Retinal ganglion cell (RGC) death is the final common pathway for glaucoma and virtually all other optic neuropathies. The initial insult in most optic nerve diseases is injury to the RGC axon, from either compression, ischemia, inflammation, or transection. Optic nerve injury results in RGC apoptosis, and this has been theorized to occur by interference with retrograde transport of target-derived neurotrophic factors or other mechanisms. Given that (1) axotomy induces RGC apoptosis and (2) most optic neuropathies are associated with initial axonal damage and subsequent RGC loss, RGC axotomy is an experimental model for understanding the pathophysiology of glaucomatous and other optic neuropathies. Our overall goal is to ascertain the molecular changes that occur within the RGC after axotomy, particularly those leading to induction of the apoptosis cascade, as well as hypothetical protective mechanisms. Our working hypothesis is that one of the critical molecular events underlying RGC death after axonal injury is generation of an intracellular reactive oxygen species (ROS) signal. Our long-term goal is to find ways of preventing RGC death from axonal injury by modulating these mechanisms. To test this hypothesis, we propose the following: (1) Determine whether generation of ROS is a necessary and sufficient step for initiation of a series of events leading to RGC apoptosis after axotomy; (2) Test whether endogenous regulation of ROS can act as a defense mechanism governing the RGC response to axotomy; (3) Test whether the mechanism by which ROS signal RGC death after axotomy involves opening of the mitochondrial permeability transition pore. Almost all optic neuropathies involve RGC axonal injury, except for a few disorders where the locus of injury is unknown. If ROS generation is essential for RGC death after axotomy, then this could serve as a critical point for therapeutic intervention. The health-relatedness of this proposal is that an understanding of the molecular response of the RGC to axonal injury would be applicable to a wide variety of diseases of the optic nerve, independent of the mechanism by which the nerve is injured. As many of these diseases (e.g., normal-tension glaucoma and ischemic optic neuropathy) are not easily treatable, determination of the regulation of cell destructive and protective mechanisms could lead to innovative new therapies.
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