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 #
5R01EY000300-39
Application #
7121077
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Mariani, Andrew P
Project Start
1977-12-01
Project End
2009-06-30
Budget Start
2006-09-20
Budget End
2007-06-30
Support Year
39
Fiscal Year
2006
Total Cost
$377,173
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
Flückiger, Rudolf; Cocuzzi, Enzo; Nagaraj, Ram H et al. (2018) DAF in diabetic patients is subject to glycation/inactivation at its active site residues. Mol Immunol 93:246-252
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
Tonade, Deoye; Liu, Haitao; Palczewski, Krzysztof et al. (2017) Photoreceptor cells produce inflammatory products that contribute to retinal vascular permeability in a mouse model of diabetes. Diabetologia 60:2111-2120
Kern, Timothy S (2017) Do photoreceptor cells cause the development of retinal vascular disease? Vision Res 139:65-71
Tonade, Deoye; Kern, Timothy S (2017) Diabetes of 5 years duration does not lead to photoreceptor degeneration in the canine non-tapetal inferior-nasal retina. Exp Eye Res 162:126-128
Tonade, Deoye; Liu, Haitao; Kern, Timothy S (2016) Photoreceptor Cells Produce Inflammatory Mediators That Contribute to Endothelial Cell Death in Diabetes. Invest Ophthalmol Vis Sci 57:4264-71
Zhang, Lingjun; Li, Yan; Payne, John et al. (2016) Presence of retinal pericyte-reactive autoantibodies in diabetic retinopathy patients. Sci Rep 6:20341
Liu, Haitao; Tang, Jie; Du, Yunpeng et al. (2016) Photoreceptor Cells Influence Retinal Vascular Degeneration in Mouse Models of Retinal Degeneration and Diabetes. Invest Ophthalmol Vis Sci 57:4272-81
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

Showing the most recent 10 out of 95 publications