Lipid peroxidation and apoptotic cell recognition

描述（由申请人提供）：细胞凋亡或程序性细胞死亡（PCD）可由外在和内在机制引发。这两种途径的不同之处在于，与外在死亡受体途径相反，内在的多巴胺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与细胞外膜磷脂酰丝氨酸（PS）的出现有关，PS为吞噬细胞识别提供信号。我们的研究结果表明，通过内在途径启动细胞凋亡的结果在细胞表面的阴离子醛氨基磷脂加合物的外观，这表明这些脂质也可以参与吞噬细胞信号转导。 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。本实验室以前的研究表明，β-2-糖蛋白1（B2 GP 1），一种普遍存在的血浆蛋白，形成了吞噬细胞识别PS表达凋亡细胞的分子桥梁。我们的研究结果表明，B2 GP 1结合，除了PS，其他阴离子磷脂，包括磷脂酰肌醇磷脂加合物形成的结果，通过内在途径诱导的细胞凋亡。 该建议的重点是结合B2 GP 1的磷脂酰肌醇-磷脂加合物和PS对凋亡细胞和这些复合物被吞噬细胞识别的机制。主要目标是表征结合B2 GP 1的新型凋亡细胞表面配体，绘制结合吞噬细胞的蛋白质上的表位，并鉴定B2 GP 1受体。

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.