Oxidized Phospholipids in Vascular Pathobiology

描述（由申请人提供）： 该计划的目标是建立对脂质氧化和血管病理学之间联系的机械理解。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测试脂蛋白和细胞膜中磷脂的氧化为血管细胞受体、转运蛋白和酶产生特异性配体的假设，这些受体、转运蛋白和酶然后急剧改变细胞功能并有助于炎症性疾病（包括动脉粥样硬化）的发病机制。项目1将结合联合收割机生物物理学和临床研究，以确定化学结构，生物物理学特性和氧化途径，参与形成，衰变和受体结合活性的一个新的家庭的特定氧化磷脂配体的B类清道夫受体CD 36。该项目还将评估特定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蛋白和转运机制，并确定连接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将定义调节单核细胞/巨噬细胞15-脂氧合酶的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显著氧化脂质。项目4将定义由特定氧化磷脂与CD 36结合引发的血管细胞信号通路，重点关注这种信号级联如何调节泡沫细胞形成，炎症反应和代谢途径。一个行政核心和两个科学核心，“分析和合成化学”和“单核细胞/巨噬细胞生物学”通过提供良好表征，统一质量的细胞，动物和化学试剂来加强该计划。

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.