SPLA2--INFLUENCE ON LIPOPROTEIN METABOLISM

描述(改编自申请人的摘要)：本提案涉及 这一论点认为，慢性炎症过程--在老年人中常见 人群--加速动脉粥样硬化的发展。炎症 可以是系统性的，比如与慢性风湿性疾病相关的 疾病，或局限于早期动脉粥样硬化病变。这里的脂类 过氧化反应触发炎症基因的表达，这些基因很可能 参与动脉粥样硬化形成的。炎症导致多种新陈代谢 这些变化中的两个具体与高密度脂蛋白的调制有关 新陈代谢。这些都是分泌细胞因子的伴随诱导。 非胰腺磷脂酶A2(SPLA2)和血清淀粉样蛋白A(SAA)。 这两种蛋白质在炎性液体中都增加了数百倍-并且 循环，并明显改变高密度脂蛋白颗粒。新陈代谢 考虑到高密度脂蛋白是 与蛋白质相关的抗动脉粥样硬化的发展。 大量证据表明，高密度脂蛋白的磷脂酶A2水解促进 脂类通过这种颗粒向细胞输送脂质。调查人员提出， SPLA2和SAA对高密度脂蛋白的这种调节有利于急性防御 和修复过程。然而，当sPLA2和SAA产生异常时 在慢性炎症性疾病或早期动脉粥样硬化病变中， 这些通常具有防御性的分子的脂质输送促进了动脉粥样硬化的形成。 调查人员证实了这种脂类输送与 人sPLA2高表达转基因小鼠模型的动脉粥样硬化形成 疾病。在这个模型中，血管脂肪沉积是 SPLA2过表达的小鼠与产仔小鼠对 高脂肪饮食。这项提议旨在探讨这一点的重要性 更深入地发现并研究两种可以解释这一现象的机制 血管脂质沉积增强。

DESCRIPTION (Adapted from applicant's abstract): This proposal addresses the thesis that chronic inflammatory processes - common in an aging population - accelerates the development of atherosclerosis. Inflammation can either be systemic such as that associated with chronic rheumatic diseases, or localized in the early atherosclerotic lesions. Here lipid peroxidation triggers the expression of inflammatory genes that are likely involved in atherogenesis. Inflammatory induces a wide variety of metabolic changes with two of these changes relating specifically to modulation of HDL metabolism. These are the concomitant induction of cytokines of secretory non-pancreatic phospholipase A2(sPLA2) and serum amyloid A protein (SAA). Both these proteins increase hundreds of fold- in inflammatory fluids and the circulation and markedly romodels the HDL particle. The metabolic implications of such remodeling is of obvious importance given that HDL is associated with protein against the development of atherosclerosis. Substantial evidence exists that phospholipaseA2 hydrolysis of HDL promotes lipid delivery by this particle to cells. The investigators propose that this modulation of HDL by sPLA2 and SAA is beneficial for the acute defense and repair process. However, when sPLA2 and SAA are aberrantly produced during chronic inflammatory diseases or in early atherosclerotic lesions, lipid delivery by these normally defensive molecules promotes atherogenesis. The investigators confirmed the relevance of this lipid delivery to atherogenesis in a human sPLA2 overexpressing transgenic mouse model of this disease. Vascular lipid deposition in this model was five times more in the sPLA2 overexpressing mice when compared to littermates in the response to a high fat diet. This proposal seeks to explore the importance of this finding in greater depth and to study two mechanisms that could explain this enhanced vascular lipid deposition.