Diabetic retinopathy is clinically defined as a disease of the retinal microvasculature, and most research on its pathogenesis to date has focused on molecular and metabolic defects within the blood vessel cells themselves. In recent years, a few papers have suggested that cells in the outer retina might play a role the development of diabetic retinopathy, but there has been little follow-up pertaining to these ideas. The current application will investigate the hypothesis that photoreceptors play a key role in initiation of th degenerative vascular lesions in early stages of diabetic retinopathy, and that this process is initiated by oxidative stress in the photoreceptor cells. Oxidative stress is known to regulate expression of pro-inflammatory proteins, and previous studies by us have implicated an important role of inflammation in the early stages of the retinopathy. Thus, the central hypothesis of our proposal is that the photoreceptors generate superoxide and other reactive products in diabetes, and that these abnormalities initiate (via local inflammatory changes in the inner retina) the structural and functional changes of the microvasculature which are clinically recognized as early diabetic retinopathy. We further predict that oxidative and inflammatory effects on the retinal vasculature in diabetes will be exacerbated by darkness, and can be inhibited with light. The research proposed will use mouse models in which photoreceptors degenerate or are functionally impaired with respect to visual cycle activity or phototransduction, or wildtype animals. Diabetes will be induced experimentally.
Specific Aims will be: (1) to differentiate the roles of photoreceptors, phototransduction and visual cycle activity in the development of the diabetes-induced vascular lesions of early diabetic retinopathy, (2) to evaluate the mechanisms by which photoreceptors contribute to the retinal oxidative stress and induction of pro-inflammatory proteins in diabetes (which have been shown to contribute to the vascular lesions of early diabetic retinopathy), and (3) to determine if inhibition of oxidative stress in photoreceptors results in inhibition of diabetes-induced defects in retinal vascular structure and function.
Aim 3 will be tested using mice having (i) photoreceptor-specific knockdown of NADPH oxidase (and for comparison, (ii) systemic inhibition of NADPH oxidase), and (iii) far-red light therapy. This is a highly novel and testable hypothesis that will be conducted by an experienced research team.

Public Health Relevance

Diabetic retinopathy is a leading cause of vision loss in working-age adults in industrialized nations. Most research on its pathogenesis to date has focused on molecular and metabolic defects within the cells of the retinal blood vessels. Evidence that oxidative stress and inflammation contribute are accumulating, but none of the available hypotheses explain why retinal blood vessels are more susceptible to adverse effects of systemic hyperglycemia than are microvessels in most other tissues. The current application will investigate the hypothesis that photoreceptors play a key role in initiation of the degenerative vascular lesions in early stages of diabetic retinopathy, and that this process is initiated by oxidative stress in the photoreceptor cells, especially in the dark. We also test several possible therapeutic options to inhibit this damage, including using NADPH oxidase inhibitor and transient exposure to light at wavelengths that improves mitochondrial function.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022938-02
Application #
8712495
Study Section
(DPVS)
Program Officer
Shen, Grace L
Project Start
2013-09-01
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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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
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
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
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

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