PHOSPHOLIPID OXIDATION AND THE SCAVENGER RECEPTOR

清道夫受体CD36参与多种生理过程。除了它的作用之外 为了识别氧化型低密度脂蛋白(OxLDL)、脂质堆积和泡沫细胞的形成， CD36的清道夫受体功能与识别衰老和凋亡的细胞有关，并且 将ox低密度脂蛋白中的配体输送到细胞内。我们最近发现了一个新的氧化胆碱家族 甘油-磷脂，作为CD36(OxPCCD36)的高亲和力配体。保守的结构主题 支持与CD36的oxLDL结合位点的高亲和力相互作用的基因被定义为：截短的sn-2 末端含有y-羟基(或氧)和a，B不饱和羰基的酰基。 在初步研究中，我们发现血浆oxPCCD36水平与 冠状动脉粥样硬化负荷的测量(通过IVUS)。我们还表明，它不是非氧化性的 磷脂酰丝氨酸(PS)，而不是氧化的PS物种(OXPS)，促进巨噬细胞识别 CD36介导的细胞凋亡。 有关磷脂CD36配体形成的结构或生化因素知之甚少。 或CD36与脂质配基的相互作用。此外，这些新的生物活性氧化的生理相关性 磷脂是未知的。这个项目的总体目标是定义结构、生化 特定氧化产物的性质、形成/衰变机制和关键的受体-配体相互作用 CD36的磷脂配体。 具体目标是： 1)确定内源性磷脂氧化产物作为高亲和力配体 巨噬细胞清道夫受体CD36和确定特定的关键结构-功能关系 氧化磷脂和脂类受体复合体与细胞凋亡和血管内皮细胞的吞噬 动脉粥样硬化的形成。 2)明确特定的oxPC和OXPS在心血管疾病中的临床相关性，并 确定参与它们在体内形成和腐烂/代谢的途径。

The scavenger receptor CD36 participates a diverse array of physiological processes. In addition to its role in recognition of oxidized low density lipoprotein (oxLDL), lipid accumulation and foam cell formation, the scavenger receptor functions of CD36 have been linked to recognition of senescent and apoptotic cells, and the delivery of ligands within oxLDL into cells. We recently identified a novel family of oxidized choline glycerol-phospholipids that serve as high affinity ligands for CD36 (oxPCCD36). A conserved structural motif that supports high affinity interactions with the oxLDL binding site of CD36 was defined: a truncated sn-2 acyl group that incorporates a terminal y-hydroxy (or oxo) and a,B unsaturated carbonyl. In preliminary studies we show that plasma levels of oxPCCD36 are strongly correlated with quantitative measures (via IVUS) of coronary artery atherosclerotic burden. We also show that it is not non-oxidized phosphatidyl serine (PS), but rather, oxidized PS species (oxPS), that promote macrophage recognition of apoptotic cells via CD36. Little is known about structural or biochemical factors involved in formation of phospholipid CD36 ligands, or CD36-lipid ligand interactions. Moreover, the physiological relevance of these novel bioactive oxidized phospholipids is unknown. The overall goals of this project are to define the structures, biochemical properties, mechanisms of formation/decay, and critical receptor-ligand interactions of specific oxidized phospholipid ligands of CD36. The Specific Aims are: 1) To identify endogenous phospholipid oxidation products that serve as high affinity ligands for the macrophage scavenger receptor CD36 and define critical structure-function relationships for specific oxidized phospholipids and lipid-receptor complexes implicated both in phagocytosis of apoptotic cells and in atherogenesis. 2) To define the clinical relevance of specific oxPC and oxPS species in cardiovascular disease, and to identify pathways involved in their in vivo formation and decay/metabolism.