Oxidized Phospholipids in Vascular Pathobiology

血管病理学中的氧化磷脂

• 批准号: 7615095
• 负责人: Roy L Silverstein
• 金额: $ 228.17万
• 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: 2007-08-06 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615095
• 关键词: Oxidized; Phospholipids; Vascular; Pathobiology

DESCRIPTION (provided by applicant): The goal of this Program is to develop a mechanistic understanding of the link between lipid oxidation and vascular pathology. The senior research team is a highly interactive multidisciplinary group with a broad range of shared expertise, including cell biology, chemical biology, biochemistry, and immunology. The 4 interrelated projects will test the hypothesis that oxidation of phospholipids in lipoproteins and cell membranes creates specific ligands for vascular cell receptors, transporters, and enzymes that then drastically alter cellular function and contribute to the pathogenesis of inflammatory diseases, including atherosclerosis. Project 1 will combine biophysical and clinical studies to define the chemical structures, biophysical properties, and oxidative pathways that participate in the formation, decay, and receptor binding activities of a novel family of specific oxidized phospholipid ligands of the Class B scavenger receptor CD36. This project will also assess the clinical relevance of specific oxidized phospholipids in human athero-sclerosis. Project 2 will determine how vascular cells clear biologically active and toxic components of oxLDL by defining the fate of extracellular oxidized phospholipids, characterizing transporters and transport mechanisms of oxidized phospholipids, and determining signaling pathways connecting oxLDL and phospholipids to cell viability. Project 3 will define complex mechanisms that regulate expression and activity of monocyte/macrophage 15- lipoxygenase, the enzyme responsible for producing 13-HPODE, an oxidation product of linoleic acid and a prominent oxidized lipid found in atheroma. Project 4 will define vascular cell signaling pathways initiated by binding of specific oxidized phospholipids to CD36, focusing on how this signaling cascade modulates foam cell formation, inflammatory responses, and metabolic pathways. An Administrative Core and 2 scientific cores, "Analytic and Synthetic Chemistry" and "Monocyte/Macrophage Cell Biology" strengthen the Program by providing well characterized, uniform-quality cellular, animal, and chemical reagents.

描述(由申请人提供)： 本项目的目标是从机理上理解脂质氧化和血管病理之间的联系。高级研究团队是一个高度互动的多学科小组，拥有广泛的共享专业知识，包括细胞生物学、化学生物学、生物化学和免疫学。这4个相互关联的项目将检验这一假设，即脂蛋白和细胞膜中的磷脂氧化产生血管细胞受体、转运体和酶的特定配体，然后显著改变细胞功能，并导致包括动脉粥样硬化在内的炎症性疾病的发病。项目1将结合生物物理和临床研究来确定参与B类清道夫受体CD36的一类新的特定氧化磷脂配体的形成、衰退和受体结合活性的化学结构、生物物理性质和氧化途径。该项目还将评估特定的氧化磷脂在人类动脉粥样硬化中的临床相关性。项目2将通过定义细胞外氧化磷脂的命运，表征氧化磷脂的转运体和转运机制，以及确定连接oxLDL和磷脂与细胞活力的信号通路，确定血管细胞如何清除oxLDL的生物活性和毒性成分。项目3将确定调节单核/巨噬细胞15-脂氧合酶表达和活性的复杂机制，该酶负责产生13-HPODE，亚油酸的氧化产物和动脉粥样硬化中发现的一种突出的氧化脂质。项目4将定义由特定的氧化磷脂与CD36结合而启动的血管细胞信号通路，重点是该信号级联如何调节泡沫细胞的形成、炎症反应和代谢通路。一个行政核心和两个科学核心，“分析和合成化学”和“单核/巨噬细胞生物学”，通过提供具有良好特征的、统一质量的细胞、动物和化学试剂来加强该计划。