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）： 该程序的目的是对脂质氧化与血管病理之间的联系发展一种机械理解。高级研究团队是一个高度互动的多学科小组，具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。 4个相互关联的项目将检验以下假设：脂蛋白和细胞膜中磷脂的氧化会为血管细胞受体，转运蛋白和酶创造特定的配体，从而极大地改变细胞功能，并有助于炎症性疾病的病原体，包括促触动性疾病。项目1将结合生物物理和临床研究，以定义参与B类可载体受体CD36的特定特异性氧化磷脂配体的新型氧化磷脂配体的新型家族的形成，衰变和受体结合活性。该项目还将评估人动脉粥样硬化中特定的氧化磷脂的临床相关性。项目2将通过定义细胞外氧化磷脂的命运，表征转运蛋白以及氧化磷脂的转运机制，确定连接OxLDL和磷脂至细胞活力的信号通路，从而确定如何通过定义细胞外氧化磷脂的命运来清除OXLDL的生物活性和有毒成分的血管细胞。项目3将定义复杂的机制，这些机制调节单核细胞/巨噬细胞的表达和活性15-脂氧合酶，脂氧合酶是负责产生13 hpode的酶，亚油酸的氧化产物和在动脉瘤中发现的显着氧化脂质的氧化产物。项目4将定义通过特异性氧化磷脂与CD36的结合引发的血管细胞信号通路，重点是该信号级联反应如何调节泡沫细胞形成，炎症反应和代谢途径。一种行政核心和2个科学核心：“分析和合成化学”和“单核细胞/巨噬细胞生物学”，通过提供良好的特征性，均匀质量的细胞，动物和化学试剂来增强该程序。