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.
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.
|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|
|Ha, Y; Liu, H; Xu, Z et al. (2015) Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma. Cell Death Dis 6:e1900|
|Boretsky, Adam; Gupta, Praveena; Tirgan, Nima et al. (2015) Nicotine accelerates diabetes-induced retinal changes. Curr Eye Res 40:368-77|
|Liu, Rong; Liu, Hua; Ha, Yonju et al. (2014) Oxidative stress induces endothelial cell senescence via downregulation of Sirt6. Biomed Res Int 2014:902842|
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