Retinopathy of prematurity (ROP) is the leading cause of blindness in the U.S. and other developed countries in the pediatric population. A pivotal aspect of early ROP is the development of retinal avascularity, which leads to advanced stages of ROP and retinal NV. Visual impairment in ROP results from retina avascularity: the ischemic/hypoxic retina produces pro-angiogenic growth factors including VEGF which stimulates retinal neovascularization. Important pathophysiologic processes underlie retinal avascularity in ROP, including oxidative stress and pro-inflammatory processes. The ability to modulate oxidative stress and inflammation in ROP, thereby facilitating physiologic retinal vascularization, would therefore be of great benefit in the treatment of ROP. Indeed, promotion of revascularization is highly desirable in a variety of retinal diseases, particularly the ischemi retinopathies. The transcription factor Nrf2 has an important cytoprotective role against oxidative stress and inflammation in multiple disease processes. Nrf2 is quite amenable to pharmacologic modulation, so its protective effects can be augmented. Our lab has been studying the role of Nrf2 in the retina. We have found that Nrf2 plays a vital protective role in the retinal response t ischemia-reperfusion injury, and have similar evidence in the context of oxygen-induced retinopathy. We hypothesize that Nrf2 is an important mechanism promoting retinal vascularization of ischemic retina, regulating oxidative stress and pro- inflammatory changes in the retina via modulation of NADPH oxidase. We propose the following 3 aims:
Specific Aim 1. Investigate the role of Nrf2 in retinal revascularization and pathologic retinal neovascularization Specific Aim 2. Investigate the hypothesis that Nrf2 regulates oxidative stress and pro- inflammatory processes in OIR via modulation of NADPH oxidase.
Specific Aim 3. Determine if pharmacologic activation of Nrf2 protects against pathophysiologic and functional changes in oxygen-induced retinopathy. We expect that these aims will allow us to identify Nrf2 as an important protective mechanism in oxygen-induced retinopathy, thereby providing a new therapeutic strategy for ROP.

Public Health Relevance

Retinopathy of prematurity (ROP) is the leading cause of blindness in the U.S. and other developed countries in the pediatric population. This research will allow us to investigate the beneficial role of the protective molecule Nrf2 using a mouse model for this condition. This could allow us to develop a new therapy for retinopathy of prematurity, aimed at enhancing the beneficial effects of Nrf2.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY022683-01
Application #
8348187
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Shen, Grace L
Project Start
2012-08-01
Project End
2016-06-30
Budget Start
2012-08-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$405,000
Indirect Cost
$155,000
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Xu, Zhenhua; Wei, Yanhong; Gong, Junsong et al. (2014) NRF2 plays a protective role in diabetic retinopathy in mice. Diabetologia 57:204-13
Wei, Yanhong; Gong, Junsong; Thimmulappa, Rajesh K et al. (2013) Nrf2 acts cell-autonomously in endothelium to regulate tip cell formation and vascular branching. Proc Natl Acad Sci U S A 110:E3910-8