Diabetes-induced changes in retinal vascular permeability (blood-retinal barrier dysfunction) are a major contributor to macular edema, the most common cause of visual loss in diabetic retinopathy. Anti-VEGF therapies have emerged as an approach to preserve or even improve visual function. However, this treatment is only partially effective and not all individuals respond. Evidence suggests that multiple other factors contribute to blood-retinal barrier dysfunction, including tumor necrosis factor and the chemokine (C-C motif) ligand 2 (CCL2). It is therefore essential to gain additional insights to allow the development of new therapeutic strategies. In the search for new treatments, there is increasing appreciation for the importance of protective mechanisms which could counteract key pathogenic processes, with the idea that enhancing these protective mechanisms could delay the progression of diabetic retinopathy. An additional important theme in the field is the growing understanding of the contribution of diverse cell types to diabetic retinopathy, including and in addition to vascular endothelial cells. During the previous funding period we identified Nrf2 as an important protective mechanism in diabetic retinopathy and other retinal conditions, impacting on diverse processes including blood-retinal barrier dysfunction and retinal neuronal dysfunction. An important basis for its action is that Nrf2 counteracts oxidative stress and regulates the cytokine environment in the retina. We also found that pharmacologic activation of Nrf2 is protective in retinal vascular disease processes, with multiple beneficial endpoints including neuroprotection. Taken together, this suggests to us that Nrf2 is a promising candidate for therapeutic modulation in DR, especially in light of emerging evidence that diabetes can impair Nrf2 activity in the retina. Here we propose to investigate the molecular basis for Nrf2's protective effect as well as to determine the cellular context for Nrf2 action in diabetic retinopathy. In addition, we will investigate a promising Nrf2 activator for treatment of blood-retinal barrier dysfunction in diabetic retinopathy. These studies will provide new insights into the mechanisms for Nrf2's beneficial effects as well as provide insights into the specific cell types in which Nrf2 function is particularly critical. Validation of pharmacologic targeting of Nrf for amelioration of pathologic endpoints could lead to direct clinical translation and implicate Nrf2 as a new therapeutic target for diabetic macular edema.

Public Health Relevance

Diabetes-induced changes in retinal vascular permeability (blood-retinal barrier/BRB dysfunction) is a major driver of macular edema, the most common cause of visual loss in diabetic retinopathy (DR). This research will allow us to investigate Nrf2 as an important molecule that modulates critical pathogenic processes in DR, thereby protecting against blood-retinal barrier and retinal dysfunction. Using pharmacologic approaches, we will investigate a promising Nrf2 activator for the treatment of DR, one that could lead to rapid clinical translation.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022383-06
Application #
9394800
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
2012-05-01
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Chen, Wan-Ju; Wu, Caiying; Xu, Zhenhua et al. (2017) Nrf2 protects photoreceptor cells from photo-oxidative stress induced by blue light. Exp Eye Res 154:151-158
Duh, Elia J; Sun, Jennifer K; Stitt, Alan W (2017) Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight 2:
Wei, Yanhong; Gong, Junsong; Xu, Zhenhua et al. (2016) Nrf2 promotes reparative angiogenesis through regulation of NADPH oxidase-2 in oxygen-induced retinopathy. Free Radic Biol Med 99:234-243
Shen, Yu-I; Cho, Hongkwan; Papa, Arianne E et al. (2016) Engineered human vascularized constructs accelerate diabetic wound healing. Biomaterials 102:107-19
Hartsock, Matthew J; Cho, Hongkwan; Wu, Lijuan et al. (2016) A Mouse Model of Retinal Ischemia-Reperfusion Injury Through Elevation of Intraocular Pressure. J Vis Exp :
Huang, Hu; He, Jianbo; Johnson, Da'Kuawn et al. (2015) Deletion of placental growth factor prevents diabetic retinopathy and is associated with Akt activation and HIF1?-VEGF pathway inhibition. Diabetes 64:200-12
Wei, Yanhong; Gong, Junsong; Xu, Zhenhua et al. (2015) Nrf2 in ischemic neurons promotes retinal vascular regeneration through regulation of semaphorin 6A. Proc Natl Acad Sci U S A 112:E6927-36
Cho, Hongkwan; Hartsock, Matthew J; Xu, Zhenhua et al. (2015) Monomethyl fumarate promotes Nrf2-dependent neuroprotection in retinal ischemia-reperfusion. J Neuroinflammation 12:239
Xu, Zhenhua; Yoshida, Takeshi; Wu, Lijuan et al. (2015) Transcription factor MEF2C suppresses endothelial cell inflammation via regulation of NF-?B and KLF2. J Cell Physiol 230:1310-20
Xu, Zhenhua; Cho, Hongkwan; Hartsock, Matthew J et al. (2015) Neuroprotective role of Nrf2 for retinal ganglion cells in ischemia-reperfusion. J Neurochem 133:233-41

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