Lipid peroxidation and apoptotic cell recognition

脂质过氧化和凋亡细胞识别

• 批准号: 6931001
• 负责人: ALAN Jay SCHROIT
• 金额: $ 23.94万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-05 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931001
• 关键词: affinity chromatography; anions; apoptosis; blood proteins; cell membrane; clinical research; flow cytometry; glycoproteins; human tissue; laboratory mouse; ligands; lipid peroxides; monoclonal antibody; peroxidation; phagocytes; phagocytosis; phosphatidylserines; polymerase chain reaction; protein purification; site directed mutagenesis; tissue /cell culture; unsaturated fatty acids

DESCRIPTION (provided by applicant): Apoptosis or programmed cell death (PCD) can be initiated by both extrinsic and intrinsic mechanisms. These two pathways differ in that the intrinsic mitochondria-dependent pathway, in contrast to the extrinsic death receptor pathway, is associated with peroxidation of polyunsaturated fatty acids and the concomitant generation of malondialdehyde and 4-hydroxynonenal adducts. Many studies have shown that PCD is associated with the appearance of phosphatidylserine (PS) in the cells outer membrane leaflet, which provides a signal for phagocyte recognition. Our results indicate that initiation of apoptosis via the intrinsic pathway results in the appearance of anionic aldehyde aminophospholipid adducts on the cell surface suggesting that these lipids could also participate in phagocyte signaling. The binding and uptake of apoptotic cells appears to involve multiple redundant receptor-mediated systems. Previous studies from this laboratory have shown that beta-2-glycoprotein 1 (B2GP1), a ubiquitous plasma protein, forms a molecular bridge for the recognition of PS-expressing apoptotic cells by phagocytes. Our results indicate that B2GP1 binds, in addition to PS, other anionic phospholipids including aldehyde-phospholipid adducts formed as a result of apoptosis induced through the intrinsic pathway. This proposal focuses on the binding of B2GP1 to aldehyde-phospholipid adducts and PS on apoptotic cells and the mechanism by which these complexes are recognized by phagocytes. The main objectives are to characterize novel apoptotic cell surface ligands that bind B2GP1, map the epitopes on the protein that bind to phagocytes and to identify the B2GP1 receptor.

描述（由申请人提供）：细胞凋亡或程序性细胞死亡（PCD）可以由外在和内在机制启动。这两种途径的不同之处在于，与外在死亡受体途径相反，内在线粒体依赖性途径与多不饱和脂肪酸的过氧化以及伴随的丙二醛和4-羟基壬烯醛加合物的生成有关。许多研究表明，PCD 与细胞外膜小叶中磷脂酰丝氨酸 (PS) 的出现有关，后者为吞噬细胞识别提供信号。我们的结果表明，通过内在途径启动细胞凋亡导致细胞表面出现阴离子醛氨基磷脂加合物，表明这些脂质也可以参与吞噬细胞信号传导。 凋亡细胞的结合和摄取似乎涉及多个冗余受体介导的系统。该实验室之前的研究表明，β-2-糖蛋白1（B2GP1）是一种普遍存在的血浆蛋白，它形成了吞噬细胞识别表达PS的凋亡细胞的分子桥。我们的结果表明，除了 PS 之外，B2GP1 还结合其他阴离子磷脂，包括由于通过内在途径诱导细胞凋亡而形成的醛-磷脂加合物。 该提案的重点是 B2GP1 与凋亡细胞上的醛磷脂加合物和 PS 的结合以及这些复合物被吞噬细胞识别的机制。主要目标是表征结合 B2GP1 的新型凋亡细胞表面配体、绘制与吞噬细胞结合的蛋白质上的表位图并鉴定 B2GP1 受体。