Lipid oxidation plays a key role in human health. It is involved in normal physiological processes such as the biosynthesis of prostaglandins, thromboxanes, and prostacyclins. It is recruited in the immune response (oxidative burst) and programmed cell death (apoptosis), and contributes to changes associated with aging. It also is involved in pathological processes such as the ischemia-reperfusion injury associated with heart attacks and stroke, the development of atherosclerotic plaques, and it may have a role in the development of Alzheimer's, Batten's, and Parkinson's diseases, as well as amyotrophic lateral sclerosis, and diseases of the eye such as macular degeneration. Oxidized phospholipids may contribute to the pathogenesis of several chronic inflammatory diseases including antiphospholipid antibody syndrome, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. They may also foster platelet activation, and hence, thrombus formation pursuant to rupture of atherosclerotic plaques. Understanding of these processes on a molecular level remains primitive. The ultimate goal of our research is to bridge this gap in existing knowledge and, thereby, to provide a basis for the rational design of therapeutic measures to prevent or ameliorate the pathological consequences of lipid oxidation. Our unique approach uses model studies and chemical logic to predict the structures of molecules produced in vivo by lipid oxidation, and to uncover their biologically important chemical interactions with other biomolecules. This modus operandi led to the discoveries of levuglandins (LGs), isoLGs, and a novel family of bioactive phospholipids. Total syntheses provide samples of these molecules that facilitate their detection in vivo, and studies of their reactions with other biomolecules and of biological activities. The immediate goals for the next five years are: (1) to determine the biological involvements of oxidized phospholipids as receptor ligands, membrane components, and electrophiles that can alter proteins and other biological nucleophiles; (2) to develop antielectrophiles and understand the processes that can alter and/or detoxify membrane-bound oxidized phospholipids; (4) to unravel the oxidative modifications of ethanolamine phospholipids; (3) to explore the utility of CEP epitopes as markers of retinal and neuronal membrane oxidation; and (5) to confirm the utility of isoLG-protein adducts as markers of an oxidative injury that is an independent defect associated with atherosclerosis but not with either total cholesterol or LDL levels and to determine factors that lower isoLG levels in vivo.
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