The objectives are to determine the importance of the process of cholesterol biosynthesis in regulating lens growth and development and to describe the role of cholesterol in maintaining the structural and functional properties of the plasma membrane of the lens fiber cell. This information should contribute to our understanding of the factors which control lens growth and development and to understanding the biochemical basis of the U18666A experimental cataract as well as human senile cataracts. Three major hypotheses are presented with specific objectives to test each one. Hypothesis one is that """"""""the ocular lens satisfies most of its requirements for cholesterol by de novo synthesis"""""""". This hypothesis will be tested, in part, i) by comparing the absolute rates of sterol synthesis (measured with 3H2-0) by the intact lens with rates of accumulation of sterol mass; ii) by measuring the capacity of lens epithelial cells in culture to supply its cholesterol by de nova synthesis versus uptake from lipoproteins; iii) by correlating the activity of HMG CoA reductase (the rate limiting enzyme in sterol synthesis) in cultured lens epithelial cells with the rate of growth of these cells. Hypothesis two is that """"""""DNA replication and division of lens epithelial cells and ultimately lens growth and development is dependent upon the process of cholesterol biosynthesis in these cells."""""""" This hypothesis will be tested, in part, by correlating inhibition of sterol metabolism with DNA replication and growth of lens epithelial cells in culture and by measuring DNA replication (from incorporation of 3H thymidine) in lens epithelial cells in vivo following blockade of lens cholesterol synthesis by treatment of the intact rat with U18666A, a potent inhibitor of sterol biosynthesis which also produces permanent nuclear cataract. Hypothesis three is that """"""""the structure and function of the fiber junction of lens plasma membranes requires a cholesterol rich environment. Depletion of lens membrane cholesterol by the agent U18666A will lead to loss of the main intrinsic protein (MP26) from the plasma membrane and fiber junction, to disruption of the structure and function of the plasma membrane and the fiber junction and to development of permanent nuclear cataracts. The hypothesis will be tested, in part, by examining the affect of altering the lipid environment of the plasma membrane upon membrane fluidity, upon the functional properties of MP26 reconstituted into liposomes, and upon the anatomy of the fiber cell plasma membrane.

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National Eye Institute (NEI)
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Visual Sciences A Study Section (VISA)
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A.T. Still University of Health Sciences
Schools of Osteopathy
United States
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Cenedella, Richard J (2009) Cholesterol synthesis inhibitor U18666A and the role of sterol metabolism and trafficking in numerous pathophysiological processes. Lipids 44:477-87
Cenedella, Richard J; Sexton, Patricia S; Brako, Lawrence et al. (2007) Status of caveolin-1 in various membrane domains of the bovine lens. Exp Eye Res 85:473-81
Cenedella, Richard J; Neely, Amanda R; Sexton, Patricia (2006) Multiple forms of 22 kDa caveolin-1 alpha present in bovine lens cells could reflect variable palmitoylation. Exp Eye Res 82:229-35
Cenedella, Richard J; Sexton, Patricia S; Krishnan, Kathiresan et al. (2005) Comparison of effects of U18666A and enantiomeric U18666A on sterol synthesis and induction of apoptosis. Lipids 40:635-40
Cenedella, Richard J; Neely, Amanda R; Sexton, Patricia (2005) Concentration and distribution of ubiquinone (coenzyme Q), the endogenous lipid antioxidant, in the rat lens: effect of treatment with simvastatin. Mol Vis 11:594-602
Cenedella, Richard J; Jacob, Robert; Borchman, Douglas et al. (2004) Direct perturbation of lens membrane structure may contribute to cataracts caused by U18666A, an oxidosqualene cyclase inhibitor. J Lipid Res 45:1232-41
Sexton, Patricia S; Neely, Amanda R; Cenedella, Richard J (2004) Distribution of caveolin-1 in bovine lens and redistribution in cultured bovine lens epithelial cells upon confluence. Exp Eye Res 78:75-82
Cenedella, Richard J; Kuszak, Jerome R; Al-Ghoul, Kristin J et al. (2003) Discordant expression of the sterol pathway in lens underlies simvastatin-induced cataracts in Chbb: Thom rats. J Lipid Res 44:198-211
Jacob, R F; Cenedella, R J; Mason, R P (2001) Evidence for distinct cholesterol domains in fiber cell membranes from cataractous human lenses. J Biol Chem 276:13573-8
Cenedella, R J (2001) Specific labeling of lens aldehyde dehydrogenase class 1 from (3)H-cholesterol or its derivatives. Ophthalmic Res 33:210-6

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