The goal of this research is to clarify the pathogenesis of diabetic retinopathy and to provide a rational basis for developing improved means to inhibit the retinopathy. The proposed studies are based on our recent findings that inhibition of PARP dramatically inhibits the development of retinopathy in diabetes. In the present application, we will start from this novel finding to investigate two important gaps in our understanding of the pathogenesis of diabetic retinopathy. The first pertains to our lack of understanding of the sequence of biochemical abnormalities that ultimately leads to death of retinal capillary cells and other cells in diabetes. The second pertains to which cell type these abnormalities occur in. For many years, some investigators have suspected that circulating blood cells such as leukocytes play a role in capillary occlusion and the development of diabetic retinopathy, but this has not been rigorously tested. We will investigate the hypothesis that inhibition of PARP inhibits retinal pathology by inhibiting formation of nitric oxide, peroxynitrite, and prostaglandins. Moreover, by producing chimeric animals that lack PARP in their marrow-derived cells (leukocytes) but have it in retinal cells (or vice versa, have PARP in marrow-derived cells but lack it in retinal cells), we will test the hypothesis that PARP-mediated histopathology in the retina in diabetes is not caused merely by biochemical abnormalities within retinal cells themselves, but is due largely to sequelae of PARP activation in marrow-derived cells. Steps downstream of peroxynitrite and prostaglandin production responsible for hyperglycemia-mediated death of retinal capillary cells then will be investigated.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY000300-41
Application #
7454205
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
1977-12-01
Project End
2009-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
41
Fiscal Year
2008
Total Cost
$367,560
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Nahomi, Rooban B; Sampathkumar, Sruthi; Myers, Angela M et al. (2018) The Absence of Indoleamine 2,3-Dioxygenase Inhibits Retinal Capillary Degeneration in Diabetic Mice. Invest Ophthalmol Vis Sci 59:2042-2053
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Liu, Haitao; Tang, Jie; Du, Yunpeng et al. (2015) Retinylamine Benefits Early Diabetic Retinopathy in Mice. J Biol Chem 290:21568-79
Saliba, Alexandra; Du, Yunpeng; Liu, Haitao et al. (2015) Photobiomodulation Mitigates Diabetes-Induced Retinopathy by Direct and Indirect Mechanisms: Evidence from Intervention Studies in Pigmented Mice. PLoS One 10:e0139003

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