Evidence generated by us and others in animals provides evidence that inflammatory processes contribute to the development of at least the early stages of diabetic retinopathy, and especially the degeneration of retinal capillaries. How this capillary degeneration in diabetes is not clear, but most studies to date have focused on metabolic defects within cells of the retina and its vasculature. The present grant proposal is based on novel observations we have made over the previous several years suggesting that proinflammatory pathways within cells derived from bone marrow are critical in the development of the retinopathy. We have found that the vascular lesions of diabetic retinopathy can be prevented merely by eliminating either iNOS or PARP-1 from the marrow-derived cells only. Which myeloid cells are responsible for development of lesions of diabetic retinopathy, how they cause the diabetes-induced abnormalities in structure and function, and how to inhibit these leukocyte-driven abnormalities are not known, and are the subjects of the proposed research. In this proposal, we will (1) characterize which marrow-derived cell types participate in the development of early stages of diabetic retinopathy, (2) determine the role of chemoattractants in recruitment of marrow-derived cells to the retina in diabetes, and if the chemoattraction is critical to diabetes-induced degeneration of retinal capillaries, and (3) investigate the mechanism(s) by which marrow-derived cells kill retinal cells in diabetes, focusing initially on the role of reactive oxygen species generated by NADPH oxidase in the development of diabetes-induced inflammation. We also will determine if the abnormalities within the marrow-derived cells cause degeneration of neuroglial cells of the retina. We postulate that these diabetes-induced degenerative changes in the retina can be inhibited by blocking the abnormal metabolism within the marrow-derived cells, or by blocking the adhesion between those blood cells and retinal vascular cells. This hypothesis offers a novel approach to inhibiting the retinopathy (cause circulating leukocytes to release a factor that inhibits binding of white blood cells to the endothelium) which we will test in this proposal. This data is novel, and indicates that views of diabetic retinopathy need to expand beyond the traditional retina- or vascular-specific view of pathogenesis to include also bone marrow-derived cells.

Public Health Relevance

Diabetic retinopathy is a leading cause of vision loss in working-age adults in industrialized nations. In addition to abnormalities that disruption of light hitting the retina (fibrovascular scars, hemorrhage, retinal thickening), there are also alterations in function of the neural cells of the retina. There is very little understanding how this pathology develops. Our preliminary studies demonstrate for the first time that white blood cells play a critical role in the early stages of diabetic retinopathy. This proposal explores which white blood cells are responsible for this abnormality, how they are attracted to the retina, and how they kill retinal cells. We also test a possible therapeutic option to stop white blood cells from interacting with endothelial cells as an option to inhibit the retinopathy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY000300-45
Application #
8523858
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Mckie, George Ann
Project Start
1977-12-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
45
Fiscal Year
2013
Total Cost
$388,409
Indirect Cost
$141,015
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
Tang, Johnny; Herda, Ashley A; Kern, Timothy S (2014) Photobiomodulation in the treatment of patients with non-center-involving diabetic macular oedema. Br J Ophthalmol 98:1013-5
Lee, Chieh Allen; Li, Guangyuan; Patel, Mansi D et al. (2014) Diabetes-induced impairment in visual function in mice: contributions of p38 MAPK, rage, leukocytes, and aldose reductase. Invest Ophthalmol Vis Sci 55:2904-10
Tang, Jie; Du, Yunpeng; Petrash, J Mark et al. (2013) Deletion of aldose reductase from mice inhibits diabetes-induced retinal capillary degeneration and superoxide generation. PLoS One 8:e62081
Du, Yunpeng; Veenstra, Alexander; Palczewski, Krzysztof et al. (2013) Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina. Proc Natl Acad Sci U S A 110:16586-91
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Talahalli, Ramaprasad; Zarini, Simona; Tang, Jie et al. (2013) Leukocytes regulate retinal capillary degeneration in the diabetic mouse via generation of leukotrienes. J Leukoc Biol 93:135-43
Tang, Johnny; Du, Yunpeng; Lee, Chieh Allen et al. (2013) Low-intensity far-red light inhibits early lesions that contribute to diabetic retinopathy: in vivo and in vitro. Invest Ophthalmol Vis Sci 54:3681-90
Berkowitz, Bruce A; Bissig, David; Ye, Yongquan et al. (2012) Evidence for diffuse central retinal edema in vivo in diabetic male Sprague Dawley rats. PLoS One 7:e29619
Zheng, Ling; Liu, Shuqing; Sun, Ming-Zhong et al. (2009) Pharmacologic intervention targeting glycolytic-related pathways protects against retinal injury due to ischemia and reperfusion. Proteomics 9:1869-82
Berkowitz, Bruce A; Gradianu, Marius; Bissig, David et al. (2009) Retinal ion regulation in a mouse model of diabetic retinopathy: natural history and the effect of Cu/Zn superoxide dismutase overexpression. Invest Ophthalmol Vis Sci 50:2351-8

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