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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY020823-04
Application #
8509696
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
2010-09-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$404,776
Indirect Cost
$144,470
Name
University of Michigan Ann Arbor
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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
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
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