Lipid peroxidation and apoptotic cell recognition

描述(申请人提供)：细胞凋亡或程序性细胞死亡(PCD)可由外在和内在两种机制启动。这两条途径的不同之处在于，与外源性死亡受体途径不同，内源性线粒体依赖途径与多不饱和脂肪酸的过氧化以及伴随而来的丙二醛和4-羟基壬烯加合物的产生有关。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，磷脂酰丝氨酸为吞噬细胞识别提供信号。我们的结果表明，通过内源性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，提示这些脂类也可能参与吞噬细胞的信号转导。 凋亡细胞的结合和摄取似乎涉及多个冗余的受体介导的系统。本实验室以往的研究表明，β-2-糖蛋白1(B2GP1)是一种普遍存在的血浆蛋白，为吞噬细胞识别表达PS的凋亡细胞提供了分子桥梁。我们的结果表明，除了PS外，B2GP1还与其他阴离子磷脂结合，包括醛-磷脂加合物，这是通过内在途径诱导细胞凋亡而形成的。 本研究的重点在于B2GP1与乙醛-磷脂加合物和PS对凋亡细胞的结合，以及这些化合物被吞噬细胞识别的机制。主要目的是鉴定与B2GP1结合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。

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.