Retinal neuronal death causes vision loss and blindness. Yet there is no therapy available to effectively protect retinal neurons. This application proposes continuation of a project designed to elucidate common mechanisms that control retinal neuronal injury in retinopathy. During the previous funding period, we demonstrated that endoplasmic reticulum (ER) stress-induced CXL10/CXCR3 axis has a key role in retinal inflammation, oxidative stress and neuronal injury. Our data suggest a model in which injured or stressed retinal neurons (e.g. retinal ganglion cells (RGCs)) release CXCL10 that directly induces RGC death by activating the cAMP/Epac1 pathway and indirectly causes RGC damage by recruiting and activating leukocytes from blood. Epacs (Epac1 and Epac2) are novel mediators of cAMP. We now propose to determine the central role of Epac1 in linking multiple insults in ischemic retinopathy to neuronal injury and further investigate the interactions between neurons and vessels. Our hypothesis is that Epac1 activation plays a causal role in retinal neuronal and vascular injury in ischemic retinopathy and pharmacologic inhibition of Epac provides a novel therapeutic intervention for ischemic retinopathy. This application will, for the first time, use Epac1 global KO mice, Epac1 conditional KO mice, AAV2-mediated gene delivery, novel Epac inhibitor, non- invasive advanced imaging and functional testing to investigate the cAMP/Epac1 pathway in retinal neuronal and vascular injury in mouse models of acute and chronic ischemic retinopathy. It will also investigate potential mechanisms of Epac1-induced retinal neuronal damage and subsequent vascular alterations. The research is expected to significantly advance the mechanistic understanding of ischemic retinopathy and should facilitate the development of novel strategies to protect retinal neurons and vessels in ischemic retinopathy. This proposal directly addresses vision research priorities identified in the NEI Publication, ?Vision Research: Needs, Gaps, & Opportunities?: 1) Apply molecular biology techniques to RGC neuroscience to dissect factors important for survival, axon regeneration, and physiology. 2) Explore neuroprotection as an approach for prolonging RGC function and survival.

Public Health Relevance

Epacs (Epac1 and Epac2) are novel mediators of cAMP, one of the most common second messengers involved in pathophysiological conditions. This project is designed to understand the role of Epac1 in retinal neuronal and vascular injury in ischemic retinopathy and investigate the therapeutic effect of Epac inhibitor.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY022694-06A1
Application #
9599354
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Greenwell, Thomas
Project Start
2012-09-30
Project End
2022-06-30
Budget Start
2018-09-01
Budget End
2019-06-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Med 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
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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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