SERUM AMYLOID A PROTEIN--ROLE IN ATHEROGENESIS

该提案阐述了慢性炎症性疾病-- 在老龄化的人口中很常见-加速发展 动脉硬化。在急性期反应期间，血清淀粉样蛋白A 蛋白质(A-SAA)，一种载脂蛋白，增加了1000倍，成为一种 高密度脂蛋白(HDL)的主要成分。尽管激烈的 现代对高密度脂蛋白粒子的兴趣，它的目的论作用 炎症时高密度脂蛋白载脂蛋白组成的变化 未知。我们认为A-SAA介导了高密度脂蛋白的重塑 在此过程中适应该粒子的修改的生理需求 炎症，即将磷脂输送到炎症部位。 A-SAA的慢性持续使高密度脂蛋白调节逆转的能力降低 胆固醇转运与低密度脂蛋白的保护作用 氧化修饰提供了增加的原因 慢性炎症性疾病患者的死亡率 心血管疾病。 除了急性A期SAA亚家族外，我们还发现了新的 人(C-SAA)和小鼠(SAA5)的载脂蛋白分子 现在组成SAA大家庭的是什么。这些形成了一个不同的亚家族 在结构上与A-SAA不同，并且它们是构成的事实 在正常的高密度脂蛋白上，它们占总SAA的95%以上 粒子。我们认为这些在这一功能中发挥了作用。 通过促进颗粒间的脂质交换使颗粒处于健康状态 脂蛋白颗粒。鉴于高密度脂蛋白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， 在动物模型上的实验是必不可少的补充 机械学研究。我们计划使用我们拥有的转基因小鼠 生成以研究SAA的两个子家族之间的相互作用 超家族及其对高密度脂蛋白的影响 以及高密度脂蛋白是否会促进动脉粥样硬化。

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.