Endothelial Cell Activation and Apoptosis in Atherogenesis

动脉粥样硬化及其并发症，包括斑块破裂，是美国发病率和死亡率的主要原因。有大量的病理学、流行病学和实验证据将动脉粥样硬化与炎症联系起来。更多的病理和实验证据表明，血管细胞的凋亡有助于动脉粥样硬化病变的进展和斑块破裂。然而，到目前为止，还没有直接的实验证据表明内皮细胞的激活或凋亡是动脉粥样硬化病变形成和发展或斑块破裂的先决条件。这一建议的中心假设是，内皮细胞激活和凋亡是动脉粥样硬化形成过程中的重要事件。这项建议的目的是在体外和体内模型中研究参与内皮细胞激活和凋亡的信号通路。我们将重点关注FADD(Fas相关死亡结构域包含蛋白)，我们已经证明FADD参与了对控制炎症反应的关键转录因子NF-v，kB的调节，以及对细胞凋亡的信号传递。为了实现这一目标，我们提出了以下具体目标：1)确定FADD在调节核因子-kB激活中的作用；2)确定参与调节核因子-kB的FADD复合体的成分；3)确定阻断内皮细胞激活和凋亡在急性炎症反应中的作用。 4)利用目的3与载脂蛋白E-/-杂交的转基因小鼠，确定内皮细胞激活和凋亡在动脉粥样硬化病变形成中的作用。

Atherosclerosis and its complications, including plaque rupture, are the major cause of morbidity and mortality in the United States. There is abundant pathological, epidemiological and experimental evidence linking atherosclerosis and inflammation. Additional pathological and experimental evidence suggests that apoptosis of vascular cells contributes to atherosclerotic lesion progression and plaque rupture. However, there is, as yet, no direct experimental evidence demonstrating that endothelial cell activation or apoptosis is prerequisite for atherosclerotic lesion formation and progression or for plaque rupture. The central hypothesis of this proposal is that endothelial cell activation and apoptosis are important events in atherogenesis. The goal of this proposal is to investigate the signaling pathways involved in endothelial cell activation and apoptosis in both in vitro and in vivo models. We will focus on FADD (Fas-associated death domain-containing protein), which we have shown is involved in the regulation ofNF-v,kB, a key transcription factor controlling inflammatory responses, as well as in signaling for apoptosis. To accomplish this goal we propose the following Specific Aims: 1) to define the role of FADD in the regulation of NF-kB activation; 2) to identify components of the FADD complex involved in regulation of NF-,kB; 3) to determine the effect of blockade of endothelial activation and apoptosis in acute inflammatory responses using inducible, endothelial-restricted transgenes that inhibit NF-vd3 activation or block caspases; and 4) to determine the role of endothelial cell activation and apoptosis in atherosclerotic lesion formation using the transgenic mice generated and characterized in Aim 3 crossed with ApoE-/-.