Autophagy and control of photoreceptor apoptosis

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): 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.