The long range goal of the project is to better understand the pathobiochemical causes of cataracts. Cataracts are the leading cause of blindness worldwide, and in the U.S. cataracts are responsible for more surgical procedures than any other cause. Better understanding of the biochemical causes and effects of cataracts eventually may lead to their early diagnosis and nonsurgical treatment. The proposed research focuses on the balance between biological stress and repair processes in lenses. Increased phospholipid (PL) synthesis occurs during formation of diabetic and galactosemic cataracts and some hereditary cataracts. This suggests the hypothesis that one mechanism by which normal lenses resist stress and prevent cumulative deterioration of cells is by regulating PL synthesis in a controlled response to provide the PL necessary for growth and for repair of damaged membranes. Lenses will be subjected to cataractogenic stress in vivo (e.g., galactosemic rats) and in culture (e.g., oxidatively stressed cultured human lens epithelial cells). Sensitive radiotracer techniques will be used to measure PL synthesis in lenses, concentric layers from lenses, and lens cells. The hypothesis predicts that PL synthesis will increase as lenses are stressed and swell, and that it will return to a baseline rate when swelling is reversed. Also, if the increased PL synthesis is for membrane growth or repair, the changes in rates of synthesis of various classes of membrane PLs should be coordinated. Finally, the hypothesis suggests that there is a threshold of stress that exceeds the ability of lenses for membrane repair. Since there is evidence that normal PL synthesis in lenses can be disrupted when stress reaches a threshold level, this could lead to a self-reinforcing cycle of membrane damage, decreased repair, and more membrane damage. If the results of the proposed experiments support these predictions and the hypothesis, then the it may be possible to find means to protect lenses and maintain stress levels below the threshold and prevent cumulative lens damage and cataract. If the hypothesis is false, then the increased PL synthesis in cataracts may only be a symptom of the degenerative process, there may be no threshold stress level, and even very low levels of damage may be cumulative and eventually cataractogenic.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007938-12
Application #
6635607
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Liberman, Ellen S
Project Start
1989-01-01
Project End
2006-04-30
Budget Start
2003-05-01
Budget End
2006-04-30
Support Year
12
Fiscal Year
2003
Total Cost
$214,500
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
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