Diabetes is a rapidly increasing public health problem. Inadequate control of hyperglycemia leads to the onset and progression of the """"""""late complications"""""""" of diabetes mellitus which in the eye include cataract and diabetic retinopathy, both of which result in vision loss. Previous studies with diabetic and galactosemic animals have demonstrated that both sugar cataract formation and retinal vascular alterations associated with diabetic retinopathy are linked to osmotic and oxidative stress associated with excess aldose reductase activity through the polyol pathway. Excess aldose reductase activity has also been linked to signal transduction changes, cytotoxic signals and activation of apoptosis. Preliminary studies also indicate that aldose reductase activity is linked to stress-related gene expression changes. In this grant application, we propose to elucidate the mechanism(s) by which aldose reductase activity and hexose-induced oxidative stress in the lens and retina are linked to altered ocular levels of insulin-like growth factor (IGF), transforming growth factor (TGF-beta) and basic fibroblast growth factor (b-FGF), three growth factors observed to be involved in cataract formation and diabetic retinopathy. The levels of MAPK, PI-3K, SMAD3 in the signaling pathways of IGF and TGF-beta and the apoptotic factors, caspase 3, p53, and p38 will be assessed. In addition, the major target genes of IGF, TGF-beta , and b-FGF signaling pathways will be identified using the Fox (IGF1), SMAD3 or 4 (TGF-p), or SAPK/JNK (b-FGF) transcriptional factors with microarray analysis. These studies will be conducted in diabetic and galactose-fed rats and in normal and transgenic mice in which the retinal pericytes contain increased levels of aldose reductase. By clarifying the source of this hexose-linked oxidative stress and identifying the specific mechanism(s) through which aldose reductase alters the ocular levels of b-FGF, IGF and TGF-beta, their associated signaling pathways and gene expression, new insights into the treatment for cataract and diabetic retinopathy can be obtained. Moreover, these studies should help identify new drug targets for the treatment of these diabetic complications.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016730-04
Application #
7635754
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
2006-08-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
4
Fiscal Year
2009
Total Cost
$321,158
Indirect Cost
Name
University of Nebraska Medical Center
Department
Other Basic Sciences
Type
Schools of Pharmacy
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Kador, Peter F; Wyman, Milton; Oates, Peter J (2016) Aldose reductase, ocular diabetic complications and the development of topical Kinostat(®). Prog Retin Eye Res 54:1-29
Guo, Changmei; Zhang, Zifeng; Zhang, Peng et al. (2014) Novel transgenic mouse models develop retinal changes associated with early diabetic retinopathy similar to those observed in rats with diabetes mellitus. Exp Eye Res 119:77-87
Zhang, Peng; Zhang, Zifeng; Kador, Peter F (2014) Polyol effects on growth factors and MAPK signaling in rat retinal capillary cells. J Ocul Pharmacol Ther 30:4-11
Kador, Peter F; Zhang, Peng; Makita, Jun et al. (2012) Novel diabetic mouse models as tools for investigating diabetic retinopathy. PLoS One 7:e49422
Zhang, Peng; Xing, Kuiyi; Randazzo, James et al. (2012) Osmotic stress, not aldose reductase activity, directly induces growth factors and MAPK signaling changes during sugar cataract formation. Exp Eye Res 101:36-43
Randazzo, James; Zhang, Zifeng; Hoff, Michael et al. (2011) Orally active multi-functional antioxidants are neuroprotective in a rat model of light-induced retinal damage. PLoS One 6:e21926
Randazzo, James; Zhang, Peng; Makita, Jun et al. (2011) Orally active multi-functional antioxidants delay cataract formation in streptozotocin (type 1) diabetic and gamma-irradiated rats. PLoS One 6:e18980
Kador, Peter F; Hamada, Tomofumi; Reinhardt, Richard A et al. (2010) Effect of an aldose reductase inhibitor on alveolar bone loss associated with periodontitis in diabetic rats. Postgrad Med 122:138-44
Kador, Peter F; Randazzo, James; Blessing, Karen et al. (2009) Polyol formation in cell lines of rat retinal capillary pericytes and endothelial cells (TR-rPCT and TR-iBRB). J Ocul Pharmacol Ther 25:299-308
Shinohara, Toshimichi; Mulhern, Michael L; Madson, Christian J (2008) Silencing gene therapy for mutant membrane, secretory, and lipid proteins in retinitis pigmentosa (RP). Med Hypotheses 70:378-80