Retinal neuronal death is a common pathological feature of many vision threatening diseases, such as diabetic retinopathy, retinal vascular occlusion, glaucoma, traumatic optic neuropathy, and others. These diseases can cause blindness, impair patients'quality of life, and stress our health care system. Retinal neuronal injury is a common pathological feature of these diseases. This study is to delineate the common mechanisms of neuronal injury during retinopathy and identify novel strategies to limit injury and preserve vision. We will use different models of retinal neuronal injury to test our novel hypothesis that endoplasmic reticulum (ER) stress- induced expression of CXCL10 has a key role in retinal neuronal damage due to CXCR3-mediated inflammatory reactions and induction of oxidative stress during retinopathy. We will use genetic and pharmacological approaches to address the following specific aims: 1) Determine the role of ER stress in increasing CXCL10 expression and retinal neuronal injury during retinopathy. 2) Investigate the role of CXCL10/CXCR3 in retinal neuronal injury during retinopathy. 3) Evaluate therapeutic benefits of neuroprotection by pharmacological blockade of ER stress or CXCR3. Outcomes from this study will provide novel common mechanisms of retinal neuronal injury and may be readily put into clinical practice for retinopathy.

Public Health Relevance

ER stress is involved in tissue injury and CXCR3 is a chemokine receptor which has an essential role in inflammation, cell death, and anti-angiogenesis. This project is designed to understand whether and how ER- stress-induced activation of CXCR3 is involved in retinal neuronal injury in retinopathy and to investigate the therapeutic benefit by blocking ER stress and CXCR3.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY022694-01
Application #
8348385
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
2012-09-30
Project End
2017-08-31
Budget Start
2012-09-30
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$366,685
Indirect Cost
$116,685
Name
University of Texas Medical Br Galveston
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Boretsky, Adam; Gupta, Praveena; Tirgan, Nima et al. (2015) Nicotine accelerates diabetes-induced retinal changes. Curr Eye Res 40:368-77
Hu, Shuqun; Liu, Hua; Ha, Yonju et al. (2015) Posttranslational modification of Sirt6 activity by peroxynitrite. Free Radic Biol Med 79:176-85
Liu, Rong; Liu, Hua; Ha, Yonju et al. (2014) Oxidative stress induces endothelial cell senescence via downregulation of Sirt6. Biomed Res Int 2014:902842
Ameri, Hossein; Liu, Hua; Liu, Rong et al. (2014) TWEAK/Fn14 pathway is a novel mediator of retinal neovascularization. Invest Ophthalmol Vis Sci 55:801-13
Liu, Hua; Zhang, Wenbo; Xu, Zhimin et al. (2013) Hyperoxia causes regression of vitreous neovascularization by downregulating VEGF/VEGFR2 pathway. Invest Ophthalmol Vis Sci 54:918-31