Lipid peroxidation and apoptotic cell recognition

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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.