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 #
5R01EY022694-04
Application #
8913190
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Mckie, George Ann
Project Start
2012-09-30
Project End
2016-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
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
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Liu, Hua; Zhang, Wenbo; Lilly, Brenda (2018) Evaluation of Notch3 Deficiency in Diabetes-Induced Pericyte Loss in the Retina. J Vasc Res 55:308-318
Ha, Yonju; Liu, Wei; Liu, Hua et al. (2018) AAV2-mediated GRP78 Transfer Alleviates Retinal Neuronal Injury by Downregulating ER Stress and Tau Oligomer Formation. Invest Ophthalmol Vis Sci 59:4670-4682
Liu, Wei; Luisi, Jonathan; Liu, Hua et al. (2017) OCT-Angiography for Non-Invasive Monitoring of Neuronal and Vascular Structure in Mouse Retina: Implication for Characterization of Retinal Neurovascular Coupling. EC Ophthalmol 5:89-98
Zhu, Shuang; Liu, Hua; Sha, Haibo et al. (2017) PERK and XBP1 differentially regulate CXCL10 and CCL2 production. Exp Eye Res 155:1-14
Nilson, Ashley N; English, Kelsey C; Gerson, Julia E et al. (2017) Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases. J Alzheimers Dis 55:1083-1099
Ha, Yonju; Liu, Hua; Zhu, Shuang et al. (2017) Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush. Am J Pathol 187:352-365
Zhu, Shuang; Luo, Huanle; Liu, Hua et al. (2017) p38MAPK plays a critical role in induction of a pro-inflammatory phenotype of retinal Müller cells following Zika virus infection. Antiviral Res 145:70-81
Gersztenkorn, David; Coletta, Ciro; Zhu, Shuang et al. (2016) Hydrogen Sulfide Contributes to Retinal Neovascularization in Ischemia-Induced Retinopathy. Invest Ophthalmol Vis Sci 57:3002-9
Hu, Shuqun; Liu, Hua; Ha, Yonju et al. (2015) Posttranslational modification of Sirt6 activity by peroxynitrite. Free Radic Biol Med 79:176-85

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