发挥重要作用 在动脉粥样硬化病变的形成过程中。多重致动脉粥样硬化 可激活核因子-kappaB的试剂使用不同的信号转导 所有的路径都汇聚在一个共同的目标IkappaB-Alpha上。 这一组分磷酸化的可诱导的磷酸化 缓蚀剂导致缓蚀剂的降解 转录激活剂移位到细胞核中。在 第一个特定目标，既有结构性的，也有诱导的 控制转录因子系统的激活将是 鉴定并推测是分子克隆的新的蛋白激酶。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 动物模型和人类的动脉粥样硬化病变 标本。在第三个具体目标中，这一点的相关性 体内动脉粥样硬化病变形成的调控系统将是 在易患动脉粥样硬化的小鼠模型上进行了测试。动脉硬化 将在具有p50靶向突变的动物身上进行检测 NF-kappaB的成分，以及在转基因动物中 IkappaB-α在内皮细胞中的表达特异性失调 细胞。这些研究的结果应该确定 核因子-kappaB/IkappaB自身调节系统在启动和 动脉粥样硬化的研究进展。

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.