The overall objective of the project outlined in the present application is to provide a mentor-based training program centered around the study of changes in GLUT1 glucose transporter gene expression in diabetic retinopathy (DR). The rationale for this project is based on the clinical observation that the chronic hyperglycemia of long-standing diabetes is associated with characteristic pathological changes in the retinal capillaries which comprise the inner blood-retinal barrier (BRB). On a molecular level, in order to initiate the biochemical and histopathological changes leading to DR, glucose must gain access to the intracellular compartment of the capillary endothelial cells of the inner BRB. It can only do so via transport by GLUT1. Therefore, changes in GLUT1 expression in the inner BRB may have a profound impact on the intracellular concentration of glucose and on the subsequent development of the pathological microvascular changes of DR. A recent pilot study by the applicant demonstrated a localized, pathological upregulation of immunoreactive GLUT1 on the inner BRB in long-standing diabetes. The proposed studies will investigate this phenomenon in 4 general areas. First, quantitative immunogold electron microscopy and in situ hybridization for GLUT1 will be performed on postmortem human retina specimens to extend observations regarding changes GLUT1 protein and mRNA expression in early DR. Second, selective overexpression of vascular endothelial GLUT1 in bovine retinal endothelial cells (BRCEC) in culture and in a transgenic mouse model will be undertaken to determine if increased expression of GLUT1 results in molecular and histopathological changes similar to those found in early DR. Third, the effects of glucose and growth factors associated with the development of DR on GLUT1 gene expression will be investigated in BRCEC culture models, and fourth, possible effects of pericyte-endothelial cell interactions on GLUT1 gene expression will be studied in cell culture.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08EY000369-04
Application #
6164632
Study Section
Special Emphasis Panel (ZEY1-VSN (01))
Program Officer
Dudley, Peter A
Project Start
1997-03-01
Project End
2002-02-28
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
4
Fiscal Year
2000
Total Cost
$127,722
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Malhotra, Ricky; Tyson, David G W; Sone, Hirohito et al. (2002) Glucose uptake and adenoviral mediated GLUT1 infection decrease hypoxia-induced HIF-1alpha levels in cardiac myocytes. J Mol Cell Cardiol 34:1063-73
DeBosch, Brian J; Deo, Baljit K; Kumagai, Arno K (2002) Insulin-like growth factor-1 effects on bovine retinal endothelial cell glucose transport: role of MAP kinase. J Neurochem 81:728-34
DeBosch, B J; Baur, E; Deo, B K et al. (2001) Effects of insulin-like growth factor-1 on retinal endothelial cell glucose transport and proliferation. J Neurochem 77:1157-67