Our 5-year plan continues to focus on, but is not limited to, the causes and consequences of disturbed ion homeostasis, with emphasis on calcium. Lens electrolytes, especially calcium are essential to normal lens function and have already been implicated in numerous pathological pathways. Our approach is to study in detail potentially important physiological processes which may depend upon calcium. Our investigation will concentrate on several established models of cataract,, including diabetic cataract as produced in alloxan treated rabbit or galactosemic rats, ultraviolet irradiation and x-irradiation cataracts in rabbits and several lipid-related cataracts: U18666A and lysophosphatidylcholine. To help ascertain whether intracellular calcium is always involved in the opacification proces, intracellular calcium measurements, both in clear and opaque regions of a given lens will be obtained. Measurements will also include free and bound levels of total calcium and intracellular pH, recently found to be associated with calcium-related opacification and aggregation of crystallins. In addition, the possibility of therapeutic intervention will be explored by studying a number of putative calcium- entry blockers, concentrating first on cultured lenses and epithelial cells exposed to calcium-enriched media and then various experimental cataracts. The other major area of study will focus on how ion homeostasis is disrupted and how the lens either adapts or attempts to restore equilibrium or achieve a new steady state. Thus, in cultured rabbit, rat and human lenses (postmortem), as well as in epithelial cells in tissue culture,k cell membranes will be investigated for normal physiologic function. Membrane integrity will be assessed by voltage and conductance measurements as well as flux analysis of the major ions and metabolites such as glucose, all of which may be sensitive to excess calcium. Three primary causes of membrane deterioration will be explored, viz. modification of membrane sulfhydryl groups and endogenous oxidants such as selenium or hydrogen peroxide;l alteration of membranes due to phospholipid degradation induced by calcium-activated phospholipase A2; and damage to membranes by osmotic stress already known to be a factor in diabetic models of cataract. Experiments are planned to investigate whether these types of insults might explain calcium accumulation characteristic of human cataracts.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY003681-12
Application #
3258106
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1981-05-01
Project End
1995-04-30
Budget Start
1992-05-01
Budget End
1993-04-30
Support Year
12
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Oakland University
Department
Type
Schools of Arts and Sciences
DUNS #
City
Rochester
State
MI
Country
United States
Zip Code
48309
Hightower, K; McCready, J (1997) The role of calcium in UVB-induced damage in irradiated ocular lenses. Photochem Photobiol 65:155-60
Hightower, K R (1995) The role of the lens epithelium in development of UV cataract. Curr Eye Res 14:71-8
Hightower, K R; McCready, J P; Borchman, D (1994) Membrane damage in UV-irradiated lenses. Photochem Photobiol 59:485-90
Hightower, K R (1994) A review of the evidence that ultraviolet irradiation is a risk factor in cataractogenesis. Doc Ophthalmol 88:205-20
Hightower, K; McCready, J (1994) Selenite-induced damage to lens membranes. Exp Eye Res 58:225-9
Hightower, K R; Reddan, J R; McCready, J P et al. (1994) Lens epithelium: a primary target of UVB irradiation. Exp Eye Res 59:557-64
Hightower, K; McCready, J (1993) Comparative effect of UVA and UVB on cultured rabbit lens. Photochem Photobiol 58:827-30
Hightower, K; McCready, J (1992) Physiological effects of UVB irradiation on cultured rabbit lens. Invest Ophthalmol Vis Sci 33:1783-7
Hightower, K; McCready, J (1992) Mechanisms involved in cataract development following near-ultraviolet radiation of cultured lenses. Curr Eye Res 11:679-89
Hightower, K R; McCready, J P (1991) Effect of selenite on epithelium of cultured rabbit lens. Invest Ophthalmol Vis Sci 32:406-9

Showing the most recent 10 out of 22 publications