Diabetes mellitus is recognized as a leading cause of new cases of blindness among Americans between the ages of 20 and 74. The prevalence of diabetic eye disease is expected to continue to increase in the American population and worldwide as a result of the dramatic increase in the number of people with diabetes. At present, there is no medical treatment to delay or prevent the onset and progression of cataract or retinopathy, the most common causes of vision loss in diabetics. We propose a study organized around two specific aims to develop novel therapeutic compounds identified from extracts of the Indian gooseberry plant Emblica officinalis. These natural compounds have activity as aldose reductase inhibitors and show promise as agents to suppress metabolic abnormalities associated with the onset and progression of diabetic cataract and retinopathy.
In aim 1, we will purify sufficient quantities of the lead compounds to conduct toxicity studies using lens and retinal pigment epithelium tissue culture systems. We will examine the efficacy of lead compounds against cataract formation in our human aldose reductase transgenic mouse model. Studies will also be carried out to evaluate the ability of lead compounds to suppress markers of inflammation in a diabetic mouse model.
In specific aim 2, we will use molecular modeling to design novel derivatives to enhance binding affinity and specificity. Derivatives will be synthesized and evaluated for efficacy in tissue culture and animal model systems. We will examine interactions between optimized compounds and human aldose reductase by steady- state kinetics. Binding specificity will be examined using several members of the aldo-keto reductase gene superfamily.

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 discover naturally occurring compounds that delay or reduce the progression of diabetic cataract and retinopathy. Novel therapeutics will be designed from natural lead compounds and will be optimized to enhance efficacy against diabetes-induced vision loss.!

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY021498-02
Application #
8337278
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Shen, Grace L
Project Start
2011-09-30
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$378,133
Indirect Cost
$128,133
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
Chang, Kun-Che; Ponder, Jessica; Labarbera, Daniel V et al. (2014) Aldose reductase inhibition prevents endotoxin-induced inflammatory responses in retinal microglia. Invest Ophthalmol Vis Sci 55:2853-61
Li, Linfeng; Chang, Kun-Che; Zhou, Yaming et al. (2014) Design of an amide N-glycoside derivative of *-glucogallin: a stable, potent, and specific inhibitor of aldose reductase. J Med Chem 57:71-7
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
Puppala, Muthenna; Ponder, Jessica; Suryanarayana, Palla et al. (2012) The isolation and characterization of ýý-glucogallin as a novel aldose reductase inhibitor from Emblica officinalis. PLoS One 7:e31399