The long-term objectives of this work are to understand how enzyme systems within mammalian photoreceptor cell outer segments contribute to the renewal of their phospholipids by molecular replacement and how these enzyme systems functions to protect the membranes from the damaging effects of photo-oxidized molecules.
The specific aims of the proposed research are 1) to estimate the overall capacity by endogenous replacement (acylation-deacylation) mechanisms, 2) to investigate the role played by these mechanisms in determining the final fatty acid and phospholipid molecular species composition of the outer segment membranes, 3) to determine how quickly and under what conditions the photo-oxidation products of polyunsaturated fatty acids, particularly those of 22:6, accumulate in outer segment membranes and how the enzymes that remove and replace them with intact fatty acids are stimulated, either by the presence of oxidized fatty acids in phospholipids or by other correlates of oxidizing conditions, and 4) to determine whether some subclasses or molecular species of other segment phospholipids are more frequently modified by the endogenous acylation-deacylation reactions, and, if so, whether this is related to a) the need to change the molecular species and fatty acid composition of newly synthesized phospholipids (which are now known to differ from their final composition), b) the greater susceptibility of some molecular species (for example, di-22:6) to photo-oxidative damage, or c) the possible function of some molecular species as donors of fatty acids to other phospholipids or proteins. We wish to understand how the polyunsaturated fatty acids of outer segment membranes, which are very likely the primary targets and subsequent agents of photo-oxidative damage to the retina, tare removed and replaced by molecular retailoring enzyme systems within the outer segment membranes themselves. Recent research has shown that these enzyme systems also play a role in establishing and maintaining the normal fatty acid and phospholipid composition of these membranes. The proposed research is therefore highly relevant to the prevention or retardation of age, disease or drug-related retinal degeneration induced primarily or secondarily by light and/or oxidizing conditions.
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