Diabetes mellitus is recognized as a leading cause of new cases of blindness among Americans between the ages of 20 and 74. Aldose reductase (AR) has been implicated in the pathogenesis of diabetic cataract and retinopathy, but we do not understand the mechanism. Diabetes causes activation of kinase signaling molecules, which stimulate production of proinflammatory molecules. AR inhibitors prevent kinase activation and suppress inflammation. Prevention of inflammation is also provided by a group of proteins called the perixosome proliferator-activated receptors (PPAR). Drugs that activate the PPAR family protect against inflammation in the diabetic retina, much like AR inhibitors. The similar benefits of AR inhibitors and PPAR agonists against diabetic retinopathy and inflammation suggest they could be operating through a common pathway. However, there is a gap in our understanding of this process. We have developed a series of mouse models to evaluate the role of AR in diabetic eye disease. We found that elevated AR expression causes activation of kinases, which leads to cell proliferation and cataracts. Evidence suggests that activated AR may lead to inflammation and suppress pathways involved in PPAR signaling. We propose a series of three specific aims to investigate a role for AR in diabetic eye disease.
In aim 1, we will test the hypothesis that activation of AR leads to imbalances in lens epithelial cell (LEC) proliferation and differentiation. We will examine kinases and differentiation markers to investigate why activation of AR causes hyperproliferation of lens epithelial cells. DNA microarray experiments will be conducted to determine if AR activation leads to up- or down-regulation of gene clusters. Cell cycle analysis will be carried out to determine if AR activation alters mechanisms of cell cycle control.
In aim 2, we will test the hypothesis that AR activation contributes to diabetic eye disease through modulation of signaling pathways. We will evaluate the consequences of AR-mediated kinase activation on the degenerative lens phenotype in our transgenic model.
In aim 3, we will test the hypothesis that AR-mediated PPAR inhibition contributes to diabetic eye disease using mice with disabled genes for AR and/or PPAR. 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.

Public Health Relevance

Diabetes mellitus is a leading cause of new cases of blindness among Americans between the ages of 20 and 74. The proposed research seeks to elucidate mechanisms behind diabetic eye disease so that strategies can be developed for development of new drugs and therapies to prevent vision loss.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY005856-30
Application #
8655849
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
1988-07-16
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
30
Fiscal Year
2014
Total Cost
$443,601
Indirect Cost
$153,666
Name
University of Colorado Denver
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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
Lee, Chieh Allen; Li, Guangyuan; Patel, Mansi D et al. (2014) Diabetes-induced impairment in visual function in mice: contributions of p38 MAPK, rage, leukocytes, and aldose reductase. Invest Ophthalmol Vis Sci 55:2904-10
Énzsöly, Anna; Markó, Katalin; Tábi, Tamás et al. (2013) Lack of association between VAP-1/SSAO activity and corneal neovascularization in a rabbit model. J Neural Transm (Vienna) 120:969-75
Chang, Kun-Che; Laffin, Brian; Ponder, Jessica et al. (2013) Beta-glucogallin reduces the expression of lipopolysaccharide-induced inflammatory markers by inhibition of aldose reductase in murine macrophages and ocular tissues. Chem Biol Interact 202:283-7
Ruiz, F Xavier; Moro, Armando; Gallego, Oriol et al. (2011) Human and rodent aldo-keto reductases from the AKR1B subfamily and their specificity with retinaldehyde. Chem Biol Interact 191:199-205
Zablocki, Gregory J; Ruzycki, Philip A; Overturf, Michelle A et al. (2011) Aldose reductase-mediated induction of epithelium-to-mesenchymal transition (EMT) in lens. Chem Biol Interact 191:351-6
Salabei, Joshua K; Li, Xiao-Ping; Petrash, J Mark et al. (2011) Functional expression of novel human and murine AKR1B genes. Chem Biol Interact 191:177-84
Barton, Kelly A; Hsu, Cheng-Da; Petrash, J Mark (2009) Interactions between small heat shock protein alpha-crystallin and galectin-related interfiber protein (GRIFIN) in the ocular lens. Biochemistry 48:3956-66
Chang, Qing; Petrash, J Mark (2008) Disruption of aldo-keto reductase genes leads to elevated markers of oxidative stress and inositol auxotrophy in Saccharomyces cerevisiae. Biochim Biophys Acta 1783:237-45
Chang, Qing; Griest, Terry A; Harter, Theresa M et al. (2007) Functional studies of aldo-keto reductases in Saccharomyces cerevisiae. Biochim Biophys Acta 1773:321-9

Showing the most recent 10 out of 11 publications