Separation of the neurosensory retina from the underlying retinal pigment epithelium (RPE) is a common form of injury that can occur alone (a retinal detachment) or as a result of other disease processes such as ocular trauma, inflammation, diabetes (due to traction on the retina) or neovascular age-related macular degeneration (due to exudation of fluid from the neovascular complex into the subretinal space). Despite significant advances in the medical and surgical management of retina-RPE separation from these various causes, patients often have significant vision loss, primarily due to the apoptotic death of the photoreceptors. Under normal physiologic conditions, the retina and retinal pigment epithelium (RPE) are intimately connected. Many consequences result from retinal-RPE separation including the FAS-mediated death of photoreceptors. Activation of the FAS-receptor leads to downstream activation of serine proteases (caspases) that ultimately result in the death and removal of the photoreceptor from the retina. At the same time, however, there is activation of the anti-apoptotic interleukin-6 (IL-6) pathway that is crucial for photoreceptor survival after retina-RPE separation. In other words, counteracting pathways are activated that promote both cell death and cell survival. The molecular mechanisms regulating the balance between the pro-survival and pro-death pathways after retinal detachment are unknown. One such pathway may involve autophagy - a mechanism by which cells initiate auto-vacuolization to recycle amino acids and other cellular components during periods of metabolic stress. Autophagy can also function to regulate apoptosis, and prevent the cell from dying until normal homeostasis is restored. In this project we will explore the mechanistic controlling relationship between autophagy and photoreceptor survival after retina-RPE separation by testing the following hypothesis: Activation of autophagy following retina-RPE separation delays photoreceptor death by inhibiting FAS-mediated apoptosis and activating IL-6 signaling.
Photoreceptor cell death is a major consequence of retinal detachment - whether the detachment occurs alone or as a result of other disease processes. Despite significant advances in the medical and surgical management of retinal detachment from these various causes, the death of the photoreceptors can leave patients with permanent and significant vision loss. In our laboratory we have shown that retinal detachment activates molecular pathways that both promote and prevent photoreceptor cell death. The molecular mechanisms that control the balance between these pro-survival and pro-death pathways are unknown. We have recently discovered that a novel molecular pathway - autophagy - becomes activated within the retina during retinal detachment. Autophagy is a process by which a cell can regulate its death or survival during periods of injury or stress, as occurs to a photoreceptor during retinal detachment. In this project we will explore and define the manner in which autophagy regulates the activity of pro-death and pro-survival pathways within the photoreceptor of the detached retina.
|Shelby, Shameka J; Angadi, Pavan S; Zheng, Qiong-Duon et al. (2015) Hypoxia inducible factor 1Î± contributes to regulation of autophagy in retinal detachment. Exp Eye Res 137:84-93|
|Yao, Jingyu; Jia, Lin; Khan, Naheed et al. (2015) Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium. Autophagy 11:939-53|
|Rao, Rajesh C; Zacks, David N (2014) Cell and gene therapy. Dev Ophthalmol 53:167-77|
|Chinskey, Nicholas D; Besirli, Cagri G; Zacks, David N (2014) Retinal cell death and current strategies in retinal neuroprotection. Curr Opin Ophthalmol 25:228-33|
|Chinskey, Nicholas D; Zheng, Qiong-Duon; Zacks, David N (2014) Control of photoreceptor autophagy after retinal detachment: the switch from survival to death. Invest Ophthalmol Vis Sci 55:688-95|
|Yao, Jingyu; Jia, Lin; Shelby, Shameka J et al. (2014) Circadian and noncircadian modulation of autophagy in photoreceptors and retinal pigment epithelium. Invest Ophthalmol Vis Sci 55:3237-46|
|Besirli, Cagri G; Zheng, Qiong-Duon; Reed, David M et al. (2012) ERK-mediated activation of Fas apoptotic inhibitory molecule 2 (Faim2) prevents apoptosis of 661W cells in a model of detachment-induced photoreceptor cell death. PLoS One 7:e46664|
|Yao, Jingyu; Jia, Lin; Khan, Naheed et al. (2012) Caspase inhibition with XIAP as an adjunct to AAV vector gene-replacement therapy: improving efficacy and prolonging the treatment window. PLoS One 7:e37197|
|Besirli, Cagri G; Chinskey, Nicholas D; Zheng, Qiong-Duan et al. (2011) Autophagy activation in the injured photoreceptor inhibits fas-mediated apoptosis. Invest Ophthalmol Vis Sci 52:4193-9|
|Yao, Jingyu; Feathers, Kecia L; Khanna, Hemant et al. (2011) XIAP therapy increases survival of transplanted rod precursors in a degenerating host retina. Invest Ophthalmol Vis Sci 52:1567-72|