The inner and outer blood-retina barriers (BRBs) are formed by tight junctions between adjacent endothelial or retinal pigment epithelial (RPE) cells. Breakdown of BRBs is a major pathological change in age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, and uveitis. While previous studies have yielded a better understanding about the roles of the inner BRB under physiological and pathological conditions, surprisingly little is known about the regulation and pathophysiology of the outer BRB. Since the outer BRB is responsible for ~85% of blood circulation to the retina, it is unimaginable that ischemia-induced pathological change in the outer BRB plays an insignificant role in the overall pathology of retinochoroidal vascular diseases. To investigate the mechanisms of outer BRB breakdown and to test the concept of inhibiting outer BRB permeability as a therapeutic strategy for retinochoroidal vascular diseases, we have prepared gene knockout systems for the mouse RPE and M?ller glia, cells that regulate the function of both inner and outer BRBs through vascular endothelial growth factor (VEGF-A). Using these conditional gene knockout systems, we have disrupted VEGF and its receptor (VEGFR2) in the mouse RPE and have generated mice with VEGF disruption in the M?ller cells.
In Specific Aim 1, we will test our hypothesis that outer BRB breakdown is a significant contributor to diabetes/ischemia-induced overall retinal """"""""vascular leakage"""""""" through autocrine VEGF/VEGF-R2 signaling in the RPE by measuring the total retinal vascular leakage, the number of significant breakpoints in the outer BRB, and the quantity of outer BRB-specific leakage in the RPE-specific VEGF and VEGFR2 knockout mice after inducing ischemia or diabetes.
In Specific Aim 2, we will test the concept of inhibiting outer BRB permeability as a therapeutic strategy for uveitis by examining the total retinal vascular leakage, the number and severity of retinal detachment, the quantity of outer BRB-specific leakage, and the expression of inflammatory biomarkers in the RPE-specific VEGFR2 knockout mice after inducing uveitis. As a control for inner BRB breakdown, we will also measure the same parameters in uveitic M?ller cell- specific VEGF knockout mice.
In Specific Aim 3, we will determine the molecular mechanism of diabetes/ischemia-induced outer BRB breakdown by investigating the biochemical pathway governing the regulation of tight-junction proteins.

Public Health Relevance

This application is relevant to an important public health issue: the pathogenic mechanism of leading causes of blindness: diabetic retinopathy, retinopathy of prematurity, and uveitis. Our study will focus on the regulatory mechanism and the pathophysiology of blood-retina barriers.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Shen, Grace L
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University of Oklahoma Health Sciences Center
Internal Medicine/Medicine
Schools of Medicine
Oklahoma City
United States
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Fu, Shuhua; Dong, Shuqian; Zhu, Meili et al. (2018) VEGF as a Trophic Factor for Müller Glia in Hypoxic Retinal Diseases. Adv Exp Med Biol 1074:473-478
Le, Yun-Zheng (2017) VEGF production and signaling in Müller glia are critical to modulating vascular function and neuronal integrity in diabetic retinopathy and hypoxic retinal vascular diseases. Vision Res 139:108-114
Hu, Jianyan; Li, Tingting; Du, Xinhua et al. (2017) G protein-coupled receptor 91 signaling in diabetic retinopathy and hypoxic retinal diseases. Vision Res 139:59-64
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Wang, Juan-Juan; Zhu, Meili; Le, Yun-Zheng (2015) Functions of Müller cell-derived vascular endothelial growth factor in diabetic retinopathy. World J Diabetes 6:726-33
Fu, Shuhua; Dong, Shuqian; Zhu, Meili et al. (2015) Müller Glia Are a Major Cellular Source of Survival Signals for Retinal Neurons in Diabetes. Diabetes 64:3554-63
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Liu, Dan; Xiong, Si-Qi; Shang, Lei et al. (2014) Expression of netrin-1 receptors in retina of oxygen-induced retinopathy in mice. BMC Ophthalmol 14:102
Dong, Shuqian; Liu, Yan; Zhu, Meili et al. (2014) Simplified system to investigate alteration of retinal neurons in diabetes. Adv Exp Med Biol 801:139-43

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