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.
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.!
| Bashyal, Bharat; Li, Linfeng; Bains, Trpta et al. (2017) Larrea tridentata: A novel source for anti-parasitic agents active against Entamoeba histolytica, Giardia lamblia and Naegleria fowleri. PLoS Negl Trop Dis 11:e0005832 |
| 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; Li, Linfeng; Sanborn, Theresa M et al. (2016) Characterization of Emodin as a Therapeutic Agent for Diabetic Cataract. J Nat Prod 79:1439-44 |
| Nagaraj, Ram H; Nahomi, Rooban B; Mueller, Niklaus H et al. (2016) Therapeutic potential of ?-crystallin. Biochim Biophys Acta 1860:252-7 |
| Li, Linfeng; Zhou, Qiong; Voss, Ty C et al. (2016) High-throughput imaging: Focusing in on drug discovery in 3D. Methods 96:97-102 |
| Chang, Kun-Che; Shieh, Biehuoy; Petrash, J Mark (2016) Aldose reductase mediates retinal microglia activation. Biochem Biophys Res Commun 473:565-71 |
| 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 |
| 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; 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 |
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