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.
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.
|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|
|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; 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|
|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|
Showing the most recent 10 out of 40 publications