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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Shen, Grace L
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Pennsylvania State University
Schools of Medicine
United States
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Kaiser, James M; Imai, Hisanori; Haakenson, Jeremy K et al. (2013) Nanoliposomal minocycline for ocular drug delivery. Nanomedicine 9:130-40
Hankins, Jody L; Ward, Katherine E; Linton, Sam S et al. (2013) Ceramide 1-phosphate mediates endothelial cell invasion via the annexin a2-p11 heterotetrameric protein complex. J Biol Chem 288:19726-38
Fox, Todd E; Young, Megan M; Pedersen, Michelle M et al. (2012) Diabetes diminishes phosphatidic acid in the retina: a putative mediator for reduced mTOR signaling and increased neuronal cell death. Invest Ophthalmol Vis Sci 53:7257-67
Fox, Todd E; Bewley, Maria C; Unrath, Kellee A et al. (2011) Circulating sphingolipid biomarkers in models of type 1 diabetes. J Lipid Res 52:509-17
Fox, Todd E; Young, Megan M; Pedersen, Michelle M et al. (2011) Insulin signaling in retinal neurons is regulated within cholesterol-enriched membrane microdomains. Am J Physiol Endocrinol Metab 300:E600-9
Winter, Jeremiah N; Fox, Todd E; Kester, Mark et al. (2010) Phosphatidic acid mediates activation of mTORC1 through the ERK signaling pathway. Am J Physiol Cell Physiol 299:C335-44