SPLA2--INFLUENCE ON LIPOPROTEIN METABOLISM

描述（改编自申请人摘要）：本提案涉及 该论文认为，慢性炎症过程-常见于老年人， 人口-加速动脉粥样硬化的发展。 炎症 可以是全身性的，例如与慢性风湿性关节炎相关的 疾病，或局限于早期动脉粥样硬化病变。 此处脂质 过氧化反应会触发炎症基因的表达， 参与动脉粥样硬化形成。 炎症诱导多种代谢 其中两种变化与HDL的调节有关 新陈代谢. 这些都是伴随诱导细胞因子的分泌 非胰腺磷脂酶A2（sPLA 2）和血清淀粉样蛋白A蛋白（SAA）。 这两种蛋白质在炎症液体中增加数百倍， 循环和显着romodels高密度脂蛋白颗粒。 代谢 这种重塑的影响是显而易见的重要性，因为HDL是 与抗动脉粥样硬化的蛋白质相关。 有大量证据表明磷脂酶A2水解HDL促进 脂质通过该颗粒输送到细胞。 调查人员提出， sPLA 2和SAA对HDL的这种调节有利于急性防御 修复过程。 然而，当sPLA 2和SAA异常产生时， 在慢性炎性疾病期间或在早期动脉粥样硬化损伤中， 这些正常防御性分子的脂质递送促进动脉粥样硬化形成。 研究人员证实了这种脂质输送与 在人sPLA 2过表达转基因小鼠模型中， 疾病 该模型中的血管脂质沉积是对照组的5倍。 与同窝小鼠相比，sPLA 2过表达小鼠对 高脂肪饮食。 本建议旨在探讨这一点的重要性， 更深入的研究，并研究两种机制，可以解释这一点 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.