Diabetes damages the retina, and the resulting diabetic retinopathy (DR) is the leading cause of visual impairment and blindness in working-aged adults. Despite this, the pathogenesis of DR is poorly understood. Research done by us and others strongly implicates inflammatory processes in the development of the critical microvascular lesions of DR, and work done during our current Merit research demonstrates that the induction of these inflammatory proteins by hyperglycemia is regulated by protein acetylation. The central hypothesis of our current proposal is that increased acetylation of proteins in diabetes contribute to the degeneration of retinal capillaries via inflammatory pathways, and that leukocytes in particular play a critical role in the pathogenesis of this acetylation-driven degeneration of retinal capillaries. Using 2 models of DR (streptozotocin to induce a Type 1 diabetes, and spontaneously diabetic db/db mice which are a model of Type 2 diabetes), research in this proposal will determine if inhibition of this acetylatin systemically (Aim 1) or in leukocytes only (Aim 2) inhibits development of the characteristic vascular lesions of early DR. These studies will be performed both as prevention trials and as intervention trials.
The third aim of this proposal will extend these studies to patients, using leukocytes from Veterans (both diabetic and nondiabetic) to determine if leukocyte- mediated killing of retinal endothelial cells in diabetes can be prevented by inhibiting or reversing acetylation of proteins in leukocytes. We also will begin to explore if the extent of acetylation-mediated killing of retinal endothelial cells by leukocytes from diabetic patients correlates with the severity of retinopathy and might predict which patients are most susceptible to develop advanced DR.

Public Health Relevance

Diabetic retinopathy is a leading cause of vision loss in working-age adults in industrialized nations, but its pathogenesis remains unclear. Evidence that inflammation contributes to the retinopathy is accumulating, but the molecular cause of this inflammation is still under investigation. We have demonstrated that histone acetylation in elevated glucose regulates induction of inflammatory proteins, and we will now test if inhibition of this increased acetylatio of proteins in diabetes can inhibit lesions of early diabetic retinopathy.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX002117-01
Application #
8540670
Study Section
Neurobiology C (NURC)
Project Start
2014-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Louis Stokes Cleveland VA Medical Center
Department
Type
DUNS #
093016124
City
Cleveland
State
OH
Country
United States
Zip Code
44141
Cheng, Yan; Du, Yunpeng; Liu, Haitao et al. (2018) Photobiomodulation Inhibits Long-term Structural and Functional Lesions of Diabetic Retinopathy. Diabetes 67:291-298
Fl├╝ckiger, 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
Roy, Sayon; Kern, Timothy S; Song, Brian et al. (2017) Mechanistic Insights into Pathological Changes in the Diabetic Retina: Implications for Targeting Diabetic Retinopathy. Am J Pathol 187:9-19
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

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