The long range goal of this project is to better understand the pathobiochemical causes of cataracts. This information may lead to means for early diagnosis and nonsurgical intervention in the cataractogenic processes. Previous phases of this project have found that cataractogenic stress causes many changes in organic phosphate compounds (organic-P), including both decreased synthesis and increased efflux of phospholipid (P-lipid) precursors. These results demonstrate an increased permeability in the membranes of the cells at the surface of the lens and suggest a decreased capacity for their repair. The next phase of this research will explore the hypothesis that cataractogenesis causes similar changes in the internal cell membranes which divide the lens into separate but interacting metabolic compartments (e.g., epithelium, cortex and nucleus). These internal changes would alter the synthesis, distribution, and rate of movement of essential metabolites among different compartments within the lens and could contribute to opacification. The integrity of lens membranes and metabolic compartmentation will be studied during in vivo cataractogenesis in galactosemic rats, in human and animal lenses stressed in vitro, and in epithelial explants from human and animal lenses. These studies will determine the local concentrations and rates of synthesis of P-lipid precursors and the rates at which they move among compartments. The results from animal studies will be validated by extensive experiments with human lenses and lens tissue to study membrane permeability and the synthesis of P-lipids and their precursors. Also, the local ATP concentrations will be compared with the rates of synthesis of organic-P compounds in stressed and cataractous lenses to test the hypothesis that stress-related changes in organic-P compounds are secondary to changes in ATP. The data gathered on compartmentation of P-lipid precursors will make possible the systematic and rigorous quantification of membrane P-lipid turnover during different stages of in vivo cataractogenesis in galactosemic rats and Emory mice, and during cataractogenic stress to lenses in vitro. (Previous studies have suggested either increased or decreased P-lipid synthesis in stressed lenses.) These aims will be accomplished using radioisotopic tracer techniques and chemical and biochemical assays previously developed or adapted for studies of lenses in this laboratory. Control, cataractous and precataractous lenses and lens tissue will be dissected from humanely euthanized animals and incubated with radiolabeled metabolic precursors in vitro. Rates of synthesis of organic-P or P-lipids will be calculated from the incorporation of radiolabel and the specific radioactivity of the precursor compounds at the sites of synthesis. The results of these studies will significantly enhance our understanding of lens P-lipid metabolism, membrane integrity and repair, and the role of compartmentation in human lenses and in animal models of cataract.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Visual Sciences A Study Section (VISA)
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University of Tennessee Health Science Center
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Jernigan Jr, Howard M; Blum, Penny S; Chakrabarti, Ipsit et al. (2005) Effects of cataractogenesis on the CDP-choline pathway: increased phospholipid synthesis in lenses from galactosemic rats and 13/N guinea pigs. Ophthalmic Res 37:7-12
Liu, Ying; Blum, Penny S; Pabst, Diana M et al. (2003) Effects of cataractogenesis on the CDP-choline pathway: changes in ATP concentration and phosphocholine synthesis during and after exposure of rat lenses to sugars in vitro and in vivo. Ophthalmic Res 35:185-91
Jernigan Jr, H M; Zigler Jr, J S; Liu, Y et al. (1998) Effects of xylose on monkey lenses in organ culture: a model for study of sugar cataracts in a primate. Exp Eye Res 67:61-71
Liu, Y; Ekambaram, M C; Blum, P S et al. (1998) Galactosemic cataractogenesis disrupts intracellular interactions and changes the substrate specificity of choline/ethanolamine kinase. Exp Eye Res 67:193-202
Ekambaram, M C; Jernigan Jr, H M (1994) Rat lens choline and ethanolamine kinases: independent kinetics in intact tissue-competition in homogenates. Biochim Biophys Acta 1213:289-94
Jernigan Jr, H M; Ekambaram, M C; Blum, P S et al. (1993) Effect of xylose on the synthesis of phosphorylcholine and phosphorylethanolamine in rat lenses. Exp Eye Res 56:291-7
Jernigan Jr, H M; Desouky, M A; Geller, A M et al. (1993) Efflux and hydrolysis of phosphorylethanolamine and phosphorylcholine in stressed cultured rat lenses. Exp Eye Res 56:25-33
Desouky, M A; Geller, A M; Jernigan Jr, H M (1992) Effect of osmotic stress on phosphorylcholine efflux and turnover in rat lenses. Exp Eye Res 54:269-76
Jernigan Jr, H M (1990) Metabolism of glutamine and glutamate in human lenses. Exp Eye Res 50:597-601