Diabetic retinopathy is a debilitating complication of diabetes and a leading cause of vision loss;however the fundamental mechanisms contributing to vision loss remain undefined. In our previously funded R03 grant, we hypothesized that altered sphingolipid metabolism contributes to diabetic complications including neuronal apoptosis within the retina. We have now published that dysfunctional glycosphingolipid metabolism may contribute to metabolic stress in diabetes and therapeutic strategies to restore normal sphingolipid metabolism may be a viable approach for treatment of diabetic retinopathy. Specifically, our published and preliminary data demonstrate that glucosylceramide accumulates within diabetic retinas in vivo and that inhibition of glucosylceramide synthase improves insulin sensitivity under hyperglycemic conditions and diminishes inflammatory cytokine-induced retinal neuronal cell death. In the present proposal, we extend these observations to more mechanistic studies. We now hypothesize that hyperglycemia and/or inflammation directly regulate glucosylceramide synthase activity, resulting in accumulation of glucosylceramides. We also hypothesize that pharmacologically targeting glucosylceramide synthase may be therapeutic for diabetic retinopathy.

Public Health Relevance

The underlying cause of diabetic retinopathy is still unknown. We have employed lipidomics, a sophisticated mass spectroscopy strategy, to quantify the mass of lipid metabolites within the diabetic retina. Preliminary and published data have identified dysfunctional glycosphingolipid metabolism in models of Type 1 diabetes. The clinical relevance of our studies is that these lipidomic studies have identified glucosylceramide synthase as a """"""""drugable"""""""" target for diabetic complications.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY018336-02
Application #
7903885
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
2009-08-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$382,178
Indirect Cost
Name
Pennsylvania State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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