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, we have provided evidence that cells in the outer retina play a critical role the development of diabetic retinopathy. The current application will investigate the hypothesis that visual cycle activity plays a key role in initiation of the degenerative vascular lesions in early stages of diabetic retinopathy, and does this by increasing oxidative stress and inflammation within rod photoreceptors. Ultimately, the stressed photoreceptors release soluble factors (including cytokines) that damage the vasculature secondary to activating circulation leukocytes. Thus, the central hypothesis of our proposal is that hyperglycemia or other abnormalities that stress photoreceptors (such as rhodopsin mutants) lead to generation superoxide and other reactive products, and that these abnormalities initiate the structural and functional changes of the microvasculature which are clinically recognized as early diabetic retinopathy.
Specific Aims will be: (1) to evaluate the roles of visual cycle activity in the retinal capillary damage caused by diabetes., (2) to investigate the roles of oxidative stress and/or inflammation within photoreceptors to initiate damage to the retinal vasculature, and (3) to identify soluble factors released by photoreceptors in diabetes, and mechanism by which those factors contribute to retinal capillary damage. The research proposed in Aim 1 will use mouse models in which RPE65 and LRAT are deficient, as well as a novel inhibitor of RPE65 to assess visual cycle activity.
Aim 2 will be tested using mice having (i) photoreceptor-specific knockdown of activities of NADPH oxidase activity and NF-?B activation. Diabetes will be induced experimentally in male and female mice. This is a highly novel and testable hypothesis that will be conducted by an experienced research team. Confirmation of retinal photoreceptor cells as contributors to retinal capillary disease in DR (and other retinal vascular diseases) will offer several novel approaches to inhibit the development of these retinopathies.

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 the visual cycle in the photoreceptor cells and retinal pigment epithelium. We also will identify foluble factors released by stressed photoreceptors that cause degeneration of retinal capillaries via activation of circulating leukocytes.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022938-08
Application #
10001512
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Shen, Grace L
Project Start
2013-09-01
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
8
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
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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
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; 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; 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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