SERUM AMYLOID A PROTEIN--ROLE IN ATHEROGENESIS

该提案提出了慢性炎症性疾病- 在人口老龄化中常见-加速发展 动脉粥样硬化 在急性期反应中，血清淀粉样蛋白A 蛋白质（A-SAA），一种载脂蛋白，增加1,000倍，成为 高密度脂蛋白（HDL）的主要成分。尽管激烈的 现代人对HDL粒子的兴趣， 炎症过程中HDL载脂蛋白组成的改变， 未知 我们认为A-SAA介导HDL的重塑， 适应该颗粒的修改的生理要求， 炎症，即磷脂递送到炎症部位。 A-SAA的慢性持续性使HDL介导逆转的能力降低 胆固醇运输和保护低密度脂蛋白， 氧化修饰提供了增加的解释， 慢性炎症性疾病患者的死亡率 心血管疾病 除了急性期A-SAA亚家族，我们还发现了新的 人载脂蛋白分子（C-SAA）和小鼠载脂蛋白分子（SAA 5）作为 现在组成了SAA家族 它们形成了一个独特的亚科 与A-SAA在结构上不同， 在正常的HDL中，它们占总SAA的95%以上， 粒子 我们认为，这些发挥作用的功能， 颗粒在健康状态下通过促进脂质之间的交换 脂蛋白颗粒。鉴于HDL在脂蛋白中的中心地位 代谢及其与其他脂蛋白的动态相互作用， 在动物模型实验是必不可少的补充更多 机械研究。 我们建议使用转基因小鼠， 研究SAA两个亚家族之间的相互作用 超家族及其如何影响HDL对其他脂蛋白的影响 以及是否存在于HDL上促进动脉粥样硬化。

The proposal addresses the thesis that chronic inflammatory diseases - common in an ageing population - accelerates the development of atherosclerosis. During the acute phase response, serum amyloid A protein (A-SAA), an apolipoprotein, increases 1,000 fold and becomes a major component of high density lipoprotein (HDL). In spite of intense modern interest in the HDL particle, the teleological role of this alteration of HDL apolipoprotein composition during inflammation is unknown. We propose that A-SAA mediate the remodelling of HDL to accommodate a modified physiological requirement for this particle during inflammation namely phospholipid delivery to sites of inflammation. Chronic persistence of A-SAA render HDL less capable of mediating reverse cholesterol transport and to protect low density lipoprotein against oxidative modification providing an explanation for the increased mortality of patients with chronic inflammatory disease from cardiovascular disease. In addition to the acute phase A-SAA subfamily, we have identified new apolipoprotein molecules in man (C-SAA) and mouse (SAA5) as members of what now constitutes a SAA family. These form a distinct subfamily differing from A-SAA in structure and the fact that they are constitutive on normal HDL where they represent more than 95% of total SAA on this particle. We propose that these play a role in the function of this particle in the healthy state by promoting lipid exchange between lipoprotein particles. Given the centrality of HDL in lipoprotein metabolism and its dynamic interaction with other lipoproteins, experiments in the animal model is essential to complement more mechanistic studies. We propose to use transgenic mice that we have generated to study the interplay between the two sub families of the SAA superfamily and how they influence HDL impacting on other lipoproteins and whether there presence on HDL promotes atherosclerosis.