PHOSPHOLIPID OXIDATION AND THE SCAVENGER RECEPTOR

磷脂氧化和清除剂受体

• 批准号: 7337244
• 负责人: Stanley L Hazen
• 金额: $ 42.48万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7337244
• 关键词: Affinity; Apoptosis; Apoptotic; Binding; Binding Sites; Biochemical; CD36 gene; Cardiovascular Diseases; Catabolism; Cells; Choline; Classification; Clinical Research; Collaborations; Complex; Coronary artery; Cyclization; Data; Eating; Elements; Family; Foam Cells; Funding; Furans; Genetically Engineered Mouse; Glycerol; Glycerophospholipids; Goals; Host Defense; Human; Hydrolase; Inflammation; Inflammatory; Insulin Resistance; Leukocytes; Ligand Binding; Ligands; Link; Lipids; Lipoprotein Binding; Lipoproteins; Mass Spectrum Analysis; Measures; Mediating; Membrane; Metabolism; Modeling; Molecular; Molecular Conformation; Mouse Strains; Multinuclear NMR; Mus; Null Lymphocytes; Oxidants; Pathway interactions; Patients; Peptide antibodies; Phagocytosis; Phospholipase; Phospholipids; Physiological; Physiological Processes; Plasma; Platelet Activating Factor; Principal Investigator; Property; Publishing; Rate; Reporting; Research; Research Personnel; Role; Serine; Signal Transduction; Signaling Molecule; Structure; Structure-Activity Relationship; Synthesis Chemistry; Testing; Ultrasonography; Vision; acyl group; atherogenesis; base; clinically relevant; design; extracellular; furan; in vivo; insight; leukocyte activation; lipid metabolism; macrophage; macrophage scavenger receptors; monocyte; multidisciplinary; neutrophil; novel; oxidation; oxidized low density lipoprotein; particle; programs; receptor; receptor function; scavenger receptor; senescence; tandem mass spectrometry

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.

清道夫受体CD 36参与多种生理过程。除了它的作用之外， 在识别氧化低密度脂蛋白（oxLDL）、脂质积聚和泡沫细胞形成方面， CD 36的清道夫受体功能与衰老和凋亡细胞的识别有关， 将oxLDL内的配体递送到细胞中。我们最近发现了一个新的氧化胆碱家族 甘油-磷脂作为高亲和力配体的CD 36（oxPCCD 36）。一个保守的结构基序 定义了支持与CD 36的oxLDL结合位点高亲和力相互作用的截短的sn-2 结合末端γ-羟基（或氧代）和α，B不饱和羰基的酰基。 在初步的研究中，我们发现oxPCCD 36的血浆水平与oxPCCD 36的定量表达密切相关。 冠状动脉粥样硬化负荷的测量（通过IVUS）。我们还表明，它不是非氧化的 磷脂酰丝氨酸（PS），而是氧化的PS物质（oxPS），促进巨噬细胞识别 凋亡细胞通过CD 36。 对磷脂CD 36配体形成中涉及的结构或生化因素知之甚少， 或CD 36-脂质配体相互作用。此外，这些新的生物活性氧化的生理相关性 磷脂未知。该项目的总体目标是确定结构，生化 特性，形成/衰变机制，以及特定氧化的关键受体-配体相互作用 CD 36的磷脂配体。 具体目标是： 1)为了鉴定内源性磷脂氧化产物，其作为高亲和力的配体， 巨噬细胞清道夫受体CD 36，并确定关键的结构-功能关系的具体 氧化磷脂和脂质受体复合物参与凋亡细胞的吞噬作用， 动脉粥样硬化 2)明确特定oxPC和oxPS在心血管疾病中的临床相关性， 鉴定参与其体内形成和衰变/代谢的途径。