Diabetes mellitus is recognized as a leading cause of new cases of blindness among Americans between the ages of 20 and 74. In comparison with the general population, diabetic patients face a 25-fold increased risk of blindness. Our long term objectives are to elucidate mechanisms involved in diabetic eye disease in order to develop strategies to prevent or delay the devastating effects of diabetes on the eye. Aldose reductase has been implicated in the pathogenesis of diabetic cataract and retinopathy, but we do not understand the mechanism. The goals of this project are to determine whether the onset and progression of diabetic eye disease is influenced by genetic manipulation of aldo-keto reductase enzyme levels.
Specific aim one will test the hypothesis that diabetic cataract formation is not dependent on production of sugar alcohols by aldose reductase. This will be accomplished with the use of transgenic mice that direct lens expression of either aldose reductase, which catalyzes conversion of glucose to sorbitol, or small intestine reductase, which does not catalyze glucose-dependent sorbitol synthesis. Consequences of transgene expression will be assessed with and without induction of experimental diabetes. Transgenic lenses will be studied for accelerated lens epithelial cell apoptosis and diabetes-induced alterations of epithelial cell morphology. Biochemical markers of oxidative stress will also be measured.
Specific aim two will test the hypothesis that deletion of genes for aldose reductase and related aldo-keto reductases will protect against diabetic retinopathy and cataract. Morphological and functional changes to retinal vascular cells following induction of experimental diabetes will be assessed in gene knockout and control mice. Measurement of apoptotic vascular cells in different lines of gene-targeted mice will reveal whether aldo-keto reductase gene expression contributes to the pathogenesis of diabetic retinopathy. Similar comparisons will be made for lens transparency to determine the influence of individual AKR genes on diabetic cataract. ? ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY005856-22
Application #
7099517
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Araj, Houmam H
Project Start
1988-07-16
Project End
2009-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
22
Fiscal Year
2006
Total Cost
$517,051
Indirect Cost
Name
Washington University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Zukin, Leonid M; Pedler, Michelle G; Groman-Lupa, Sergio et al. (2018) Aldose Reductase Inhibition Prevents Development of Posterior Capsular Opacification in an In Vivo Model of Cataract Surgery. Invest Ophthalmol Vis Sci 59:3591-3598
Zhang, Chi; Lai, Maria B; Pedler, Michelle G et al. (2018) Endothelial Cell-Specific Inactivation of TSPAN12 (Tetraspanin 12) Reveals Pathological Consequences of Barrier Defects in an Otherwise Intact Vasculature. Arterioscler Thromb Vasc Biol 38:2691-2705
Chang, Kun-Che; Shieh, Biehuoy; Petrash, J Mark (2017) Influence of aldose reductase on epithelial-to-mesenchymal transition signaling in lens epithelial cells. Chem Biol Interact 276:149-154
Chang, Kun-Che; Shieh, Biehuoy; Petrash, J Mark (2016) Aldose reductase mediates retinal microglia activation. Biochem Biophys Res Commun 473:565-71
Chang, Kun-Che; Li, Linfeng; Sanborn, Theresa M et al. (2016) Characterization of Emodin as a Therapeutic Agent for Diabetic Cataract. J Nat Prod 79:1439-44
Diego, Jose L; Bidikov, Luke; Pedler, Michelle G et al. (2016) Effect of human milk as a treatment for dry eye syndrome in a mouse model. Mol Vis 22:1095-1102
Nagaraj, Ram H; Nahomi, Rooban B; Mueller, Niklaus H et al. (2016) Therapeutic potential of ?-crystallin. Biochim Biophys Acta 1860:252-7
Chang, Kun-Che; Petrash, J Mark (2015) Aldose Reductase Mediates Transforming Growth Factor ?2 (TGF-?2)-Induced Migration and Epithelial-To-Mesenchymal Transition of Lens-Derived Epithelial Cells. Invest Ophthalmol Vis Sci 56:4198-210
Snow, Anson; Shieh, Biehuoy; Chang, Kun-Che et al. (2015) Aldose reductase expression as a risk factor for cataract. Chem Biol Interact 234:247-53
Chang, Kun-Che; Snow, Anson; LaBarbera, Daniel V et al. (2015) Aldose reductase inhibition alleviates hyperglycemic effects on human retinal pigment epithelial cells. Chem Biol Interact 234:254-60

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