Zafer Gurel, PhD
Position title: Associate Scientist, Department of Ophthalmology and Visual Sciences
Phone: (608) 265-3049
9418 Wi Institute Medical Research
1111 Highland Ave
Madison, WI 53705
BS Medical Biology, 1991, University of Istanbul
MSc Biophysics, 1995, University of Istanbul
PhD Biophysics, 2001, University of Istanbul
Postdoctoral Fellowship, Pediatric Hematology & Oncology, 2007, UW-Madison
Molecular and cellular regulation of angiogenesis, O-GlcNAc modification and diabetic retinopathy:
O-GlcNAc modification Hyperglycemia, the hallmark symptom of diabetes, is the primary cause of diabetes complications including Diabetic Retinopathy (DR). However, the precise early molecular and cellular changes, which occur under hyperglycemic conditions, remain poorly understood. One of the earliest vascular changes during the pathogenesis of DR is loss of retinal pericytes (PC) in retina, but the detailed mechanisms remain mainly undefined.
The O-linked β-N-acetylglucosamine (O-GlcNAc) modification is one of the important targets for elucidation of the pathogenesis of DR, in part because this modification is controlled by the hexosamine biosynthetic pathway (HBP) which can be activated by hyperglycemia. Several studies suggest that altered O-GlcNAcylation may be involved in the insulin resistance and the pathogenesis of diabetes. However, very little is known about how this modification and its targets are altered in the retina, and more specifically during the pathogenesis of DR. O-GlcNAc modification is one of the most common posttranslational modifications involving a wide-range of proteins including cytoplasmic, mitochondrial and nuclear. The end product of HBP, uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) is used for O-GlcNAc modification of proteins. In our recent work, we have shown that the level of O-GlcNAcylation varies both at the basal level and under high glucose conditions in different retinal vascular cells. Furthermore, high glucose and agents used to increase the levels of O-GlcNAc modifications, Thiamet-G and PUGNAc, attenuated the migratory activities of only retinal PC. We have also found that high glucose and elevated O-GlcNAc modification increased apoptosis of retinal PC, but not retina endothelial cells (EC) and astrocytes (AC). By using an alkynyl-modified GlcNAc analog (GlcNAlk) in combination with a biotin affinity-tag, we were able to identify O-GlcNAc modified proteins in retinal PC. With this approach, we successfully identified 431 target proteins, of which more than 200 targeted proteins were not previously reported and thus considered novel. Currently, we have begun to focus on the O-GlcNAc modified proteins in the retinal PC that are have been shown in the literature to be involved in apoptosis. We aim to delineate the relationship in between increased O-GlcNAc modification of these specific proteins and PC loss under hyperglycemia.
Data generated from this research should provide important information about hyperglycemia-induced alterations in retinal cells and a better understanding on the pathogenesis of DR.